A bias-reduced generalized estimating equation approach for proportional odds models with small-sample longitudinal ordinal data.

BACKGROUND: Longitudinal ordinal data are commonly analyzed using a marginal proportional odds model for relating ordinal outcomes to covariates in the biomedical and health sciences. The generalized estimating equation (GEE) consistently estimates the regression parameters of marginal models even if the working covariance structure is misspecified. For small-sample longitudinal binary data, recent studies have shown that the bias of regression parameters may result from the GEE and have addressed the issue by applying Firth's adjustment for the likelihood score equation to the GEE as if generalized estimating functions were likelihood score functions. In this manuscript, for the proportional odds model for longitudinal ordinal data, the small-sample properties of the GEE were investigated, and a bias-reduced GEE (BR-GEE) was derived. METHODS: By applying the adjusted function originally derived for the likelihood score function of the proportional odds model to the GEE, we produced the BR-GEE. We investigated the small-sample properties of both GEE and BR-GEE through simulation and applied them to a clinical study dataset. RESULTS: In simulation studies, the BR-GEE had a bias closer to zero, smaller root mean square error than the GEE with coverage probability of confidence interval near or above the nominal level. The simulation also showed that BR-GEE maintained a type I error rate near or below the nominal level. CONCLUSIONS: For the analysis of longitudinal ordinal data involving a small number of subjects, the BR-GEE is advantageous for obtaining estimates of the regression parameters of marginal proportional odds models.

A SARS-CoV-2 recombinant spike protein vaccine (S-268019-b) for COVID-19 prevention during the Omicron-dominant period: A phase 3, randomised, placebo-controlled clinical trial.

Clinical trials of new vaccines based on existing variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are often impacted by the emergence of new virus variants. We evaluated the efficacy, immunogenicity, and safety of S-268019-b, a recombinant spike protein subunit vaccine based on the ancestral strain, for preventing symptomatic coronavirus disease 2019 (COVID-19) during the Omicron (BA.2)-dominant period in Vietnam. In this multicentre, phase 3, randomised (2:1), observer-blind, placebo-controlled crossover study, participants received 2 intramuscular doses (28 days apart) of either 10 µg of S-268019-b (Recombinant S-protein vaccine) or placebo. The primary endpoint was incidence of laboratory-confirmed symptomatic COVID-19 before crossover, with onset within 14 days following the second dose, in participants who were seronegative and reverse transcription polymerase chain reaction (RT-PCR)-negative at baseline. The secondary endpoints included immunogenicity and safety. In total, 8,594 participants were randomised (S-268019-b [n = 5,727]; placebo [n = 2,867]). Vaccine efficacy versus placebo was 39·1 % (95 % confidence interval [CI]:26·6-49·5; one-sided P = 0·0723). The incidence rate (95 % CI) of symptomatic COVID-19 was 776·41/1,000 person-years (682·04-880·19) in the S-268019-b group and 1272·87/1,000 person-years (1101·32-1463·57) in the placebo group. The geometric mean titres (95 % CI) of the SARS-CoV-2 neutralising antibody increased on Day 57 versus baseline with S-268019-b (34·66 [27·04-44·41] versus 2·50 (non-estimable) but not with placebo. There were no safety concerns regarding S-268019-b. S-268019-b did not demonstrate the targeted efficacy threshold against symptomatic COVID-19; however, findings were comparable with other prophylactic vaccines based on ancestor strain during the Omicron-dominant period. S-268019-b demonstrated immunogenicity and was well-tolerated. ClinicalTrials.gov identifier: NCT05212948.

A phase 3 randomized controlled trial of a COVID-19 recombinant vaccine S-268019-b versus ChAdOx1 nCoV-19 in Japanese adults.

