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Background Restless legs syndrome (RLS), a neurological disorder, often affects sleep quality in hemodialysis patients. This study aimed to evaluate acupressure's effect on the severity of RLS symptoms and sleep quality in hemodialysis patients with RLS. Material and methods This study is a cluster-randomized crossover pilot study. Patients were randomized to two sequences: acupressure for one month and observation for another month (AC); and observation for one month and acupressure for another month (CA). For the four-week acupressure intervention, patients received 36 min of acupressure three times weekly during their hemodialysis sessions. The acupoints were on the bilateral lower limbs, including Zusanli (ST36), Yanglingquan (GB34), Sanyinjiao (SP6), Xuanzhong (GB39), Chengshan (BL57), and Taichong (LR3). RLS severity and sleep quality (measured with the Pittsburgh sleep quality index, PSQI) were measured at baseline, month 1, and month 2. Results AC sequence (n = 14) was similar to the CA sequence (n = 9) in terms of gender, age, education, employment, marital status, comorbid disease, BMI, duration of dialysis, medication for RLS and insomnia, RLS severity, and PSQI. The general linear mixed model revealed no significant carryover effect on RLS severity, PSQI, and the seven subscales of PSQI. A significant treatment effect (acupressure) was only observed in RLS severity (p = 0.0013) but not in PSQI and the seven subscales. The significant period effect was observed in RLS severity (p = 0.0250) and the subscale of sleep disturbance (p = 0.0021). Conclusion In hemodialysis patients with RLS, acupressure can alleviate the severity of RLS but cannot improve sleep quality.

Colorectal cancer (CRC) is one of the most common cancers worldwide. In this study, we explored the role of RNA binding motif protein 15 (RBM15)-mediated MyD88 mRNA N6-methyladenosine (m6A) in CRC development. Cell proliferation, apoptosis, and invasion were detected by EdU, Annexin V-FITC/PI staining, and Transwell assays, respectively. RBM15 and MyD88 expression was detected by RT-qPCR and Western blot. RNA-seq, RIP-seq, and MeRIP-seq were used for RBM15 downstream target gene prediction and expression detection. In this research, we confirmed that RBM15 was highly expressed in CRC tissues and was negatively correlated with overall and disease-free survival rate. Silencing RBM15 significantly inhibited the proliferative and invasive abilities and promoted cell apoptosis in the CRC cell lines (SW480 and HCT116). Moreover, tumor growth and CRC liver metastasis were inhibited by silencing RBM15 in vivo. m6A methylation level was decreased in RBM15-silenced SW480 and HCT116 cells. MyD88 was the target mRNA of RBM15-mediated m6A methylation in CRC. MyD88 was lowly expressed in CRC and negatively correlated with RBM15 expression. Taken together, RBM15 silencing inhibited the CRC growth and metastasis in vitro and in vivo. RBM15 mediated m6A methylation modification of MyD88 mRNA in CRC cells.

To report three-decade changes of clinical characteristics, progress of treatments, and risk factors associated with mortality and enucleation in patients with retinoblastoma in China.Retrospective cohort study.This multicenter study included 2552 patients diagnosed with retinoblastoma in 38 medical centers in 31 provinces in China from 1989 to 2017, with follow-up data. Kendall's tau-b value was used to describe correlation coefficients between the three eras (between 1989 and 2008, between 2009 and 2013, and between 2014 and 2017) and clinical or demographic features. Hazard ratios and odds ratios were applied to measure risk factors.A total of 324 (13%) patients died and 1414 (42%) eyes were removed. The 1-year, 3-year, and 5-year overall survival rates were 95%, 86%, and 83%, respectively. Patients were diagnosed at a better stage by International Classification for Retinoblastoma over time (Kendall's tau-b value = -0.084, P.001). Pathological risk factors were also observed less in recent eras. New conservative therapies were adopted and used in more patients. The eye removal rate gradually decreased (Kendall's tau-b value = -0.167, P.001). The overall survival rates were 81%, 83%, and 91% in the three eras. By multivariate Cox regression, bilateral tumors and extraocular extension were identified as risk factors for death. Among intraocular disease, Group E indicated higher risk of mortality. By multivariate logistics regression, unilateral tumors, earlier era of diagnosis, and extraocular extension were risk factors for eye salvage failure. Among intraocular retinoblastoma, Groups D and E had higher risk of eye salvage failure.Patients were diagnosed at an earlier stage in recent eras. Conservative therapies, including intra-arterial chemotherapy, were increasingly being used. The above changes may contribute to the decreasing enucleation rate. Although no significant impact was identified on the mortality by the three eras, a decreasing trend was shown.

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). Objective: This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. Method: We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. Results: BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. Conclusion: Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Background Emergence delirium (ED) is a common phenomenon occurring in the recovery period. The aim of this study was to investigate the incidence, risk factors, and consequences of ED in adults after elective brain tumor resection. Methods We retrospectively analyzed the data of a prospective cohort performed in a tertiary university hospital. Adult patients admitted to the intensive care unit (ICU) immediately after elective brain tumor resection were consecutively enrolled. Level of consciousness was assessed using the Richmond Agitation–Sedation Scale and ED was assessed using the Confusion Assessment Method for the ICU. Risk factors for ED were determined by multivariable logistic regression. Results A total of 659 patients met the inclusion criteria, of which 41 patients with coma were excluded. Among the remaining 618 patients, 131 (21.2%) developed ED. Independent risk factors for ED were: age, education level, use of anticholinergic and mannitol, Glasgow Coma Score and arterial partial pressure of oxygen postoperatively, postoperative pain, malignant tumor, and frontal approach craniotomy. ED was associated with increased postoperative delirium, longer length of hospital stay, and higher hospitalization costs. There was no significant difference in the neurological function deficits (modified Rankin Scale score) between ED and non-ED groups. Conclusions ED has a high incidence and is associated with poor outcomes in adults after elective brain tumor resection. Early screening and prevention for ED should be established in perioperative management of this population.

