[Effect of prenatal stressful life event exposure on child emotional and behavioral problem at age 2-6 years].

Objective: To investigate the influence of prenatal stressful life event (SLE) exposure on child emotional and behavioral problem at age 2-6 years and identify the most risk exposure period. Methods: A total of 2 524 mother-child pairs were selected from Shanghai Maternal-Child Pairs Cohort based on pregnant women form 2016 to 2018 in Shanghai. Prenatal SLE exposure was assessed by Life Events Scale for Pregnant Women Questionnaire during the first and third trimester of pregnancy. Child emotional and behavioral problem was evaluated by Strengths and Difficulties Questionnaire at age 2-6 years. Multivariate binary logistic regression model and generalized estimating equation were conducted to quantify the association between prenatal SLE exposure and child emotional and behavioral problem at age 2-6 years, and identify the pregnancy period with strongest adverse effect. Results: The 2 524 mother-child pairs were divided into 4 groups: group with consistent low exposure to SLE (61.8%), group with high exposure to SLE in the first trimester (13.2%), group with high exposure to SLE in the third trimester (13.2%) and group with consistent high exposure to SLE (11.8%). The detection rates of emotional problem, hyperactivity, peer interaction problem and total difficulty score in children aged 3-6 years were highest in the group with consistent high exposure to SLE. Generalized estimating equation analysis showed that after controlling the confounding factors, compared with the consistent low exposure group, the children in the group with high exposure to SLE in the first trimester had significant increased risk for conduct problem at age 2-6 years (aOR=1.41, 95%CI:1.07-1.87). The children in the group with consistent high exposure to SLE were at increased risk for emotional problem, peer interaction problem, and high total difficulty score with the aOR of 1.41 (95%CI: 1.09-1.83), 1.46 (95%CI: 1.15-1.86) and 1.51(95%CI: 1.17-1.93). Conclusion: These findings indicated that prenatal exposure to SLE have adverse effect on child emotional and behavioral problem at age 2-6 years, especially the exposure in the first trimester.

Socio-economic factors and medical conditions affecting regular stomach cancer screening in Korea: a retrospective longitudinal study using national public health data for 11 years.

OBJECTIVE: This study aimed to explore socio-economic factors and medical conditions that affect regular stomach cancer (SC) screening among Korean adults. STUDY DESIGN: This was a retrospective observational study. METHODS: Study subjects were 5545 adults aged ≥40 years who participated in the 2007-2012 Korean National Health and Nutrition Examination Survey and were followed up to year 2017 based on data linking to the Korean National Health Insurance Service and Korean Health Insurance Review and Assessment. Socio-economic factors included sex, age, residential area, education, occupation, marital status, disability, public and private health insurance, service through local public health organizations, history of cancer except for SC, and family history of SC. Medical factors included six gastric lesions with the possibility of facilitating SC screening, including benign gastric neoplasm, chronic atrophic gastritis, gastric polyp, Helicobacter pylori infection, intestinal metaplasia, and peptic ulcers. The outcome was adherence to SC screening, which was divided into non-adherence, irregular adherence, and regular adherence. RESULTS: After adjusting for the effects of socio-economic factors, multivariate ordinal logistic regression revealed that participants with a history of four types of gastric lesions were more likely to regularly participate in SC screening: chronic atrophic gastritis (odds ratio [OR] 1.567; 95% confidence interval [CI] = 1.276-1.923), gastric polyps (OR 1.565; 95% CI = 1.223-2.003), H. pylori infection (OR 1.637; 95% CI = 1.338-2.003), and peptic ulcer (OR 2.226; 95% CI 1.750-2.831). CONCLUSIONS: To improve participation in SC screening, it is necessary to implement personalized strategies for individuals at risk for gastric cancer in addition to population-based strategies for vulnerable groups.

Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration.

Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation in vitro and in cells. We show that simultaneous inhibition of both Sirt2 activities results in strongly reduced levels of the oncoprotein c-Myc and an inhibition of cancer cell migration. Furthermore, we describe the development of a NanoBRET-based assay for Sirt2, thereby providing a method to study cellular target engagement for Sirt2 in a straightforward and accurately quantifiable manner. Applying this assay, we could confirm cellular Sirt2 binding of our new Sirt2 inhibitors and correlate their anticancer effects with their cellular target engagement.

A Comparison of Folinic Acid, Fluorouracil and Irinotecan (FOLFIRI) plus Bevacizumab and FOLFIRI plus Aflibercept as Second-line Treatment for Metastatic Colorectal Cancer.

AIM: To compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy. MATERIALS AND METHODS: We analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab. RESULTS: The overall response rate (ORR) was 13.6% (95% confidence interval 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% confidence interval 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752). Patients in the FOLFIRI-bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI-aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group. CONCLUSION: FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

Osteoconductivity of Porous Titanium Structure on Implants in Osteoporosis.

In compromised bone conditions such as osteoporosis, developments of the implant surface are necessary to secure the stability of implants. This study investigated the effect of the surface porous titanium structure (PS) on the osseointegration of implants in osteoporotic bone. Bilateral ovariectomy (OVX) was performed in 4 female beagle dogs to induce osteoporosis for 32 wk. Success of induction was based on the evaluation of bone mineral density by Hounsfield units (HU) in computed tomography images. Posterior teeth in both mandibles were extracted 1 wk after OVX, and a total of 30 implants (15 implants in each group) were placed after 32 wk of osteoporosis induction. The control group implant underwent resorbable blast media (RBM) surface treatment, whereas the test group underwent RBM surface treatment in the coronal two-thirds and a PS added to the apical 3-mm portion. HU values in the mandibular trabecular bone, lumbar, and femoral head significantly decreased 32 wk after OVX, confirming osteoporotic condition after induction. Resonance frequency analysis and removal torque test showed comparable values between the 2 groups at 4 wk after implant placement. The surface topography of the implant after removal showed hard tissue integration at the PS in the test group. Bone-to-implant contact length was greater in the apical portion of the test group, although statistical significance was not found between the groups. Interthread bone area in the apical portion of the test group showed a significant increase compared to the control group (control: 0.059 ± 0.041 mm2, test: 0.121 ± 0.060 mm2, P = 0.028) with the histological feature of bone ingrowth at the PS. The findings of the study demonstrated that the surface PS could improve osteoconductivity in the osteoporotic trabecular bone by bone ingrowth at the pore space, thereby enhancing the osseointegration and stability of the implants.

Mask-induced dermatoses during the COVID-19 pandemic: a questionnaire-based study in 12 Korean hospitals.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, various adverse skin reactions to long-term mask wearing have been reported. AIM: To assess the clinical features of mask-induced dermatoses and to recommend prevention and treatment options. METHODS: From April to August 2020, questionnaires including topics such as demographic information, pre-existing skin disorders, reported mask-related symptoms, daily mask-wearing duration and frequency, types of masks used and whether the participant was a healthcare worker, were distributed to patients in 12 hospitals. Dermatologists assessed skin lesions, confirmed diagnosis and recorded treatments. RESULTS: Itchiness was the most frequent symptom, mostly affecting the cheeks. The most common skin disease was new-onset contact dermatitis (33.94%), followed by new-onset acne (16.97%) and worsening of pre-existing acne (16.97%). Daily wearing of masks was significantly (P = 0.02) associated with new-onset contact dermatitis. More than half of patients with pre-existing skin problems experienced disease worsening while wearing masks. Longer duration of wearing (> 6 h/day, P = 0.04) and use of cotton masks (P < 0.001) significantly increased acne flare-up. Healthcare workers had a higher incidence of skin disease. Skin lesions were generally mild and well tolerated with topical treatment. The study had some limitations: the effect of seasonal characteristics and other risk factors were not assessed, and the patients were visiting dermatological clinics and had interest in their skin status, thus, there may have been selection bias. CONCLUSION: Mask-induced/-triggered dermatoses contribute to increase the dermatological burden during the pandemic.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: a multicenter retrospective study of the Korean Cancer Study Group (KCSG).

BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

A Scoring System for Prediction of Cervical Lymph Node Metastasis in Patients with Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: An accurate and comprehensive assessment of lymph node metastasis in patients with head and neck squamous cell cancer is crucial in daily practice. This study constructed a predictive model with a risk scoring system based on CT characteristics of lymph nodes and tumors for patients with head and neck squamous cell carcinoma to stratify the risk of lymph node metastasis. MATERIALS AND METHODS: Data included 476 cervical lymph nodes from 191 patients with head and neck squamous cell carcinoma from a historical cohort. We analyzed preoperative CT images of lymph nodes, including diameter, ratio of long-to-short axis diameter, necrosis, conglomeration, infiltration to adjacent soft tissue, laterality and T-stage of the primary tumor. The reference standard comprised pathologic results. Multivariable logistic regression analysis was performed to develop the risk scoring system. Internal validation was performed with 1000-iteration bootstrapping. RESULTS: Shortest axial diameter, ratio of long-to-short axis diameter, necrosis, and T-stage were used to develop a 9-point risk scoring system. The risk of malignancy ranged from 7.3% to 99.8%, which was positively associated with increased scores. Areas under the curve of the risk scoring systems were 0.886 (95% CI, 0.881-0.920) and 0.879 (95% CI, 0.845-0.914) in internal validation. The Hosmer-Lemeshow goodness-of-fit test indicated that the risk scoring system was well-calibrated (P = .160). CONCLUSIONS: We developed a comprehensive and simple risk scoring system using CT characteristics in patients with head and neck squamous cell carcinoma to stratify the risk of lymph node metastasis. It could facilitate decision-making in daily practice.

Vitamin D receptor interacts with NLRP3 to restrict the allergic response.

Vitamin D receptor (VDR) mediates various biochemical activities between the cytoplasm and the nucleus in the cell. The nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) protein is involved in the T helper type 2 (Th2) response. This study tests a hypothesis that VDR interacts with NLRP3 to restrict the Th2-biased response. In this study, VDR-/- mice and WT (WT) mice were used. Th2 cell differentiation between VDR-/- mice and WT mice was observed. We observed that CD4+ T cell activation was higher in VDR-/- mice. The VDR-/-CD4+ T cells were prone to Th2 polarization. VDR-/- mice produced more immunoglobulin (Ig)E. VDR bound NLRP3 to prevent Th2 differentiation by restricting IL4 gene transcription. Th2 biased inflammation spontaneously developed in the intestine of VDR-/- mice. In conclusion, VDR binds NLRP3 to restrict IL4 gene transcription and prevent biased Th2 polarization.

Viscoelastic Properties of Contemporary Bulk-fill Restoratives: A Dynamic-mechanical Analysis.

This study investigated the viscoelastic properties of contemporary bulk-fill restoratives in distilled water and artificial saliva using dynamic mechanical analysis. The materials evaluated included a conventional composite (Filtek Z350), two bulk-fill composites (Filtek Bulk-fill and Tetric N Ceram), a bulk-fill giomer (Beautifil-Bulk Restorative), and two novel reinforced glass ionomer cements (Zirconomer [ZR] and Equia Forte [EQ]). The glass ionomer materials were also assessed with and without resin coating (Equia Forte Coat). Test specimens 12 × 2 × 2 mm of the various materials were fabricated using customized stainless-steel molds. After light polymerization/initial set, the specimens were removed from the molds, finished, measured, and conditioned in distilled water or artificial saliva at 37°C for seven days. The materials (n=10) were then subjected to dynamic mechanical testing in flexure mode at 37°C and a frequency of 0.1 to 10 Hz. Storage modulus, loss modulus, and loss tangent data were subjected to normality testing and statistical analysis using one-way analysis of variance/Dunnett's test and t-test at a significance level of p < 0.05. Mean storage modulus ranged from 3.16 ± 0.25 to 8.98 ± 0.44 GPa, while mean loss modulus ranged from 0.24 ± 0.03 to 0.65 ± 0.12 GPa for distilled water and artificial saliva. Values for loss tangent ranged from 45.7 ± 7.33 to 134.2 ± 12.36 (10-3). Significant differences in storage/loss modulus and loss tangent were observed between the various bulk-fill restoratives and two conditioning mediums. Storage modulus was significantly improved when EQ and ZR was not coated with resin.