We assessed S-268019-b, a recombinant spike protein vaccine with a squalene-based adjuvant, for superiority in its immunogenicity over ChAdOx1 nCoV-19 vaccine among adults in Japan. In this multicenter, randomized, observer-blinded, phase 3 study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve participants (aged ≥ 18 years, without prior infection or vaccination against SARS-CoV-2) were randomized (1:1) to receive either S-268019-b or ChAdOx1 nCoV-19 as two intramuscular injections given 28 days apart. Participants who provided consent for a booster administration received S-268019-b at Day 211. The primary endpoint was SARS-CoV-2 neutralizing antibody (NAb) titer on Day 57; the key secondary endpoint was the seroconversion rate for SARS-CoV-2 NAb titer on Day 57. Other endpoints included anti-SARS-CoV-2 S-protein immunoglobulin (Ig)G antibody titer and safety. The demographic and baseline characteristics were generally comparable between S-268019-b (n = 611) and ChAdOx1 nCoV-19 (n = 610) groups. S-268019-b showed superior immunogenicity over ChAdOx1 nCoV-19, based on their geometric mean titers (GMTs) and GMT ratios of SARS-CoV-2 NAb on Day 57 by cytopathic effect assay (GMT [95% confidence interval {CI}] 19.92 [18.68, 21.23] versus 3.63 [3.41, 3.87]; GMT ratio [95% CI] 5.48 [5.01, 6.00], respectively; two-sided p-values < 0.0001). Additionally, NAb measured using a cell viability assay also showed similar results (GMT [95% CI] 183.25 [168.04, 199.84] versus 24.79 [22.77, 27.00]; GMT ratio [95% CI] 7.39 [6.55, 8.35] for S-268019-b versus ChAdOx1 nCoV-19, respectively; p < 0.0001). The GMT of anti-SARS-CoV-2 S-protein IgG antibody was 370.05 for S-268019-b versus 77.92 for ChAdOx1 nCoV-19 on Day 57 (GMT ratio [95% CI] 4.75 [4.34, 5.20]). Notably, immune responses were durable through the end of the study. S-268019-b elicited T-helper 1 skewed T-cell response, comparable to that of ChAdOx1 nCoV-19. After the first dose, the incidence of solicited systemic treatment-related adverse events (TRAEs) was higher in the ChAdOx1 nCoV-19 group, but after the second dose, the incidence was higher in the S-268019-b group. Headache, fatigue, and myalgia were the most commonly reported solicited systemic TRAEs, while pain at the injection site was the most frequently reported solicited local TRAE following both doses in both groups. No serious treatment-related adverse serious TRAEs events were reported in the two groups. S-268019-b was more immunogenic than ChAdOx1 nCoV-19 vaccine and was well tolerated (jRCT2051210151).

Results from a preclinical study in rodents and a Phase 1/2, randomized, double-blind, placebo-controlled, parallel-group study of COVID-19 vaccine S-268019-a in Japanese adults.

BACKGROUND: In early 2020, developing vaccines was an urgent need for preventing COVID-19 from a contingency perspective. METHODS: S-268019-a is a recombinant protein-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a modified recombinant spike protein antigen adjuvanted with agatolimod sodium, a Toll-like receptor-9 agonist. In the preclinical phase, it was administered intramuscularly twice at a 2-week interval in 7-week-old mice. Immunogenicity was assessed, and the mice were challenged intranasally with mouse-adapted SARS-CoV-2 at 2 and 8 weeks, respectively, after the second immunization. After confirming the preclinical effect, a Phase 1/2, randomized, parallel-group clinical study was conducted in healthy adults (aged 20-64 years). All participants received 2 intramuscular injections at various combinations of the antigen and the adjuvant (S-910823/agatolimod sodium, in µg: 12.5/250, 25/250, 50/250, 25/500, 50/500, 100/500, 10/500, 100/100, 200/1000) or placebo (saline) in an equivalent volume at a 3-week interval and were followed up until Day 50 in this interim analysis. RESULTS: In the preclinical studies, S-268019-a was safe and elicited robust immunoglobulin G (IgG) and neutralizing antibody responses in mice. When challenged with SARS-CoV-2, all S-268019-a-treated mice survived and maintained weight until 10 days, whereas all placebo- or adjuvant-treated (without antigen) mice died within 6 days. In the Phase 1/2 trial, although S-268019-a was well tolerated in adult participants, was safe up to Day 50, and elicited robust anti-spike protein IgG antibodies, it did not elicit sufficient neutralizing antibody levels. CONCLUSIONS: The S-268019-a vaccine was not sufficiently immunogenic in Japanese adults despite robust immunogenicity and efficacy in mice. Our results exemplify the innate challenges in translating preclinical data in animals to clinical trials, and highlight the need for continued research to overcome such barriers. (jRCT2051200092).

Synthesis and Evaluation of in Vivo Anti-hypothermic Effect of the N- and C-Terminus Modified Thyrotropin-Releasing Hormone Mimetic: [(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide.

We explored orally effective thyrotropin-releasing hormone (TRH) mimetics, which show high central nervous system effects in structure-activity relationship studies based on in vivo antagonistic activity on reserpine-induced hypothermia (anti-hypothermic effect) in mice starting from TRH. This led us to the TRH mimetic: [(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide 1, which shows a higher anti-hypothermic effect compared with that of TRH after oral administration. We next attempted further chemical modification of the N- and C-terminus of 1 to find more orally effective TRH mimetics. As a result, we obtained several N- and C-terminus modified TRH mimetics which showed high anti-hypothermic effects.

Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 3: Structure-activity relationships of pyrropyrazolone derivatives.

The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.

Synthesis and evaluation of in vivo anti-hypothermic effect of all stereoisomers of the thyrotropin-releasing hormone mimetic: Rovatirelin Hydrate.

