Effects of jaw movement in bimaxillary orthognathic surgery on the upper airway: Computational fluid dynamics analysis.

Maxillomandibular repositioning in orthognathic surgeries has both morphologic and functional effects. These surgeries are thought to change the pharyngeal space and cause obstructive sleep apnoea syndrome, however. The primary purpose of this study is to evaluate the effects of jaw movement in bimaxillary orthognathic surgery on airway function and to identify the morphometric factors that can predict postoperative airway function. The subjects were 11 males and 12 females who had undergone orthognathic surgeries of the maxilla and mandible. The results of cephalometric analysis, cross-sectional area of the pharynx (CSA), pharyngeal volume and computational fluid dynamics (CFD) were compared. The CSA of the nasal (CSA1), total volume and total nasal volume decreased after surgery with statistical significance. Velocity at the oropharyngeal space (V2) increased after surgery with statistical significance. V2, CSA of the oropharyngeal space (CSA2) and PV were correlated with the horizontal posterior movement of point B, point Menton and overjet. V2 and CSA2 were correlated with SNB before and after surgery in all 46 analyses. Changes in pharyngeal airflow were more affected by pressure drop in the pharyngeal space (ΔPp) than by pressure drop in the nasal space (ΔPn). The relationship between the actual amount of change in the cephalometric reference point and the airway function is evident. CFD may thus be very useful as morphological analysis in preoperative treatment decision making.

Three-dimensional Analysis of Factors Related to the Effective Alveolar Molding in Presurgical Infant Orthopedics: Findings From a Pilot Study.

OBJECTIVE: Presurgical infant orthopedics (PIO) reduces the severity of the original cleft and burden on patients and their parents, provides better esthetics and function, and enables surgeons to achieve better surgical repair. To reduce the alveolar cleft width and to predict treatment difficulty using PIO, various measures were examined in pretreatment cast models. DESIGN: Retrospective case-control pilot study. PATIENTS: The patients were 22 infants with non-syndromic unilateral cleft lip and palate (UCLP), and cast models of these infants were used. METHODS: After PIO using passive plates, infants with UCLP were divided into two groups: contact group (12 cases with close proximity of the greater and lesser segments) and non-contact group (10 cases without proximity of segments). The two groups were compared, and variables related to the proximity between alveolar clefts were examined. RESULTS: There was no significant difference in age at PIO initiation between the two groups. However, the treatment duration was significantly longer in the non-contact group than in the contact group. Among the 13 variables, the initial lateral deviation of the nasal septum was significantly larger in the contact group than in the non-contact group. A significant positive correlation was observed between the initial lateral deviation of the nasal septum and reduction of the alveolar cleft width by PIO. CONCLUSION: Initial lateral deviation of the nasal septum is a predictive factor for the proximity between alveolar segments in infants with UCLP at the PIO.

Orthodontic treatment of a skeletal Class III malocclusion with severe root resorption of the maxillary anterior teeth. Autotransplantation using a 3-dimensional printed replica of the donor tooth.

This case report describes the successful orthodontic treatment of a 12-year-old girl with skeletal Class III malocclusion and severe root resorption of the maxillary anterior teeth. Ectopic eruption and mesial inclination of the bilateral maxillary canines caused severe root resorption of the right central and lateral incisors and the left lateral incisor. These 3 teeth were extracted, and traction was applied to the maxillary right and left canines toward the extracted right central incisor and left lateral incisor, respectively. In the mandibular arch, the bilateral first premolars were extracted, and the crowding was corrected. The extracted mandibular right first premolar was transplanted after extraction of the maxillary right lateral incisor. To prepare for the tooth transplantation, a cone-beam computed tomography image was used to fabricate a 3-dimensional printed replica of the donor tooth. The crown shape of the maxillary anterior teeth was corrected, and the patient achieved functional occlusion with pleasing esthetics. Root resorption was negligible in the transplanted tooth. This study demonstrates the satisfactory treatment outcome and an effective 3-dimensional simulation for tooth transplantation.

Association between N-desethylamiodarone/amiodarone ratio and amiodarone-induced thyroid dysfunction.

PURPOSE: We used a retrospective data mining approach to explore the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and thyroid-related hormone levels. METHODS: Laboratory data sets from January 2012 to April 2016 were extracted from the computerized hospital information system database at the National Cerebral and Cardiovascular Center (NCVC). Data sets that contained serum AMD and DEA concentrations and thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were analyzed. RESULTS: A total of 1831 clinical laboratory data sets from 330 patients were analyzed. Data sets were classified into five groups (euthyroidism, hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, and subclinical hypothyroidism) based on the definition of thyroid function in our hospital. Most abnormal levels of thyroid hormones were observed within the therapeutic range of serum AMD and DEA concentrations. The mean DEA/AMD ratio in the hyperthyroidism group was significantly higher than that in the euthyroidism group (0.95 ± 0.42 vs. 0.87 ± 0.28, p = 0.0209), and the mean DEA/AMD ratio in the hypothyroidism group was significantly lower than that in the euthyroidism group (0.77 ± 0.26 vs. 0.87 ± 0.28, p = 0.0038). The suppressed TSH group (0.98 ± 0.41 vs. 0.87 ± 0.28, p < 0.001) and the elevated FT4 level group (0.90 ± 0.33 vs. 0.84 ± 0.27, p = 0.0037) showed significantly higher DEA/AMD ratios compared with normal level groups. The elevated TSH group showed a significantly lower DEA/AMD ratio compared with the normal group (0.81 ± 0.25 vs. 0.87 ± 0.28, p < 0.0001). CONCLUSIONS: High and low DEA/AMD ratios were associated with AMD-induced hyperthyroidism and hypothyroidism, respectively. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.

Angiotensin receptor blockers and the risk of cancer: data mining of a spontaneous reporting database and a claims database
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OBJECTIVE: The aim of this study was to examine the associations between angiotensin receptor blockers (ARBs) and the risk of 10 major cancers by employing different pharmacoepidemiological assessments. MATERIALS AND METHODS: Data from the first quarter of 2004 through 2012 were downloaded from the US Food and Drug Administration Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR) and information component (IC) were used to detect the signals. Furthermore, symmetry analysis was applied to the claims database to identify the risk of cancer after using ARBs from January 2005 to July 2013. RESULTS: Significant inverse associations were found for all cancer types assessed as a whole (ROR: 0.78, 95% confidence interval (CI): 0.75 - 0.80; IC: -0.36, 95% CI: -0.40 to -0.31) in the analyses of FAERS database. Likewise, significant inverse association was found for all cancer types assessed as a whole (adjusted sequence ratio: 0.89, 95% CI: 0.82 - 0.96) in claims database. In addition, a significantly decreased risk for breast cancer and increased risks for pancreatic and prostate cancer were found in patients treated with ARBs in the analyses of individual cancers. CONCLUSIONS: Significant inverse association was found between ARB use and all cancer types assessed as a whole. However, in the analyses of individual cancers, the risks of ARB-induced cancer may differ according to cancer site. It may be reasonable to assume that the risks of ARB-induced cancer may differ according to cancer site.
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Association between Benzodiazepine Use and Dementia: Data Mining of Different Medical Databases.

Purpose: Some studies have suggested that the use of benzodiazepines in the elderly is associated with an increased risk of dementia. However, this association might be due to confounding by indication and reverse causation. To examine the association between benzodiazepine anxiolytic drug use and the risk of dementia, we conducted data mining of a spontaneous reporting database and a large organized database of prescriptions. Methods: Data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 through the end of 2013 and data from the Canada Vigilance Adverse Reaction Online Database from the first quarter of 1965 through the end of 2013 were used for the analyses. The reporting odds ratio (ROR) and information component (IC) were calculated. In addition, prescription sequence symmetry analysis (PSSA) was performed to identify the risk of dementia after using benzodiazepine anxiolytic drugs over the period of January 2006 to May 2014. Results: Benzodiazepine use was found to be associated with dementia in analyses using the FAERS database (ROR: 1.63, 95% CI: 1.61-1.64; IC: 0.66, 95% CI: 0.65-0.67) and the Canada Vigilance Adverse Reaction Online Database (ROR: 1.88, 95% CI: 1.83-1.94; IC: 0.85, 95% CI: 0.80-0.89). ROR and IC values increased with the duration of action of benzodiazepines. In the PSSA, a significant association was found, with adjusted sequence ratios of 1.24 (1.05-1.45), 1.20 (1.06-1.37), 1.23 (1.11-1.37), 1.34 (1.23-1.47), 1.41 (1.29-1.53), and 1.44 (1.33-1.56) at intervals of 3, 6, 12, 24, 36, and 48 months, respectively. Furthermore, the additional PSSA, in which patients who initiated a new treatment with benzodiazepines and anti-dementia drugs within 12- and 24-month periods were excluded from the analysis, demonstrated significant associations of benzodiazepine use with dementia risk. Conclusion: Multi-methodological approaches using different methods, algorithms, and databases suggest that long-term use of benzodiazepines and long-acting benzodiazepines are strongly associated with an increased risk of dementia.

Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases.

PURPOSE: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. METHODS: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. RESULTS: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. CONCLUSION: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.

Long-term impact of therapeutic drug monitoring on the risk of hypoglycemia in HOCM patients on cibenzoline therapy
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OBJECTIVE: The purpose of this study was to evaluate the long-term impact of therapeutic drug monitoring (TDM) services on the risk of hypoglycemia in cibenzoline therapy. In addition, we evaluated the impact of changes in clinical setting or patient background on the risk of hypoglycemia in patients receiving cibenzoline. METHODS: TDM services for cibenzoline have been performed at the Japan National Cerebral and Cardiovascular Center since March 1998. A case-control study was performed from September 2012 to February 2013, and the calculated risk of hypoglycemia associated with cibenzoline use was compared with data from our previous studies, which were performed ~ 15 years ago. RESULTS: A significantly increased risk for hypoglycemia was observed for users of cibenzoline (adjusted OR: 2.6; 95% CI: 1.5 - 4.7). In an additional analysis, the calculated risk was slightly reduced (adjusted OR; 2.1, 95% CI; 1.1 - 3.8) and hypertrophic obstructive cardiomyopathy (HOCM) was identified as a possible risk factor for hypoglycemia (adjusted OR: 4.7, 95% CI: 1.8 - 12.3). There was a significant difference in the mean level of cibenzoline between outpatients with and without HOCM (360.5 ± 166.9 ng/mL vs. 276.4 ± 136.3 ng/mL). An inverse relationship was observed between the percentage of outpatients whose cibenzoline serum level had been measured and their risk of hypoglycemia. CONCLUSIONS: Consistent TDM services for cibenzoline have contributed to a reduced risk of hypoglycemia associated with cibenzoline therapy. Patients with HOCM have a higher risk of developing hypoglycemia. Clinicians should therefore carefully monitor serum glucose levels in patients with HOCM taking cibenzoline.
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Association between statin use and cancer: data mining of a spontaneous reporting database and a claims database.

PURPOSE: In recent years, the potential risk of cancer associated with statin use has been a focus of much interest. However, it remains uncertain whether statin therapy is associated with cancer risk. To examine the association between statin use and the risk of cancer, we conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database of claims constructed by a database vendor (The Japan Medical Data Center Co., Ltd, Tokyo, Japan [JMDC]). METHODS: Relevant reports in the FAERS, which included data from the first quarter of 2004 through the end of 2012, were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals and was calculated using the case/non-case method. Additionally, signals were detected via the information component (IC) using the IC025 metric. Furthermore, event sequence symmetry analysis (ESSA) was applied to identify the risk of cancer following treatment with statins over the period January 2005 to July 2013. RESULTS: In the FAERS database analyses, significant signals for colorectal cancer and pancreatic cancer were found for statins as a class. In the ESSA, significant associations between statin use and colorectal cancer and pancreatic cancer were found, with adjusted sequence ratios (95% confidence intervals) of 1.20 (1.08-1.34) and 1.31 (1.13-1.53), respectively, at an interval of 48 months. CONCLUSIONS: Multi-methodological approaches using different algorithms and databases suggest that statin use is associated with an increased risk for colorectal cancer and pancreatic cancer.

Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2.

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by heterotopic endochondral ossification in soft tissue. A mutation in the bone morphogenetic protein (BMP) receptor ALK2, R206H, has been identified in patients with typical FOP. In the present study, we established murine embryonic stem (ES) cells that express wild-type human ALK2 or typical mutant human ALK2 [ALK2(R206H)] under the control of the Tet-Off system. Although wild-type ALK2 and mutant ALK2(R206H) were expressed in response to a withdrawal of doxycycline (Dox), BMP signaling was activated only in the mutant ALK2(R206H)-expressing cells without the addition of exogenous BMPs. The Dox-dependent induction of BMP signaling was blocked by a specific kinase inhibitor of the BMP receptor. The mutant ALK2(R206H)-carrying cells showed Dox-regulated chondrogenesis in vitro, which occurred in co-operation with transforming growth factor-ß1 (TGF-ß1). Overall, our ES cells are useful for studying the molecular mechanisms of heterotopic ossification in FOP in vitro and for developing novel inhibitors of chondrogenesis induced by mutant ALK2(R206H) associated with FOP.

Difference in risk of gastrointestinal complications between users of enteric-coated and buffered low-dose aspirin.

OBJECTIVE: Difference in the risk of gastrointestinal (GI) complications between users of enteric-coated and buffered low-dose aspirin (LDA) is unclear. The purpose of the study is to examine the difference in risk of GI damage between enteric-coated and buffered LDA products. METHODS: A large and chronologically organized receipt database constructed by a database vendor was utilized. Prescription and event sequence symmetry analysis was used to identify the risk of LDA-induced GI complications over the period from January 2005 to July 2011. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was examined by prescription sequence symmetry analysis. Likewise, symmetry analysis was undertaken to evaluate the association between the diagnosis of GI disease and the prescription of LDA products. RESULTS: In July 2011, enteric-coated LDA users were more frequently co-administered PPIs than buffered LDA users (25.4% vs. 14.4%). Prescription sequence symmetry analysis of acid inhibitor use found no significant associations with enteric-coated LDA use and buffered LDA use. The event sequence symmetry analysis of ulcer, gastritis and duodenitis, and melena found significant associations with entericcoated LDA use, with adjusted sequence ratios (ASRs) of 1.58 (1.23 - 2.06), 1.30 (1.03 - 1.65), and 14.38 (2.19 - 607.95), respectively, at the 6-month interval. At the 12-month interval, analysis of ulcers and melena found significant associations for enteric-coated LDA users, with ASRs of 1.39 (1.13 - 1.73) and 20.83 (3.33 - 863.25), respectively. CONCLUSIONS: Our findings do not support that there is no difference in the risk of GI complications between enteric-coated LDA and buffered LDA, but rather may imply that the risk of GI complications associated with enteric-coated LDA is higher than that with buffered LDA.

Statin-associated lower urinary tract symptoms: data mining of the public version of the FDA adverse event reporting system, FAERS.

OBJECTIVE: To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) in reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) between 2004 and 2011. METHODS: Relevant reports in the FAERS were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals, calculated using the case/non-case method. Cases were identified by the presence of reports of an adverse drug reaction (ADR) in which statins were the suspected drug. Non-cases were all the reports of the same reactions induced by drugs other than statins. The reporting odds ratio (ROR) and 95% confidential interval (CI) was calculated as a measure of disproportionality. RESULTS: A total of 44,959,104 drug-reaction pairs was found in 2,681,739 reports. Significant RORs were found for both voiding (ROR; 1.16, 95% CI; 1.10 - 1.23) and storage symptoms (ROR; 1.25, 95% CI; 1.20 - 1.30). Analysis of individual statins showed that rosuvastatin, atorvastatin, and lovastatin had significant disproportionality for voiding symptoms, while simvastatin, rosuvastatin, pravastatin, atorvastatin, pitavastatin, and lovastatin had significant disproportionality for storage symptoms. Of the four voiding symptoms, significant RORs were found for urine flow decrease and dysuria. Of the four storage symptoms, significant RORs were found for pollakiuria and nocturia. No fundamental differences in disproportionality were observed between genders. CONCLUSIONS: Analysis of the FAERS database showed small but reliable signals for LUTS in statin users. The mechanism responsible for these reactions is unknown. However, these adverse events should be monitored closely.

Association of statin use with storage lower urinary tract symptoms (LUTS): data mining of prescription database.

OBJECTIVE: The efficacy and safety of statins have been studied in a number of clinical trials and epidemiological studies. In recent years, the Medicine and Healthcare Products Regulatory Agency (MHRA) has assessed the evidence available on the following adverse reactions associated with the use of statins: sleep disturbances, memory loss, micturition disorders (problems with urination), sexual disturbances, depression, and interstitial pneumopathy. However, the association between statin use and the risk of these adverse reactions remains unclear. To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) or the disorder causing LUTS, we carried out data mining using a prescription database. METHODS: A large organized database of prescriptions constructed by a database vendor was used in the study. Symmetry analysis was used to identify the risk of LUTS after using statins over the period January 2006 to August 2013. Statin use in combination with drugs administered for storage LUTS was examined by prescription sequence symmetry analysis (PSSA). RESULTS: A significant association between statins and drugs for storage LUTS was found, with adjusted sequence ratios (ASRs) of 1.21 (95% CI, 1.00 - 1.46), 1.19 (95% CI, 1.04 - 1.38), and 1.17 (95% CI, 1.05 - 1.30) for intervals of 91, 182, and 365 days, respectively. In the analyses of individual statins, significant associations were found only for pravastatin. Significant associations with individual drugs for storage LUTS were found for solifenacin succinate with ASRs of 1.36 (95% CI, 1.02 - 1.81), 1.48 (95% CI, 1.19 - 1.84), and 1.47 (95% CI, 1.25 - 1.73) for intervals of 91, 182, and 365 days, for flavoxate hydrochloride with an ASR of 1.56 (95% CI, 1.13 - 2.17) at an interval of 182 days, and for oxybutynin hydrochloride with ASRs of 2.06 (95% CI, 1.11 - 3.94) and 1.71 (95% CI, 1.09 - 2.72) at intervals of 182 and 365 days. Significant associations with gender were found only in females with ASRs of 1.25 (95% CI, 1.04 - 1.51) and 1.23 (95% CI, 1.07 - 1.41) at intervals of 182 and 365 days, respectively. CONCLUSIONS: Analysis of the prescription database showed significant association for storage LUTS in statin users.

Crystal structure of Hfq from Bacillus subtilis in complex with SELEX-derived RNA aptamer: insight into RNA-binding properties of bacterial Hfq.

Bacterial Hfq is a protein that plays an important role in the regulation of genes in cooperation with sRNAs. Escherichia coli Hfq (EcHfq) has two or more sites that bind RNA(s) including U-rich and/or the poly(A) tail of mRNA. However, functional and structural information about Bacillus subtilis Hfq (BsHfq) including the RNA sequences that specifically bind to it remain unknown. Here, we describe RNA aptamers including fragment (AG)(3)A that are recognized by BsHfq and crystal structures of the BsHfq-(AG)(3)A complex at 2.2 Å resolution. Mutational and structural studies revealed that the RNA fragment binds to the distal site, one of the two binding sites on Hfq, and identified amino acid residues that are critical for sequence-specific interactions between BsHfq and (AG)(3)A. In particular, R32 appears to interact with G bases in (AG)(3)A. Poly(A) also binds to the distal site of EcHfq, but the overall RNA structure and protein-RNA interaction patterns engaged in the R32 residues of BsHfq-(AG)(3)A differ from those of EcHfq-poly(A). These findings provide novel insight into how the Hfq homologue recognizes RNA.

An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs.

Different computational approaches are employed to efficiently identify novel repositioning possibilities utilizing different sources of information and algorithms. It is critical to propose high-valued candidate-repositioning possibilities before conducting lengthy in vivo validation studies that consume significant resources. Here we report a novel multi-methodological approach to identify opportunities for drug repositioning. We performed analyses of real-world data (RWD) acquired from the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) and the claims database maintained by the Japan Medical Data Center (JMDC). These analyses were followed by cross-validation through bioinformatics analyses of gene expression data. Inverse associations revealed using disproportionality analysis (DPA) and sequence symmetry analysis (SSA) were used to detect potential drug-repositioning signals. To evaluate the validity of the approach, we conducted a feasibility study to identify marketed drugs with the potential for treating inflammatory bowel disease (IBD). Primary analyses of the FAERS and JMDC claims databases identified psycholeptics such as haloperidol, diazepam, and hydroxyzine as candidates that may improve the treatment of IBD. To further investigate the mechanistic relevance between hit compounds and disease pathology, we conducted bioinformatics analyses of the associations of the gene expression profiles of these compounds with disease. We identified common biological features among genes differentially expressed with or without compound treatment as well as disease-perturbation data available from open sources, which strengthened the mechanistic rationale of our initial findings. We further identified pathways such as cytokine signaling that are influenced by these drugs. These pathways are relevant to pathologies and can serve as alternative targets of therapy. Integrative analysis of RWD such as those available from adverse-event databases, claims databases, and transcriptome analyses represent an effective approach that adds value to efficiently identifying potential novel therapeutic opportunities.

Association between Serum Amiodarone and N-Desethylamiodarone Concentrations and Development of Thyroid Dysfunction.

OBJECTIVE: This retrospective cohort study was performed to examine the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and the development of thyroid dysfunction. METHODS: Patients treated with AMD from January 2012 to April 2016 were identified from the computerized hospital information system database at the National Cerebral and Cardiovascular Center. Only patients whose serum AMD and DEA concentrations had been determined at least once were included in the study. RESULTS: A total of 377 patients were enrolled. Consequently, 54 (14.3%) and 60 (15.9%) patients who developed AMD-induced thyrotoxicosis and hypothyroidism were included. The mean DEA/AMD ratio during the pre-index period in the thyrotoxicosis group (0.86 ± 0.24) was significantly higher than in the hypothyroidism (0.68 ± 0.27) and euthyroidism (0.78 ± 0.30; p < 0.0001) groups. In addition, the mean DEA/AMD ratio during the post-index period in the thyrotoxicosis group (1.05 ± 0.40) was significantly higher than in the hypothyroidism (0.81 ± 0.24) and euthyroidism (0.88 ± 0.22; p < 0.0001) groups. A persistently higher DEA/AMD ratio was observed throughout the study period in the thyrotoxicosis group. In addition, good correlations between the DEA/AMD ratio and the levels of free thyroxine, free triiodothyronine levels, and log (thyroid-stimulating hormone) were observed in the thyrotoxicosis and euthyroidism groups. CONCLUSION: Patients with AMD-induced thyrotoxicosis had an increased DEA/AMD ratio and patients with AMD-induced hypothyroidism had a decreased DEA/AMD ratio before the development of thyroid dysfunction. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.

Effects of FKBP12 and type II BMP receptors on signal transduction by ALK2 activating mutations associated with genetic disorders.

Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2. We also examined the effect of the suppressor FKBP12 on the signal transduction of a further 14 ALK2 mutations associated with FOP and/or DIPG. To varying extents FKBP12 over-expression suppressed the basal signaling induced by thirteen of the ALK2 mutants, whereas PF197-8L was uniquely resistant. In the PF197-8L mutant, the modelled ALK2 residue L197 induced a steric clash with the D36 residue in FKBP12 and dissociated their interaction. The co-expression of BMP type II receptors or stimulation with ligands relieved the suppression by FKBP12 by disrupting the interaction between mutant ALK2 and FKBP12. Taken together, FKBP12 binds to and suppresses mutant ALK2 proteins associated with FOP and DIPG, except for PF197-8L.

Monovalent manganese based anodes and co-solvent electrolyte for stable low-cost high-rate sodium-ion batteries.

The demand of sustainable power supply requires high-performance cost-effective energy storage technologies. Here we report a high-rate long-life low-cost sodium-ion battery full-cell system by innovating both the anode and the electrolyte. The redox couple of manganese(I/II) in Prussian blue analogs enables a high-rate and stable anode. Soft X-ray absorption spectroscopy and resonant inelastic X-ray scattering provide direct evidence suggesting the existence of monovalent manganese in the charged anode. There is a strong hybridization between cyano ligands and manganese-3d states, which benefits the electronic property for improving rate performance. Additionally, we employ an organic-aqueous cosolvent electrolyte to solve the long-standing solubility issue of Prussian blue analogs. A full-cell sodium-ion battery with low-cost Prussian blue analogs in both electrodes and co-solvent electrolyte retains 95% of its initial discharge capacity after 1000 cycles at 1C and 95% depth of discharge. The revealed manganese(I/II) redox couple inspires conceptual innovations of batteries based on atypical oxidation states.