Background The insidious nature of BCG-osteomyelitis makes it challenging for clinicians to detect it early on. Methods This 12-year retrospective analysis was conducted at a single tertiary hospital in central Taiwan. Electronic medical records of pediatric patients treated for BCG-osteomyelitis were reviewed. Demographics, clinical features, and laboratory findings were compared with patients diagnosed with culture-proven pyogenic osteomyelitis. Results In total, eight patients fulfilled our inclusion criteria. Their median age was 16 months, and no obvious gender prevalence was found. Six of the eight patients had lesions involving the lower extremities. When compared with the pyogenic osteomyelitis group, age of disease onset was found to be significantly younger in the BCG osteomyelitis group (p=0.038). Absence of fever and pain in the BCG osteomyelitis group was found to be statistically significant when compared with the pyogenic group (p=0.002 and p=0.026 respectively). CRP and ESR were found to be significantly higher in the pyogenic osteomyelitis group (p=0.000 and p=0.004 respectively). Conclusion BCG-related osteomyelitis must be considered when evaluating an afebrile child presenting with an unexplainable swelling or limp, and especially when the lesion is located on a lower limb. Laboratory studies may reveal normal WBC and CRP, with a normal to modest elevation of ESR. Imaging studies, including plain radiographs, magnetic resonance imaging (MRI), or computed tomography (CT) should be employed to rule out BCG-related osteomyelitis. Early diagnosis help minimize inappropriate antibiotics use, and may lead to a better outcome.

Background/Purpose The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Background: In patients with lymphedema (LE), in addition to hand dominance, between-group comparisons of interlimb soft tissue differences need to account for differences in whole-body adiposity, measured directly by dual energy X-ray absorptiometry (DXA) or indirectly by body mass index. No study has evaluated the effects of hand dominance and whole-body adiposity on limb composition in patients with LE. This study's purpose was to compare soft tissue composition of affected and unaffected limbs of women with breast cancer, who did and did not have LE, controlling for dominance and percent body fat. Methods and Results: Whole-body DXA scans were acquired and included measures of percent body fat, upper limb total mass, upper limb fat mass, and upper limb fat-free mass. Participants were classified into one of three groups: women without LE; women with only subjective LE; and women with objective signs of LE at the time of assessment. Differences among the LE groups were evaluated using analysis of variance (ANOVA) and Chi-square analyses. Analysis of covariance (ANCOVA) was used to control for percent body fat and for the affected limb dominance. Compared to women without LE, women with objective signs of LE have greater total limb mass, fat mass, and fat-free mass in their affected limbs, independent of affected side dominance and percent body fat. In addition, the interlimb differences in total mass, fat mass, and fat-free mass were greater for the women with objective signs of LE, compared to the other two groups. Conclusions: DXA is useful in identifying soft tissue changes in patients with LE. Given that limb circumferences measure only changes in limb volume and that bioimpedance provides estimates of extracellular fluid, DXA has the advantage of being able to estimate the volumes of specific tissues in the limb.

BACKGROUND The relationship of early catheter-related bloodstream infections (CRBSIs) with perioperative neutropenia and antibiotic prophylaxis is not well established. We sought to evaluate perioperative factors associated with early CRBSIs in newly diagnosed pediatric cancer patients, particularly hematological indices and antibiotic use. METHODS We retrospectively reviewed national registry records of newly diagnosed pediatric cancer patients with port-a-caths inserted using standardized perioperative protocols where only antibiotic use was not regulated. Thirty-day postoperative CRBSI incidence was correlated with preoperative factors using logistic regression and with postoperative blood counts using linear trend analysis. RESULTS Among 243 patients, 17 CRBSIs (7.0%) occurred at median 14 (range, 8-28) postoperative days. Early CRBSIs were significantly associated with cancer type [acute myeloid leukemia and other leukemias (AML/OLs) vs. solid tumors and lymphomas (STLs): odds ratio (OR), 5.09; P = 0.0036; acute lymphoblastic leukemia vs. STL: OR 0.83; P = 0.0446] but not preoperative antibiotics, absolute neutrophil counts and white blood cell counts. Thirty-day postoperative absolute neutrophil counts and white blood cell trends differed significantly between patients with acute lymphoblastic leukemia and STLs (OR 0.83, P < 0.05) and between AML/OLs and STLs (OR 5.09, P < 0.005), with AML/OL patients having the most protracted neutropenia during this period. CONCLUSIONS Contrary to common belief, low preoperative absolute neutrophil counts and lack of preoperative antibiotics were not associated with higher early CRBSI rates. Instead, AML/OL patients, particularly those with prolonged neutropenia during the first 30 postoperative days, were at increased risk. Our findings do not support the use of empirical preoperative antibiotics and instead identify prolonged postoperative neutropenia as a major contributing factor for early CRBSI.

Background/purpose Taiwan Drug-Injury Relief System (TDRS) has been implemented since 1999. More than 60% of the approved applications were associated with severe cutaneous adverse reactions (SCARs). Studies assessing SCARs using real-world evidence are very limited. TDRS offers abundant case information as a source of real-world evidence to investigate the characteristics of SCARs in Taiwan. The purpose of this study is to understand the trends and characteristics of SCARs in Taiwan. Methods Applications from Drug-Injury Relief Database (TDRD) from 1999 to 2016 were retrospectively analyzed. Results A declining trend in SCARs application was noticed after 2012, and 952 applications of SCARs were identified. The most common subtypes of SCARs were SJS/TEN (n = 455/206), DRESS (n = 228), GBFDE (n = 34) and AGEP (n = 18). The most common culprit drugs were allopurinol, carbamazepine, phenytoin, diclofenac and lamotrigine for SJS/TEN; allopurinol, phenytoin, co-trimoxazole, carbamazepine and phenobarbital for DRESS; mefenamic acid for GBFDE; non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibacterials for AGEP. The proportions of mortality cases were 28.9% for SJS/TEN; 36% for DRESS; 11.8% for GBFDE and 5.6% for AGEP. The mean latent period of SJS/TEN, DRESS, GBFDE and AGEP were 21.8 days, 29.2 days, 3.3 days and 6.7 days, respectively. Conclusions The approved drug-injury relief applications associated with SCARs were mainly SJS, TEN and DRESS. The most common culprit drugs were antiepileptics, antibacterials, antigout agents, and NSAIDs. The latent periods showed some distinct features for different types of SCARs. In light of the high mortality rate, public awareness and vigilance of SCARs are crucial for the patient safety.

Blau syndrome (BS) is a monogenic autoinflammatory disease caused by mutations in nucleotidebinding oligomerization domain containing 2 (NOD2). BS is characterized by the clinical triad of granulomatous dermatitis, arthritis and recurrent uveitis. Due to the low incidence of BS and the lack of treatment studies with large samples, a specific treatment scheme has not been established. We report the case of a patient with BS that was uncontrollable with various immunosuppressive therapies but had a good response to thalidomide. She had the typical triad of rash, arthritis and uveitis. Gene sequencing indicated a NOD2 heterozygous missense variant (c.1759C > T, p.R587C), which has been reported as a pathogenic mutation. The BS diagnosis was confirmed. After treatment with methotrexate, an anti-tumour necrosis factor (TNF)-α inhibitor and corticosteroids, the patient's clinical symptoms and inflammatory indicators remained uncontrolled, and she experienced multiple side effects, such as hypertension and growth retardation attributed to prolonged corticosteroid use. After treatment with thalidomide, her condition was controlled without recurrence or side effects, and corticosteroids were stopped as soon as possible. This report suggests that thalidomide may be effective for BS treatment, but more research is needed to evaluate its long-term efficacy and side effects.

Objective Suicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. Methods 77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Asberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. Results Patients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p Conclusion This study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.

Profilin-1 is involved in macroangiopathy induced by advanced glycation end products via vascular remodeling and inflammation

BACKGROUND Autoimmune atrophic gastritis (AAG) is a type of chronic gastritis that mainly affects the gastric corpus. Due to the lack of standard diagnostic criteria and overlaps with the courses of Helicobacter pylori-related atrophic gastritis, reports on the diagnostic strategy of AAG at an early stage are limited. CASE SUMMARY A 71-year-old woman with severe anemia was diagnosed with AAG. Endoscopic views and pathological findings showed the coexistence of normal mucosa in the gastric antrum and atrophic mucosa in the gastric fundus. Serological tests showed that anti-parietal cell antibodies and anti-intrinsic factor antibodies were both positive. Immunohistochemical results, which showed negative H+-K+ ATPase antibody staining and positive chromogranin A (CgA) staining, confirmed the mechanism of this disease. After vitamin B12 and folic acid supplementation, the patient recovered well. CONCLUSION Successful diagnosis of AAG includes serological tests, endoscopic characteristics, and immunohistochemistry for H+-K+ ATPase and CgA antibodies.

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 μg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

OBJECTIVE To evaluate the changes of uterine leiomyoma size during pregnancy and determine the factors influencing it. METHODS A prospective study was conducted from June 2016 to June 2018. Women with pregnancies complicated by leiomyoma were recruited. Ultrasound examinations were conducted to measure the size of leiomyoma during 6-7, 11-14, 22-24, 28-34 weeks of pregnancy and before delivery. The clinical characteristics and delivery details of the pregnant women were collected. Changes in leiomyoma size during different gestation periods and the influencing factors were analyzed. RESULTS Leiomyoma size commonly increased before 22-24 weeks of pregnancy and the fastest growth occurred before 11-14 weeks. From 22-24 weeks to the date of delivery, the size of leiomyoma remained unchanged. The initial size of the leiomyoma showed negative correlation with the changes in leiomyoma diameters during pregnancy. Pre-pregnancy body mass index, fetus number, leiomyoma location, and parity were positively correlated with the size changes in leiomyoma from 22-24 to 28-34 weeks of pregnancy. CONCLUSION Before 22-24 weeks of pregnancy, the size of the leiomyoma was gestation-dependent, which increases with gestational weeks. The fastest growth rate was before 11-14 weeks. The growth of leiomyoma is affected by multiple factors, and different factors can play different roles during different periods of the pregnancy.

BACKGROUND We explored the associations between serum leptin concentration and cardiovascular prognosis in maintenance hemodialysis patients. METHODS In our prospective study with no intervention, demographics data at baseline were collected from electronic medical records. Serum leptin concentration was determined by ELISA. Patients underwent body composition assessment and echocardiographic measurements after hemodialysis. The primary endpoints were defined as cardiovascular events (CVEs), cardiovascular death (CVD) and all-cause death. RESULTS A total of 165 eligible patients aged 51(43-65) y were enrolled and the mean serum leptin concentration was 35.49 (29.98) ng/ml. During a median follow-up of 18 (12-22) months, CVEs occurred in 37 (22.42%) patients and the cardiovascular and all-cause mortality was 10.91% and 21.82%. Serum leptin concentration was associated with CVEs (HR = 0.982, p = 0.003), CVD (HR = 0.934, p = 0.002) and all-cause death (HR = 0.943, p

STUDY OBJECTIVES: To compare the efficiency of a TCM scoring system that includes 3 independent predictors obtained by physical examination, computed tomography, and polysomnography with the standard Friedman staging system that includes only physical examination variables for predicting surgical outcomes in patients with obstructive sleep apnea syndrome who undergo velopharyngeal surgery. METHODS: This prospective study was carried out in 265 patients with obstructive sleep apnea syndrome who underwent velopharyngeal surgery. All these patients were re-examined with polysomnography for evaluation of surgical outcomes at least 3 months after surgery. The efficacies in the surgical outcome prediction of 2 systems were calculated and compared. RESULTS: The overall response rate and cure rate was 63.8% (169/265) and 22.3% (59/265), respectively. There were 32 patients with Friedman stage I, with a response rate and cure rate of 81.3% (26/32) and 28.1% (9/32), respectively, and 70 patients with TCM scores of

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Introduction The transplantation of mesenchymal stem cells (MSCs) in patients with premature ovarian failure (POF) could lead to clinical improvement. The transplantation to the ovaries among other transplantation methods have been reported in various animal models, however, there is little evidence regarding the optimal method, including the clinical safety and the efficiency for the treatment of age associated ovarian hypofunction. Objectives To establish the most effective transplantation route of MSCs, explore the resistance to therapy, its safety and role in the natural aging process of the ovaries. Methods Highly purified MSCs were injected intraperitoneally, directly into the ovaries or tail-intravenously in mice animal model. The ovarian function, quantity and quality of oocytes, cell viability/apoptosis, were evaluated, applying chemiluminescence analysis (CLIA), western blotting, immunofluorescence staining, transmission electron microscope (TEM), TdT mediated dUTP Nick End Labeling (TUNEL) assay and other techniques. The organ tumorigenicity was also evaluated by long-term observation and histopathological examination. The efficiency of MSCs was further verified in non-human primates by the most effective transplantation route. Results The 32nd week was ultimately determined as the time point of MSCs transplantation. Our results showed that the intra-ovarian injection was the best transplantation method with a more conspicuous effect. With deeper investigations, we found that the transplanted MSCs showed an effective influence on the follicular number, promoted follicle maturation and inhibited cell apoptosis, which was further verified in non-human primates. In addition, the long-term observation and the histopathological examinations ruled out neoplasms or obvious prosoplasia after MSCs transplantation. Conclusion MSCs transplantation by intra-ovarian injection could within a month exert the most conspicuous anti-age-associated ovarian hypofunction effects, which may improve the quantity and quality of oocytes by changing the mitochondrial structure, regulating mitochondrial function and attenuating cell apoptosis to increase the storage of the follicle pool without a remarkable potential of tumorigenicity.