We discovered the orally active thyrotropin-releasing hormone (TRH) mimetic: (4S,5S)-5-methyl-N-{(2S)-1-[(2R)-2-methylpyrrolidin-1-yl]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl}-2-oxo-1,3-oxazolidine-4-carboxamide 1 (rovatirelin). The central nervous system (CNS) effect of rovatirelin after intravenous (iv) administration is 100-fold higher than that of TRH. As 1 has four asymmetric carbons in its molecule, there are 16 stereoisomers. We synthesized and evaluated the anti-hypothermic effect of all stereoisomers of 1, which has the (4S),(5S),(2S),(2R) configuration from the N-terminus to the C-terminus, in order to clarify the structure-activity relationship (SAR) of stereoisomers. The (4R),(5R),(2R),(2S)-isomer 16 did not show any anti-hypothermic effect. Only the (4S),(5S),(2S),(2S)-isomer 10, which has the (2S)-2-methylpyrrolidine moiety at the C-terminus showed the anti-hypothermic effect similar to 1. Stereoisomers, which have the (5R) configuration of the oxazolidinone at the N-terminus and the (2R) configuration at the middle-part, showed a much lower anti-hypothermic effect than that of 1. On the other hand, stereoisomers, which have the (4R) configuration of the oxazolidinone at the N-terminus or the (2S) configuration of the C-terminus, have little influence on the anti-hypothermic effect.

Correction to Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

[This corrects the article DOI: 10.1021/acsomega.8b01481.].

Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies.

OBJECTIVE: This post hoc, pooled, subgroup analysis of two randomised studies evaluated baseline characteristics that may influence the efficacy and safety of naldemedine in patients with opioid-induced constipation (OIC) and cancer. METHODS: Data for patients who received 0.2 mg naldemedine or placebo were pooled from randomised, placebo-controlled, phase IIb and phase III studies. Proportions of spontaneous bowel movement (SBM) responders and patients with diarrhoea were assessed for each treatment group. For the patient subgroups with or without possible blood-brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores were assessed. RESULTS: A total of 307 patients were included in this analysis (naldemedine: n=155; placebo: n=152). The pooled proportion of SBM responders was 73.5% with naldemedine versus 35.5% with placebo. There was a significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p<0.0001). Greater proportions of SBM responders and patients who experienced diarrhoea were observed with naldemedine versus placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases. CONCLUSIONS: Although not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal-even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhoea in patients who received naldemedine. TRIAL REGISTRATION NUMBERS: JapicCTI-111510 and JapicCTI-132340.

Pyrrolinone derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of orally bioavailable compounds.

Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.

Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies.

INTRODUCTION: Naldemedine is a peripherally-acting µ-opioid-receptor antagonist, approved in Japan for opioid-induced constipation (OIC). In two open-label, single-arm, Phase III studies, we evaluated the safety and efficacy of naldemedine in Japanese patients with OIC receiving regular-use opioids (COMPOSE-6) or prolonged-release oxycodone (COMPOSE-7) for chronic noncancer pain. METHODS: Eligible Japanese adults with OIC and chronic noncancer pain received once-daily oral naldemedine 0.2 mg for 48 weeks, irrespective of food intake. Primary end points included measures of treatment-emergent adverse events (TEAEs), pain intensity, and opioid withdrawal. Secondary efficacy end points were evaluated at treatment week 2. Patient Assessment of Constipation Symptoms (PAC-SYM) and Quality of Life (PAC-QOL) scores were evaluated in both 48-week studies. RESULTS: Of patients enrolled in COMPOSE-6 (N = 43) and COMPOSE-7 (N = 10), TEAEs were reported in 88% (95% CI 74.9-96.1) and 90% (95% CI 55.5-99.7), respectively. The most frequently reported TEAEs, nasopharyngitis and diarrhea, were mostly mild or moderate in severity. Assessments of pain intensity and opioid withdrawal remained stable over the 48-week treatment periods of both studies. The proportion of spontaneous bowel-movement responders at week 2 in COMPOSE-6 was 81.0% (95% CI 65.9-91.4) and 90.0% (95% CI 55.5-99.7) in COMPOSE-7. Significant and sustained improvements in PAC-SYM and PAC-QOL scores were also observed in both studies (all P<0.05). CONCLUSION: Side effects that occurred with naldemedine were mostly mild or moderate in severity, and the data suggested that naldemedine can improve bowel function and QOL in Japanese patients with OIC receiving regular-use opioids or prolonged-release oxycodone for chronic noncancer pain.

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate).

We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure-activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

Impaired central coherence in patients with anorexia nervosa.