Predictors of compartment syndrome of the foot after fracture of the calcaneus.

Aims: Identifying predictors of compartment syndrome in the foot after a fracture of the calcaneus may lead to earlier diagnosis and treatment. The aim of our study was to identify any such predictors. Patients and Methods: We retrospectively reviewed 303 patients (313 fractures) with a fracture of the calcaneus who presented to us between October 2008 and September 2016. The presence of compartment syndrome and potential predictors were identified by reviewing their medical records. Potential predictors included age, gender, concomitant foot injury, mechanism of injury, fracture classification, time from injury to admission, underlying illness, use of anticoagulant/antiplatelet agents, smoking status and occupation. Associations with predictors were analyzed using logistic regression analysis. Results: Of the 313 fractures of the calcaneus, 12 (3.8%) developed a compartment syndrome. A Sanders type IV fracture was the only strongly associated factor (odds ratio 21.67, p = 0.007). Other variables did not reach statistical significance. Conclusion: A Sanders type IV fracture is the best predictor of compartment syndrome after a fracture of the calcaneus. Cite this article: Bone Joint J 2018;100-B:303-8.

Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF-ß expression and Foxp3+ Treg cells.

BACKGROUND: Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. METHODS: Wild-type and Chit1-deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. RESULTS: The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF-ß1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1-/- mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF-ß-stimulated conversion of CD4+ CD25- naïve T cells to CD4+ Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF-ß1 in Treg cell differentiation. CONCLUSION: Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF-ß expression and Foxp3+ Treg cells.

Activated leucocyte cell adhesion molecule (ALCAM/CD166) regulates T cell responses in a murine model of food allergy.

Food allergy is a major public health problem. Studies have shown that long-term interactions between activated leucocyte cell adhesion molecule (ALCAM/CD166) on the surface of antigen-presenting cells, and CD6, a co-stimulatory molecule, influence immune responses. However, there are currently no studies on the functions of ALCAM in food allergy. Therefore, we aimed to identify the functions of ALCAM in ovalbumin (OVA)-induced food allergy using ALCAM-deficient mice. Wild-type (WT) and ALCAM-deficient (ALCAM-/- ) mice were sensitized intraperitoneally and with orally fed OVA. The mice were killed, and parameters related to food allergy and T helper type 2 (Th2) immune responses were analysed. ALCAM serum levels increased and mRNA expression decreased in OVA-challenged WT mice. Serum immunoglobulin (Ig)E levels, Th2 cytokine mRNA and histological injuries were higher in OVA-challenged WT mice than in control mice, and these were attenuated in ALCAM-/- mice. T cell proliferation of total cells, CD3+ CD4+ T cells and activated T cells in immune tissues were diminished in OVA-challenged ALCAM-/- mice. Proliferation of co-cultured T cells and dendritic cells (DCs) was decreased by the anti-CD6 antibody. In addition, WT mice sensitized by adoptive transfer of OVA-pulsed ALCAM-/- BM-derived DCs showed reduced immune responses. Lastly, serum ALCAM levels were higher in children with food allergy than in control subjects. In this study, serum levels of ALCAM were elevated in food allergy-induced WT mice and children with food allergy. Moreover, immune responses and T cell activation were attenuated in OVA-challenged ALCAM-/- mice. These results indicate that ALCAM regulates food allergy by affecting T cell activation.

Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease.

BACKGROUND: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. RESULTS: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. CONCLUSIONS: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL.