Meta-regression Analysis of Study Heterogeneity for Systemic Outcomes after Periodontal Therapy.

INTRODUCTION: The contribution of periodontal disease to adverse systemic consequences remains controversial. This analysis examined 2 well-investigated conditions independently and combined-adverse pregnancy outcomes and glycemic control for patients with diabetes-based on shared pathogenic mechanisms of periodontal infection and inflammation. It was proposed that inconsistencies in study design significantly contribute to outcome discrepancies found between periodontal intervention studies undergoing meta-analysis. METHODS: Meta-analyses evaluating periodontal interventions on the rate of preterm birth and changes in glycated hemoglobin A1c in type 2 diabetes populations were conducted based on a systematic review of randomized controlled trials. Meta-regression covariates for exploring heterogeneity included sample size, level of medical management, and bias risk as moderator variables in a random-effects meta-regression. RESULTS: Systematic review identified 17 studies of diabetes and 13 of pregnancy outcomes. Analyses of these studies identified 0.50% reduction in HbA1c and 0.78 odds ratio for preterm births. The heterogeneity associated with the models was high (I2 = 92.4 and I2 = 62.7%, respectively). The adjusted models evaluating each systemic condition separately accounted for 52.2% of the effect for diabetes and 81.4% for pregnancy outcome effects independently, and 63.5% collectively, across interventional studies. CONCLUSION: This systematic review with meta-regression analysis of heterogeneity demonstrates that disparate results seen in randomized controlled trials of periodontal therapy affecting systemic outcomes may be explained in large part by study design, specifically stringency in consideration of medical management and sample size. The potential for confounding factors to influence outcomes remains a concern in understanding the implications of oral health on systemic conditions. KNOWLEDGE TRANSFER STATEMENT: The findings of this study demonstrate that much of the benefits seen from periodontal therapy on adverse systemic outcomes for diabetes and pregnancy are due to limitations in study design.

Immunohistochemical expression levels of cyclin D1 and CREPT reflect the course and prognosis in oral precancerous lesions and squamous cell carcinoma.

Cyclin D1 is the most essential progressive regulator of the cell cycle, and its transcription is enhanced by CREPT (cell cycle-related and expression-elevated protein in tumour). These molecules regulate cell growth, and their aberrant expression can cause malignant transformation. In this study, the expression of these molecules was explored to investigate the molecular alterations in oral precancerous lesions and squamous cell carcinoma. Cyclin D1 and CREPT expression was examined immunohistochemically in tissue specimens from 55 patients with oral epithelial precursor lesions (OEPLs) and 84 patients with oral squamous cell carcinoma (OSCC). Associations between the results and clinicopathological variables were examined. Cyclin D1 and CREPT expression levels were higher in OSCC than in OEPLs. Furthermore, there were statistically significant differences in cyclin D1 expression among the different grades of OEPLs and OSCC lesions. In OSCC, there were statistically significant differences in CREPT expression according to sex, T stage, and degree of differentiation. In addition, the expression of both molecules was significantly correlated with postoperative metastasis and modes of invasion. The expression of cyclin D1 and CREPT was found to depend upon the state of development and progression of the oral epithelial lesions, and clinicopathological behaviours might be affected by these molecules in OSCC.

Electric Quadrupolar Contributions in the Magnetic Phases of UNi_{4}B.

We present acoustic signatures of the electric quadrupolar degrees of freedom in the honeycomb-layer compound UNi_{4}B. The transverse ultrasonic mode C_{66} shows softening below 30 K both in the paramagnetic phase and antiferromagnetic phases down to ∼0.33 K. Furthermore, we traced magnetic field-temperature phase diagrams up to 30 T and observed a highly anisotropic elastic response within the honeycomb layer. These observations strongly suggest that Γ_{6}(E_{2g}) electric quadrupolar degrees of freedom in localized 5f^{2} (J=4) states are playing an important role in the magnetic toroidal dipole order and magnetic-field-induced phases of UNi_{4}B, and evidence some of the U ions remain in the paramagnetic state even if the system undergoes magnetic toroidal ordering.

All-suture anchor pullout results in decreased bone damage and depends on cortical thickness.

PURPOSE: To evaluate the influence of cortical and cancellous bone structure on the biomechanical properties of all-suture and conventional anchors and compare the morphological bone damage after their failure. The hypothesis of the study is that all-suture anchor pullout is less invasive and that the pullout force is influenced by the cortical thickness. METHODS: Thirty human humeri were biomechanically tested as follows: starting with a load cycle from 20 to 50 N, a stepwise increase of the upper peak force by 0.05 N for each cycle at a rate of 1 Hz was performed. Analysis included maximum pullout strength for three different anchor implantation angles (45°, 90°, 110°) of the two anchor types. After anchor pullout, every sample underwent micro-CT analysis. Bone mineral density (BMD) and cortical thickness were determined at the anchor implantation site. Furthermore, the diameter of the cortical defect and the volume of the bone cavity were identified. RESULTS: The maximum pullout strength of all-suture anchors demonstrates a strong correlation to the adjacent cortical thickness (r = 0.82, p ≤ 0.05) with at least 0.4 mm needed to withstand 200 N. No correlation could be seen in conventional anchors. Moreover, no correlation could be detected for local BMD in both anchors. All-suture anchors show a significantly narrower cortical defect as well as a smaller bone cavity following pullout (4.3 ± 1.3 mm vs. 5.3 ± 0.9 mm, p = 0.037; 141 mm3 vs. 212 mm3; p = 0.009). The cortical defect is largest if the anchors are placed at a 45° angle. CONCLUSION: In contrast to conventional anchors, the pullout force of all-suture anchors depends on the thickness of the humeral cortex. Furthermore, all-suture anchors show a significantly smaller cortical defect as well as decreased bone damage in the case of pullout. Therefore, the clinical implication of this study is that all-suture anchors are advantageous due to their bone preserving ability. Also, intraoperative decortication should not be performed and cortical thickness should be preoperatively evaluated to decrease the risk of anchor failure.

New physician specialty training system impact on distribution of trainees in Japan.

OBJECTIVES: The problem of uneven distribution of medical services and inequitable distribution of physicians is drawing much attention worldwide. Revealing how changes in the specialty training system in Japan have affected the distribution of doctors could help us understand this problem. In 2018, a new and standardized specialty training system was implemented by the Japanese Medical Specialty Board, which is recognized by the Ministry of Health, Labor and Welfare. The purpose of this study was to investigate how this new system has affected the geographical distribution of doctors commencing specialty training (trainees) and choice of specialty in Japan. STUDY DESIGN: Retrospective observational study. METHODS: The change in the number of trainees between the control period (2012-2014) and 2018 was investigated, taking into account the prefecture and specialty selected. Population, the proportion of residents aged 65 years or older (aging rate), and the total number of overall doctors in each prefecture were considered as the background characteristics of each prefecture. We created a Lorenz curve and calculated the Gini coefficient for the distribution of trainees. RESULTS: In 2018, the number of trainees per 100,000 population increased to 6.6 nationwide compared with 5.5 during the control period. The number of trainees per 100,000 population in 2018 increased in prefectures with a large population of ≧ 2,000,000, a low aging rate (<27%), and a high doctor density (≧ 250 doctors per 100,000 population). The Gini coefficient showed an increase to 0.226 in 2018 compared with only 0.160 during the control period. CONCLUSIONS: After the implementation of the new training system, there was an increase in the number of doctors enrolling in specialty programs, and the specialties other than internal medicine and surgery have attracted more trainees. Inequality in the distribution of doctors between urban and rural prefectures worsened. This indicates the need to explore new ways of balancing distribution while maintaining optimal opportunities for specialist training.

Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer.

BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

Oral administration of heat-killed Lactobacillus brevis SBC8803 elevates the ratio of acyl/des-acyl ghrelin in blood and increases short-term food intake.

It is known that gastrointestinal microbiota, probiotics and heat-killed microbes can regulate intestinal immunity; however, their effect on the secretion of gastrointestinal hormones is unclear. The secretion of gastrointestinal hormones can be mediated by the elevation of intracellular Ca2+ concentration, suggesting that these hormones may act through common mechanisms. We have previously shown that heat-killed Lactobacillus brevis SBC8803 (hk-SBC8803) induced the secretion of serotonin and elevated intracellular Ca2+ concentration in serotonin-producing RIN-14B cells, suggesting that hk-SBC8803 could potentially cause the same effect on other gastrointestinal hormones, including hunger hormone ghrelin. Here, we tested this hypothesis by treating cultured cells and experimental animals with hk-SBC8803 and assessing ghrelin secretion, expression of ghrelin-related genes, and food intake. The results indicated that hk-SBC8803 treatment for 30 min significantly upregulated the secretion of acyl ghrelin (active form) (P=0.046) and mRNA expression of the Syt3 (synaptotagmin 3) gene related to ghrelin exocytosis (P<0.05) in primary mouse stomach cells. In addition, oral administration of 500 mg/kg hk-SBC8803 to rats tended to upregulate acyl ghrelin concentration (P=0.10) and significantly increased the ratio of acyl to des-acyl (inactive) ghrelin (P=0.027) in blood, which corresponded to a tendency of stimulating food intake (P=0.087) at 30 min post-treatment. However, when in order to minimise individual differences we normalised the data on food intake to those on one-day food intake prior to food deprivation, the resultant food intake ratio showed a significant increase (by 5% compared to control; P=0.032) at 30 min after hk-SBC8803 treatment, indicating that hk-SBC8803 administration stimulated rats to take more food during the first meal after fasting. These results suggest that hk-SBC8803 induces short-term ghrelin secretion and transiently increases appetite, which is an important effect for individuals with low energy intake.

Regulatory T cells and M2-polarized tumour-associated macrophages are associated with the oncogenesis and progression of oral squamous cell carcinoma.