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

Chylothorax is an infrequent pleural effusion often caused by traumatic or nontraumatic injury to the thoracic duct. Nontraumatic chylothorax caused by chronic lymphocytic leukemia (CLL) is rarely reported. Previous experience has implied that the main factor affecting the treatment of chylothorax is whether the anti-cancer treatment is effective. The patient diagnosed with chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) before the hospital admission, and not received any treatment. After four months, he had progressive dyspnea. Chest computed tomography (CT) scan showed bilateral pleural effusion with progressive lymphadenopathy, and massive chylous pleural effusion was drained by closed thoracic drainage. After a course of chemotherapy including fludarabine, cyclophosphamide and rituximab (FCR), the patient developed agranulocytosis and his pleural effusion was still abundant. After careful consideration, the patient refused to receive following chemotherapy and chose to take ibrutinib orally. Two months after oral ibrutinib, ultrasound examination showed that pleural effusion completely disappeared. In the next one year, the patient had a routine follow-up and was in good condition. To our knowledge, this is the first report of ibrutinib in the treatment of chylothorax associated with CLL. Ibrutinib provides a more palliative treatment for elderly CLL patients with chylothorax.

The imbalance between oxidants and antioxidants in cancer cells would evoke oxidative stress-induced cell death, which has been demonstrated to be highly effective in treating malignant tumors. Sonodynamic therapy (SDT) adopts ultrasound (US) as the excitation source to induce the production of reactive oxygen species (ROS), which emerges as a noninvasive therapeutic strategy with deep tissue penetration depth and high clinical safety. Herein, we construct novel sonoactivated oxidative stress amplification nanoplatforms by coating MnO2 on Au nanoparticle-anchored black phosphorus nanosheets and decorating soybean phospholipid subsequently (Au/BP@MS). The Au/BP@MS exhibit increased ROS generation efficiency under US irradiation in tumor tissues due to Au/BP nanosensitizer-induced improvement of electron-hole separation as well as MnO2-mediated O2 generation and GSH depletion, thus leading to notable inhibition effect on tumor growth. Moreover, tumor microenvironment-responsive biodegradability of Au/BP@MS endows them with enhanced magnetic resonance imaging guidance and clinical potential for cancer theranostics., Graphical abstract A novel sonoactivated tumor theranostic nanoplatform was successfully constructed by coating MnO2 on Au nanoparticle-anchored black phosphorus nanosheets, which resulted in improved separation of electron-hole pairs for enhanced sonodynamic effect.Image 1, Highlights • The anchored Au NPs on BP nanosheets could prominently improve electron-hole separation for enhanced SDT. • The MnO2 coating on Au/BP could strengthen SDT efficacy through O2 generation and GSH depletion. • The release of Mn2+ in acidic tumor microenvironment would function as T1-weighted MR imaging agents. • Au/BP@MS exhibited superior biocompatibility and biodegradability.

This regional 2-center study was designed 1) to analyze the clinical features of all patients with odontogenic orofacial infection as per type of visit, 2) to analyze the clinical features of diabetic patients compared with nondiabetic patients, and 3) to identify potential variables that may associate with long length of stay (LOS) of patients admitted for orofacial odontogenic infection in Northern Peninsular Malaysia.All adult patients with orofacial odontogenic infections who attended the Oral and Maxillofacial Department of Hospital Raja Permaisuri Bainun and Hospital Sultan Abdul Halim from March 2015 to February 2019 were included. Data on patients' demography, medical history, smoking status, clinical presentation, and LOS were collected. Multivariate logistic regression analysis was performed using the dichotomous dependent variable, namely, short LOS (LOS5 days) and long LOS (LOS ≥5 days).A total of 355 patients were reported with the mean age of 39.93 ± 15.95 years old. Multivariate analysis revealed that diabetes (adjusted odds ratio = 4.387, 95% confidence interval = 1.453 to 13.241, P value = .009) and multiple space involvement (adjusted odds ratio = 4.859, 95% confidence interval = 1.280, 18.454, P value = .020) were responsible for long LOS.Judicious treatment is recommended when treating patients of such infection that involves multiple spaces with underlying diabetes mellitus.

Tourette syndrome (TS) is a neurodevelopmental movement characterized by abrupt, rapid, repetitive, and non-rhythmic tics. While TS is not life-threatening, such tics and comorbidities affect a children's physical and mental health and social interactions. Treatment is necessary when the children experience physical discomfort, functional dysfunction, and poor interpersonal interaction and mental health. Common management strategies for TS include psychological interventions and pharmacological treatment. Additionally, it is important to consider the individual needs of youths with TS and reassess the treatment outcomes and the need to receive continuous treatment regularly. This review summarizes the symptom management and nursing care measures for youths with TS. Understanding and listening to the healthcare problems of youths with TS can help providers develop healthcare interventions tailored to the youths' needs. Providing the youths with strategies to reduce the tics' interference with their learning outcomes and helping them develop strategies to cope with diverse interpersonal interactions at school are also important. Further, enhancing acceptance given by parents, teachers, and peers, as well as improving the general public's understanding of TS are important measures that promote the youths' social adjustment as well as their ability to coexist with TS.

This case-series aims to report three cases of endogenous endophthalmitis due to invasive Klebsiella pneumoniae syndrome. Case 1 A 34-year-old lady who was admitted for pneumonia developed painful blurring of vision and redness in the right eye (RE) for one week. An examination of the RE revealed visual acuity (VA) of light perception (PL) with positive relative afferent pupillary defect (RAPD), proptosis, and restriction of extraocular movement with hypopyon. The patient was treated for RE panophthalmitis with a lung abscess and was started on systemic and topical antibiotics. The vitreous tap culture grew Klebsiella pneumoniae. Despite treatment, the patient's condition deteriorated, and evisceration was undertaken. Case 2 A 38-year-old lady presented with a sudden painful RE associated with blurred vision and redness for two days, and fever for one week. RE VA was hand movement with a positive RAPD and anterior chamber cells of 2+. A B-scan revealed a dome-shaped subretinal mass with exudative retinal detachment. The patient was treated for RE panophthalmitis complicated by a basal ganglia abscess. The urine and vitreous tap cultures grew Klebsiella pneumoniae. She responded to high-dose intravenous and intravitreal antibiotics. Unfortunately, her RE became phthisical. Case 3 A 70-year-old lady presented with painless blurring of vision over the RE. The blood and urine cultures grew Klebsiella pneumoniae. RE VA was PL, and she was treated for endogenous endophthalmitis. The vitreous culture grew Klebsiella pneumoniae. Unfortunately, the RE became phthisical. In conclusion, endophthalmitis due to Klebsiella pneumoniae is invasive and carries a poor prognosis if prompt treatment is not rendered.

The clinical utility of Dixon water-fat separation coronary MR angiography (CMRA) with compressed sensing (CS) reconstruction has not been determined in a patient population. This study was designed to evaluate the performance of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA sequence in vitro and in vivo.In vitro phantom MRI, we compared key parameters of the SENSE and CS images. And in this prospective in vivo study, from November 2019 to October 2020, 94 participants were recruited for 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA. The accuracy of CMRA for detecting a ≥ 50% reduction in diameter was determined using X-ray coronary angiography (CA) as the reference method.Compared with SENSE, CS with an appropriate acceleration factor offers both higher SNR/CNR (p0.05) and a shortened acquisition. Fifty-eight patients successfully completed the CMRA and CA. The sensitivity, specificity, positive predictive values, negative predictive values, and accuracy of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA according to a patient-based analysis were 96.4%, 66.7%, 73.0%, 95.2% and 81.0%, respectively. The area under the receiver-operator characteristic (ROC) curve (AUC) of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA for detecting significant coronary artery stenosis is 0.908, 0.895, and 0.904 in patient-, vessel-, and segment-based analyses respectively.3.0 T non-contrast-enhanced Dixon water-fat separation whole-heart CMRA using appropriate CS is a promising noninvasive and radiation-free technique to detect clinically significant coronary stenosis on patients with suspected CAD.

OBJECTIVE To determine the risk for pulmonary embolism (PE) and explore the relationship between the site of thrombosis and PE in patients with acute lower extremity deep vein thrombosis (DVT). METHODS 1585 hospitalized patients first diagnosed with acute lower extremity DVT were investigated retrospectively. The patients were divided into two groups: the non-PE group (Group 1) and the PE group (Group 2). Then, Group 2 was divided into two subgroups: asymptomatic pulmonary embolism (asPE, Group 2a) and symptomatic pulmonary embolism (sPE, Group 2b). Kaplan-Meier curves and logistic regression analysis were used to explore the relevant risk factors for PE. RESULTS Among 1585 patients, 458 patients suffered from PE, accounting for 28.9%. 102 (22.3%) of them had the typical clinical manifestations of PE and were defined as sPE, and the remaining 356 (77.7%) patients were classified as asPE. Patients with proximal lower extremity DVT were significantly more predominant in the PE group than in the non-PE group (92.8% vs. 86.2%, p

Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed.To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib.Patients enrolled in KEYNOTE-426 were included in this study.Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s).The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred.A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment.Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Background Out-of-pocket (OOP) drug costs for Medicare Fee-for-Service (FFS) beneficiaries with heart failure with reduced ejection fraction (HFrEF) are not well characterized. This study evaluated Part D OOP spending by Medicare beneficiaries with chronic HFrEF, stratified by those with and without a worsening HF event (WHFE). Methods Medicare FFS 100% Part D claims were used to identify HFrEF patients with 12 months of continuous Part D enrollment in 2018. HFrEF was defined as 1 inpatient or 2 outpatient claims of systolic HF or 1 systolic HF plus 1 HF outpatient claim. WHFE was defined as having a HF hospitalization or intravenous diuretic use within 12 months of HFrEF index date. OOP costs by Medicare Part D coverage phase for all covered drugs were calculated for HFrEF patients, and those with and without WHFE. Results Of 305,373 Medicare patients with HFrEF, 26% had a WHFE. Total mean (SD) OOP drug costs among all HFrEF patients was $1,166 (1,205)/year. Patients with WHFE and patients without WHFE had respectively a mean (SD) annual OOP costs of $1,302 (1,273) and $1,117 (1,176). Over 39% of HFrEF patients entered the "donut hole" (44% and 37% of patients with WHFE and without WHFE, respectively), while 11% of HFrEF patients entered the catastrophic phase (13% and 10% of patients with and without WHFE, respectively). Conclusion More than 1 in 10 patients with heart failure entered the catastrophic phase within Medicare-Fee-For-Service, whereas in 2018 only 10% of costs were attributable to heart failure medication and 90% to comorbidities.

Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.

Background: Previous epidemiological investigations examining the association between Kawasaki disease (KD) and cerebrovascular disease have had conflicting results. We analyzed the association between KD and cerebrovascular disease by conducting a population-based retrospective cohort study designed to investigate the hypothesis that KD could be a risk factor for subsequent cerebrovascular disease. Methods: From the National Health Insurance Research Database of Taiwan, the data of children (aged 0–18 years old) with KD (n=8467) were collected. Starting with the first year of study observation (referred to as the baseline year), data was collected for each child with KD, and 4 non-KD patients matched for sex, urbanization level of residence, and parental occupation were randomly selected to form the non-KD cohort (n=33 868) for our analysis. For the period from January 1, 2000, to December 31, 2012, we calculated the follow-up person-years for each patient, which is the time from the index date to the diagnosis of cerebrovascular disease, death, or the end of 2012. Furthermore, we compared the incidence, the incidence rate ratio, and the 95% CI of cerebrovascular disease between the KD and non-KD cohorts. Results: The overall cerebrovascular disease incidence rate was found to be 3.19-fold higher, which is significantly higher, in the KD cohort than in the non-KD cohort (14.73 versus 4.62 per 100 000 person-years), and the overall risk of cerebrovascular disease remained higher in the KD cohort (adjusted hazard ratio, 3.16 [95% CI, 1.46–6.85]). Furthermore, children aged Conclusions: This nationwide retrospective cohort study shows that KD may increase the risk of subsequent cerebrovascular disease, especially in those with KD aged

No study on the relationship between hepatic steatosis and sex hormone levels in male patients with chronic hepatitis B (CHB) infection has been conducted.We aimed to investigate the association between serum sex hormones and hepatic steatosis among a cohort of males with CHB.In this cross-sectional study, 268 male patients with CHB were enrolled. All participants underwent anthropometric measurement, blood testing, and FibroScan test. Multiple logistic regression analysis was used to investigate the association of serum sex hormones with hepatic steatosis.We included 137 males with and 131 without hepatic steatosis in this study. Subjects with serum testosterone (T) levels in the highest tertile had an odds ratio (OR) (95% confidence interval [CI]) of 0.35 (0.18-0.70) (P for trend=0.003); those with serum prolactin (PRL) levels in the highest tertile had an OR (95%CI) of 0.21 (0.10-0.45) (P for trend0.001); and those with serum estradiol/testosterone (E2/T) in the highest tertile had an OR (95%CI) of 4.02 (1.97-8.20) (P for trend0.001) for hepatic steatosis.Lower serum total T and PRL levels and higher total E2/T are independently associated with presence of hepatic steatosis in male patients with CHB.

The emergence of computer graphics processing units (GPUs), improvements in mathematical models, and the availability of big data, has allowed artificial intelligence (AI) to use machine learning and deep learning (DL) technology to achieve robust performance in various fields of medicine. The DL system provides improved capabilities, especially in image recognition and image processing. Recent progress in the sorting of AI data sets has stimulated great interest in the development of DL algorithms. Compared with subjective evaluation and other traditional methods, DL algorithms can identify diseases faster and more accurately in diagnostic tests. Medical imaging is of great significance in the clinical diagnosis and individualized treatment of ophthalmic diseases. Based on the morphological data sets of millions of data points, various image-related diagnostic techniques can now impart high-resolution information on anatomical and functional changes, thereby providing unprecedented insights in ophthalmic clinical practice. As ophthalmology relies heavily on imaging examinations, it is one of the first medical fields to apply DL algorithms in clinical practice. Such algorithms can assist in the analysis of large amounts of data acquired from the examination of auxiliary images. In recent years, rapid advancements in imaging technology have facilitated the application of DL in the automatic identification and classification of pathologies that are characteristic of ophthalmic diseases, thereby providing high quality diagnostic information. This paper reviews the origins, development, and application of DL technology. The technical and clinical problems associated with building DL systems to meet clinical needs and the potential challenges of clinical application are discussed, especially in relation to the field of optic nerve diseases.

Background Double diapering may help to maintain a baby's hips in flexion and abduction posture, but the efficacy in facilitating hip maturation has never been verified. We investigated whether double diapering results in greater improvement of the alpha angle in newborn babies. Methods This prospective study enrolled newborns with Graf type IIa immature hips and assigned them to the double-diaper or single-diaper group by the day of birth in a week. Parents were instructed on proper hip positioning, except for diapering. Change in the alpha angle from newborn to 1 month after birth, rate of improvement to bilateral Graf type I hips in 1 month, and number of ultrasound examinations and orthopaedic clinic visits in the first year were compared between the two groups. Results Seventy newborns with 102 type IIa hips were included from January to December 2017. They were allocated to the double-diaper group (n = 33) and single-diaper group (n = 37). With a comparable sex ratio, gestational age, and newborn alpha angle, the double-diaper group had a greater increase of alpha angles in 1 month than the single-diaper group (+7.9° vs. +5.2°, t-test, p = 0.011). Twenty-eight babies in the double-diaper group (84.8%) and 20 babies in the single-diaper group (54.1%) improved to having bilateral Graf type I hips (chi-square test, p = 0.006). Under the same clinical management pathway, subsequent clinical visits and hip ultrasounds before 1 year were significantly reduced in the double-diaper group. Conclusion Double diapering enhances hip maturation and reduces clinical costs in newborns with physiological immature hips, but the therapeutic role for hip dysplasia requires further study.

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

Background The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). Objective This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. Patients/methods Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. Results Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30×109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n=339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. Conclusion The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

Objective To analyze the components of resistance training (RT) exercises and evaluate the effects of RT on improving muscle strength and oxygen consumption (VO2) peak based on either center-based rehabilitation or home-based rehabilitation in patients with heart failure with reduced ejection fraction (HFrEF). Methods According to the PRISMA guidelines, articles were searched through five databases, including Embase, MEDLINE, CINAHL, PEDro and Cochrane. RevMan 5.3 software was used to perform the meta-analysis. Results Nine randomized controlled trial studies met the study criteria, including a total of 299 respondents. In the center-based respondents (n = 81 for intervention group vs. n = 81 for control group), RT resulted in significant effects on both muscle strength of lower extremity (SDM = 1.46, 95% CI = 0.41–2.50, n = 151) and upper extremity (SDM = 0.46, 95% CI = 0.05–0.87, n = 97) and VO2 peak (MD = 1.45 ml/kg/min, 95% CI = 0.01–2.89, n = 114). In the home-based respondents (n = 71 for intervention group vs. n = 66 for control group), RT resulted in significant effects on muscle strength of both lower extremity (SDM = 0.58, 95% CI: 0.20–0.97, n = 113) and upper extremity (SDM = 0.84, 95% CI: 0.24–1.44, n = 47) and VO2 peak (MD = 5.43 ml/kg/min, 95% CI: 0.23–10.62, n = 89). Conclusion The RT exercise could increase muscle strength and VO2 peak at either center-based or home-based rehabilitation and should be considered as a part of the care of patients with HFrEF.

To ascertain if assisted hatching (AH) increases the risk of placenta-associated diseases and perinatal outcomes after frozen–thawed cleavage-stage embryo transfer. We retrospectively evaluated 924 women who conceived with frozen–thawed cleavage-stage embryos transfer with (n = 390) or without (n = 534) laser-AH between 2013 and 2015. Data were obtained from the database on in vitro fertilization (IVF) patients in Shanghai First Maternity and Infant Hospital. We assessed neonatal (preterm birth, low birthweight, fetal macrosomia, stillbirth) and obstetric (miscarriage, ectopic pregnancy, post-term pregnancy, gestational diabetes (GDM), preeclampsia, intrahepatic cholestasis (ICP), placenta previa, placental abruption, premature rupture of membranes) outcomes. In twins, the median birthweight was lower in the AH group than that in the control group, and the prevalence of low birthweight (

Background: Postoperative delirium (POD) is a significant clinical problem in neurosurgical patients after intracranial surgery. Identification of high-risk patients may optimise individual perioperative management, but an adequate and simple risk model for use at super early phase after operation has not been developed.Methods: Adult patients were admitted to the ICU after elective intracranial surgery under general anaesthesia. The POD was diagnosed as Confusion Assessment Method for the ICU positive on postoperative day 1 to 3. Multivariate logistic regression analysis was used to develop the early prediction model (E-PREPOD-NS) and the final model was validated with 200 bootstrap samples.Results: Among 800 patients included in the study, POD occurred in 157 cases (19.6%). We identified nine variables independently associated with POD in the final E-PREPOD-NS model: age > 65 years [odds ratio (OR) = 3.336, 95% confidence interval (CI) = 1.765-6.305, 1 risk score point], education level < 9 years (OR = 2.528, 95% CI = 1.446-4.419, 1 point), history of smoking (OR = 2.582, 95% CI = 1.611-4.140, 1 point), history of diabetes (OR = 2.541, 95% CI = 1.201-5.377, 1 point), supra-tentorial lesions (OR = 3.424, 95% CI = 2.021-5.802, 1 point), anesthesia duration > 360 min (OR = 1.686, 95% CI = 1.062-2.674, 0.5 point), GCS P = 0.593).Conclusions: The E-PREPOD-NS model based on nine perioperative risk factors can predict POD in patients admitted to the ICU after elective intracranial surgery with fairly good accuracy. External validation is needed before use in clinical practice.

Si-Yu Long,1 Le Wang,1,2 Hai-Qin Jiang,1 Ying Shi,1 Wen-Yue Zhang,1 Jing-Shu Xiong,1 Pei-Wen Sun,1,2 Yan-Qing Chen,1 You-Ming Mei,1 Chun Pan,1 Gai Ge,1 Zhen-Zhen Wang,1 Zi-Wei Wu,1 Mei-Wen Yu,1,2 Hong-Sheng Wang1– 3 1Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of China; 2National Centre for Leprosy Control, China CDC, Nanjing, People’s Republic of China; 3Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Hong-Sheng Wang; Mei-Wen YuJiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, St 12 Jiangwangmiao, Nanjing, Jiangsu, 210042, People’s Republic of ChinaEmail whs33@vip.sina.com; yumeiwen@163.comBackground: Genome-wide association studies (GWASs) have identified some immune-related single-nucleotide polymorphisms (SNPs) to be associated with leprosy.Methods: This study investigated the association of 17 SNPs based on previously published GWAS studies with susceptibility to leprosy, different polar forms and immune states of leprosy in a case–control study from southwestern China, including 1344 leprosy patients and 2732 household contacts (HHCs) (1908 relatives and 824 genetically unrelated contact individuals). The differences of allele distributions were analyzed using chi-squared analysis and logistic regression.Results: After adjusting covariate factors, rs780668 and rs3764147 polymorphisms influenced susceptibilities to genetically related or unrelated leprosy contact individuals. rs142179458 was associated with onset early cases, rs73058713 A allele and rs3764147 A allele increased the risk of reversal reaction, while rs3764147 G allele had higher risk to present lepromatous leprosy and erythema nodosum leprosum.Conclusion: Our results demonstrated that genetic variants in the LACC1, HIF1A, SLC29A3 and CDH18 genes were positively correlated with the occurrence of leprosy and leprosy clinical phenotypes, providing new insights into the immunogenetics of the disease.Keywords: leprosy, association study, susceptibility gene, polymorphisms

BACKGROUND Sodium valproate is widely used in the treatment of epilepsy in clinical practice. Most adverse reactions to sodium valproate are mild and reversible, while serious idiosyncratic side effects are becoming apparent, particularly hepatotoxicity. Herein, we report a case of fatal acute liver failure (ALF) with thrombotic microangiopathy (TMA) caused by treatment with sodium valproate in a patient following surgery for meningioma. CASE SUMMARY A 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue, severe jaundice accompanied by oliguria, soy sauce-colored urine, and ecchymosis. His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level, severe liver and kidney dysfunction, and disturbance of the coagulation system. He was diagnosed with drug-induced liver failure combined with TMA. After plasma exchange combined with hemoperfusion, pulse therapy with high-dose methylprednisolone, and blood transfusion, his liver function deteriorated, and finally, he died. CONCLUSION ALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.

BACKGROUND Pheochromocytomas are rare endocrine tumors with various clinical manifestations, and few of them might present with profound, life-threatening conditions. CASE SUMMARY We report the case of a 65-year-old man who complained of sudden dyspnea and hemoptysis for half a day. There was no obvious cause for the patient to have dyspnea, coughing, or coughing up to approximately 100 mL of fresh blood. Finally, he was diagnosed with pheochromocytoma crisis (PCC), coexisting with an abdominal aortic aneurysm (AAA). CONCLUSION We report a case of pheochromocytoma presenting with recurrent hemoptysis, dyspnea and hypotension coexisting with an AAA. It not only proved the uncommon manifestations of pheochromocytoma but also directed clinicians to consider PCC among the possible diagnoses when meeting similar cases. Moreover, surgical excision is the most beneficial method for the treatment of pheochromocytoma coexisting with AAA when the situation is stable.

Objective Leptomeningeal metastases (LM) occur in up to 5% of non–small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM. Materials and methods Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed. Results A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4–2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1–13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1–4.9 months) and 5.4 months (95% CI: 0.5–10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR/ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups. Conclusion NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required.

The cT3 substage criteria based on extramural depth of tumor invasion in rectal cancer have several limitations.This study proposed that the distance between the deepest tumor invasion and mesorectal fascia on pretherapy MRI can distinguish the prognosis of patients with cT3 rectal cancer.This is a cohort study.This study included a prospective, single-center, observational cohort and a retrospective, multicenter, independent validation cohort.Patients who had cT3 rectal cancer with negative mesorectal fascia undergoing neoadjuvant chemoradiotherapy followed by radical surgery were included in 4 centers in China from January 2013 to September 2014.Baseline MRI with the distance between the deepest tumor invasion and mesorectal fascia, extramural depth of tumor invasion, and mesorectum thickness were measured.The cutoff of the distance between the deepest tumor invasion and mesorectal fascia was determined by time-dependent receiver operating characteristic curves, supported by a 5-year progression rate from the prospective cohort, and was then validated in a retrospective cohort.There were 124 and 274 patients included in the prospective and independent validation cohorts. The distance between the deepest tumor invasion and mesorectal fascia was the only predictor for cancer-specific death (HR, 0.1; 95% CI, 0.0-0.7) and was also a significant predictor for distant recurrence (HR, 0.4; 95% CI, 0.2-0.9). No statistically significant difference was observed in prognosis between patients classified as T3a/b and T3c/d.The sample size is relatively small, and the study focused on cT3 rectal cancers with a negative mesorectal fascia.A cutoff of 7 mm of the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI can distinguish cT3 rectal cancer from a different prognosis. We recommend using the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI for local and systemic risk assessment and providing a tailored schedule of neoadjuvant treatment. See Video Abstract at http://links.lww.com/DCR/B682.CORRELACIÓN ENTRE LA DISTANCIA DE LA FASCIA MESORRECTAL Y EL PRONÓSTICO DEL CÁNCER DE RECTO cT3: RESULTADOS DE UN ESTUDIO MULTICÉNTRICO DE CHINAANTECEDENTES:Los criterios de subestadificación cT3 basados en la profundidad extramural de invasión tumoral en el cáncer de recto tienen varias limitaciones.OBJETIVO:Este estudio propuso que la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética preterapia puede distinguir el pronóstico de los pacientes con cT3.DISEÑO:Estudio de cohorte.ENTORNO CLINICO:El estudio incluyó una cohorte observacional, prospectiva, unicéntrica, y una cohorte de validación retrospectiva, multicéntrica e independiente.PACIENTE:Se incluyeron pacientes con cáncer de recto cT3 con fascia mesorrectal negativa sometidos a quimio-radioterapia neoadyuvante seguida de cirugía radical en cuatro centros de China desde enero de 2013 hasta septiembre de 2014.INTERVENCIÓN:Imágenes de resonancia magnética de referencia fueron medidas con la distancia entre la invasión tumoral más profunda y la fascia mesorrectal; la profundidad extramural de la invasión tumoral y el grosor del mesorrecto.PRINCIPALES MEDIDAS DE VALORACION:El límite de la distancia entre la invasión tumoral más profunda y la fascia mesorrectal se determinó mediante curvas características operativas del receptor dependientes del tiempo y se apoyó en la tasa de progresión a 5 años de la cohorte prospectiva, y luego se validó en una cohorte retrospectiva.RESULTADOS:Se incluyeron 124 y 274 pacientes en la cohorte de validación prospectiva e independiente, respectivamente. La distancia entre la invasión tumoral más profunda de la fascia mesorrectal fue el único predictor de muerte específica por cáncer (Hazard ratio: 0.1, 95% CI, 0,0-0,7); y también fue un predictor significativo de recurrencia distante Hazard ratio: 0,4, 95% CI, 0,2-0,9). No se observaron diferencias estadísticamente significativas en el pronóstico entre los pacientes clasificados como T3a/b y T3c/d.LIMITACIONES:El tamaño de la muestra es relativamente pequeño y el estudio se centró en los cánceres de recto cT3 con fascia mesorrectal negativa.CONCLUSIONES:Un límite de 7 mm de distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia puede distinguir el cáncer de recto cT3 de diferentes pronósticos. Recomendamos la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia para la evaluación del riesgo local y sistémico, proporcionando un programa personalizado de tratamiento neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B682. (Traducción- Dr. Francisco M. Abarca-Rendon).

Gouty arthritis is a very familiar inflammatory arthritis. Controlling inflammation is the key to preventing gouty arthritis. However, colchicine, the most highly represented drug used in clinical practice, has strict contraindications owing to some severe side effects. Curcumin (Cur), a natural anti-inflammatory drug, has demonstrated good safety and efficacy. However, the rapid degradation, poor aqueous solubility, and low bioavailability of Cur limit its therapeutic effect. To strengthen the effectiveness and bioavailability of Cur. Cur loaded tetrahedral framework nucleic acids (Cur-TFNAs) were synthesized to deliver Cur. Compared with free Cur, Cur-TFNAs exhibit a preferable drug stability, good biocompatibility (CCK-8 assay), ease of uptake (immunofluorescence), and higher tissue utilization (in vivo biodistribution). Most importantly, Cur-TFNAs present better anti-inflammatory effect than free Cur both in vivo and in vitro experiments through the determination of inflammation-related cytokines expression. Therefore, we believe that Cur-TFNAs have great prospects for the prevention of gout and similar inflammatory diseases., Graphical abstract Schematic illustration of treating acute gouty arthritis with Cur loaded TFNAs. Cur-TFNAs were absorbed by inflammatory RAW264.7 cells and inhibited the activation of NF-κB, which decreased the levels of ROS, NO and inflammatory factors (IL-6, IL-1β and TNF-α), thus affecting the progression of acute gouty arthritis.Image 1, Highlights • The drug curcumin system based on DNA nanostructures (Cur-TFNAs) were developed to obtain a novel nanomaterial with high water solubility, large encapsulation efficiency, sustained drug release and excellent drug stability. • Based on cellular uptake and in vivo drug imaging, Cur-TFNAs improve the retention of Cur in cells and tissues. • Cur-TFNAs prevent acute gouty arthritis through mediating anti-inflammatory and antioxidant responses of macrophage.

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

Spinal muscular atrophy was recently added to the Wisconsin newborn screening panel. Here we report our screening methods, algorithm, and outcomes. Methods: A multiplex real-time PCR assay was used to identify newborns with homozygous SMN1 exon 7 deletion, and those newborns’ specimens further underwent a droplet digital PCR assay for SMN2 copy number assessment. An independent dried blood spot specimen was collected and tested to confirm the initial screening results for SMN1 and SMN2. Results: From October 15, 2019 to October 14, 2020, a total of 60,984 newborns were screened for spinal muscular atrophy. Six newborns screened positive for and were confirmed to have spinal muscular atrophy, making the Wisconsin spinal muscular atrophy birth prevalence 1 in 10,164. Of these six infants, two have two copies of SMN2, two have three copies of SMN2, and two have four copies of SMN2. Five newborns received Zolgensma therapy, and one newborn received Spinraza therapy. Conclusions: Our screening method'spositive predictive value is 100%. This comprehensive approach, providing both timely SMN2 information and SMN1 and SMN2 confirmation as parts of the algorithm for spinal muscular atrophy newborn screening, facilitated timely clinical follow-up, family counseling, and treatment planning.

Purpose This study attempted to estimate the impact of eye-preserving therapies for the long-term prognosis of patients with advanced retinoblastoma with regard to overall survival and ocular salvage. Design Retrospective cohort study covering all 31 provinces (38 retinoblastoma treating centers) of mainland China. Participants One thousand six hundred seventy-eight patients diagnosed with group D or E retinoblastoma from January 2006 through May 2016. Methods Chart review was performed. The patients were divided into primary enucleation and eye-preserving groups, and they were followed up for survival status. The impact of initial treatment on survival was evaluated by Cox analyses. Main Outcome Measures Overall survival and final eye preservation. Results After a median follow-up of 43.9 months, 196 patients (12%) died, and the 5-year overall survival was 86%. In total, the eyeball preservation rate was 48%. In this cohort, 1172 patients (70%) had unilateral retinoblastoma, whereas 506 patients (30%) had bilateral disease. For patients with unilateral disease, 570 eyes (49%) underwent primary enucleation, and 602 patients (51%) received eye-preserving therapies initially. During the follow-up (median, 45.6 months), 59 patients (10%) from the primary enucleation group and 56 patients (9.3%) from the eye-preserving group died. Multivariate Cox analyses indicated no significant difference in overall survival between the 2 groups (hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.85–1.84; P = 0.250). For patients with bilateral disease, 95 eyes (19%) underwent primary enucleation, and 411 patients (81%) received eye-preserving therapies initially. During the follow-up (median, 40.1 months), 12 patients (13%) from the primary enucleation group and 69 patients (17%) from the eye-preserving group died. For bilateral retinoblastoma with the worse eye classified as group E, patients undergoing primary enucleation exhibited better overall survival (HR, 2.35; 95% CI, 1.10–5.01; P = 0.027); however, this survival advantage was not evident until passing 22.6 months after initial diagnosis. Conclusions Eye-preserving therapies have been used widely for advanced retinoblastoma in China. Patients with bilateral disease whose worse eye was classified as group E and who initially underwent eye-preserving therapies exhibited a worse overall survival. The choice of primary treatment for advanced retinoblastoma should be weighed carefully.