The purpose of this study was to investigate the characteristics of central coherence in patients with anorexia nervosa (AN). 22 female patients with AN (median age = 31.50 (QD = 8.13) years) and 33 female healthy controls (HC) (median age = 28.00 (QD = 8.50) years) participated in the study. Their central coherence was assessed with the Rey Complex Figure Task (RCFT). Clinical symptoms were evaluated with the Beck Depression Inventory-II and the State-Trait Anxiety Inventory-Form JYZ. The results showed that AN patients' Central Coherence Index and accuracy scores in copy, 3-min delayed recall and 30-min delayed recall tasks of the RCFT were significantly lower than those of HC. Moreover, the significant differences in Central Coherence Index score in copy task and accuracy scores in 3-min delayed recall and 30-min delayed recall tasks remained when the effects of depression, anxiety and starvation were eliminated statistically. These findings may explain some characteristics of AN patients such as focusing on local rather than global picture in their perception of body or life.

Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer.

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids-common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting µ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.

Influence of cognitive function on quality of life in anorexia nervosa patients.

AIM: The purpose of this study was to elucidate determinants of quality of life (QOL) in anorexia nervosa (AN) patients. METHODS: Twenty-one female patients with AN participated in the study. QOL was assessed with the 36-Item Short Form Health Survey (SF-36), and cognitive function was evaluated using the Wisconsin Card Sorting Test Keio version, the Rey Complex Figure Test, and the Social Cognition Screening Questionnaire. Clinical symptoms were evaluated with the Beck Depression Inventory-II, the State-Trait Anxiety Inventory-Form JYZ (STAI-JYZ), and the Maudsley Obsessive Compulsive Inventory. RESULTS: The Difficulty Maintaining Set score of the Wisconsin Card Sorting Test Keio version was negatively correlated to the SF-36 Physical Component Summary. Scores of the Beck Depression Inventory-II and the STAI-JYZ State and Trait were negatively correlated to the SF-36 Mental Component Summary (MCS), and the Central Coherence Index 30-min Delayed Recall score of the Rey Complex Figure Test was positively correlated with the MCS. Stepwise regression analysis showed that the Difficulty Maintaining Set score was an independent predictor of the Physical Component Summary and scores for Central Coherence Index 30-min Delayed Recall and the STAI-JYZ Trait-predicted MCS. CONCLUSION: These results suggest that not only trait anxiety but also poor central coherence and impaired ability to maintain new rule worsen AN patients' QOL.

Impaired social cognition in anorexia nervosa patients.

BACKGROUND: The purpose of this study was to investigate the characteristics of social cognition in patients with anorexia nervosa (AN). METHODS: Eighteen female patients with AN (mean age =35.4±8.6 years) and 18 female healthy controls (HC) (mean age =32.8±9.4 years) participated in the study. Their social cognition was assessed with the Social Cognition Screening Questionnaire (SCSQ). RESULTS: The results showed that total score of the SCSQ and scores of theory of mind and metacognition were significantly lower in AN group than those in HC group. Moreover, significant differences in theory of mind, metacognition, and total score of the SCSQ remained when the effects of depression, anxiety, and starvation were eliminated statistically. CONCLUSION: These results suggest that patients with AN may have difficulty inferring other people's intention and also monitoring and evaluating their own cognitive activities. Therefore, these features may explain some aspects of the pathology of AN.

CT-based automated planning of acetabular cup for total hip arthroplasty (THA) based on hybrid use of two statistical atlases.

PURPOSE: This study describes the use of CT images in atlas-based automated planning methods for acetabular cup implants in total hip arthroplasty (THA). The objective of this study is to develop an automated cup planning method considering the statistical distribution of the residual thickness. METHODS: From a number of past THA planning datasets, we construct two statistical atlases that represent the surgeon's expertise. The first atlas is a pelvis-cup merged statistical shape model (PC-SSM), which encodes global spatial relationships between the patient anatomy and implant. The other is a statistical residual thickness map (SRTM) of the implant surface, which encodes local spatial constraints of the anatomy and implant. In addition to PC-SSM and SRTM, we utilized the minimum thickness as a threshold constraint to prevent penetration. RESULTS: The proposed method was applied to the pelvis shapes segmented from CT images of 37 datasets of osteoarthritis patients. Automated planning results with manual segmentation were compared to the plans prepared by an experienced surgeon. There was no significant difference in the average cup size error between the two methods (1.1 and 1.2 mm, respectively). The average positional error obtained by the proposed method, which integrates the two atlases, was significantly smaller (3.2 mm) than the previous method, which uses single atlas (3.9 mm). In the proposed method with automated segmentation, the size error of the proposed method for automated segmentation was comparable (1.1 mm) to that for manual segmentation (1.1 mm). The average positional error was significantly worse (4.2 mm) than that using manual segmentation (3.2 mm). If we only consider mildly diseased cases, however, there was no significance between them (3.2 mm in automated and 2.6 mm in manual segmentation). CONCLUSION: We infer that integrating PC-SSM and SRTM is a useful approach for modeling experienced surgeon's preference during cup planning.

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming.

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.