Regulatory T cells (Tregs) and tumour-associated macrophages (TAMs) contribute to the tumour microenvironment by inhibiting anti-tumour immune responses. This study was performed to investigate the roles of Tregs and TAMs in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPL). The expression of Treg markers CD25 and FoxP3 and TAM markers CD163 and CD204 was investigated in 82 OSCC and 45 OEPL specimens, and their associations with clinicopathological parameters were analyzed. Correlations were found among CD25, FoxP3, CD163, and CD204 levels (P < 0.001), and these targets were up-regulated in OSCC compared to OEPL (P < 0.001). In OSCC, infiltration of Tregs and/or M2 TAMs was associated with sex and clinicopathological features, such as tumour size, nodal metastasis, tissue differentiation, stromal reaction, invasive behaviour, and invasive depth. In OEPL, CD25, FoxP3, CD163, and CD204 immunoreactivities were significantly associated with sex, postoperative recurrence, and cancerization to OSCC. This study is novel in showing that the infiltration of Tregs and M2 TAMs is significantly associated with the progression of premalignant lesions to OSCC. This suggests that these cells represent prognostic biomarkers for premalignant lesion progression and that immunotherapeutic approaches to control Treg/M2 TAM numbers could protect against progression to malignancy.

Complex networks for tracking extreme rainfall during typhoons.

Reconciling the paths of extreme rainfall with those of typhoons remains difficult despite advanced forecasting techniques. We use complex networks defined by a nonlinear synchronization measure termed event synchronization to track extreme rainfall over the Japanese islands. Directed networks objectively record patterns of heavy rain brought by frontal storms and typhoons but mask out contributions of local convective storms. We propose a radial rank method to show that paths of extreme rainfall in the typhoon season (August-November, ASON) follow the overall southwest-northeast motion of typhoons and mean rainfall gradient of Japan. The associated eye-of-the-typhoon tracks deviate notably and may thus distort estimates of heavy typhoon rainfall. We mainly found that the lower spread of rainfall tracks in ASON may enable better hindcasting than for westerly-fed frontal storms in June and July.

Effect of serotonin transporter genotype on self-reported efficacy and activity changes of brain prefrontal area in response to placebo.

Patients benefit from drug therapy not only through pharmacological mechanisms, but also through non-pharmacological action (placebo effect), which may be mediated in part by the prefrontal area of the brain. We consider that the difference between responders and non-responders to placebo might be related to polymorphisms in the serotonin transporter-linked polymorphic region (5-HTTLPR). To study this idea, we performed a randomized double-blind clinical trial using caffeine and lactose (placebo). Activity in the prefrontal area of the brain was measured in terms of blood flow by means of near-infrared spectroscopy (NIRS) as an objective indicator. Self-reported feelings of drowsiness on established scales were used as subjective indicators. Twenty-one subjects in block A took caffeine on the first day and placebo on the third day, and 21 in block B took placebo on the first day and placebo on the third day. After placebo administration, improvement of sleepiness was significantly enhanced, a similar extent to that after caffeine medication. Among the 42 subjects, 22 showed S/S type polymorphism in the serotonin transporter (52.4 %), 17 showed S/L type (40.5 %) and 3 showed L/L type (7.10 %). Statistical analysis of the results indicate that subjects with L/L genotype showed a significantly greater placebo response in terms of both self-reported feeling of drowsiness and blood flow in the prefrontal area of the brain associated with working memory (46 area). Our results indicate that the L/L genotype of 5-HTTLPR, which is rare in Japanese (3.2 %) but common in Americans (32.2 %), may be associated with a greater placebo effect.

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma.

This corrects the article DOI: 10.1038/bcj.2015.86.

Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro.

Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.

An update on stem cell biology and engineering for brain development.

Two recent technologies, induced-pluripotent stem cells (iPSCs) and direct somatic reprogramming, have shown enormous potential for cell-based therapies against intractable diseases such as those that affect the central nervous system. Already, methods that generate most major cell types of the human brain exist. Whether the cell types are directly reprogrammed from human somatic cells or differentiated from an iPSC intermediate, the overview presented here demonstrates how these protocols vary greatly in their efficiencies, purity and maturation of the resulting cells. Possible solutions including micro-RNA switch technologies that purify target cell types are also outlined. Further, an update on the transition from 2D to 3D cultures and current organoid (mini-brain) cultures are reviewed to give the stem cell and developmental engineering communities an up-to-date account of the progress and future perspectives for modeling of central nervous system disease and brain development in vitro.

Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles.

STUDY QUESTION: Are pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Letrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles. WHAT IS KNOWN ALREADY: Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known. STUDY DESIGN SIZE, DURATION: A retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013. PARTICIPANTS/MATERIALS SETTING METHODS: A total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics. MAIN RESULTS AND THE ROLE OF CHANCE: The rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41-1.55) and 1.62 (95% CI: 1.54-1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88-0.93) and 0.84 (95% CI: 0.82-0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles. LIMITATIONS REASONS FOR CAUTION: Important limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).