Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early.

OBJECTIVE: In modern psychiatry, depression is diagnosed with the diagnostic criteria; however, the trajectory of each of the criterion symptoms is unknown. This study aims to examine this. METHODS: We made repeated assessments of the nine diagnostic criterion symptoms with the Patient Health Questionnaire-9 (PHQ-9) among 2011 participants of a 25-week pragmatic randomised controlled trial of sertraline and/or mirtazapine for hitherto untreated major depressive episodes. The changes from baseline were estimated with the mixed-effects model with repeated measures. The time to disappearance of each symptom was modeled using the Kaplan-Meier survival analysis. RESULTS: The total score on PHQ-9 was 18.5 (SD = 3.9, n = 2011) at baseline, which decreased to 15.3 (5.2, n = 2011) at week 1, to 11.5 (5.9, n = 1953) at week 3, to 7.8 (6.0, n = 1927) at week 9, and to 6.0 (5.9, n = 1910) at week 25. Suicidal ideas, psychomotor symptoms decreased rapidly, while anergia and sleep disturbance also decreased but only slowly. The survival analyses confirmed the primary analyses. CONCLUSIONS: Upon initiation of antidepressant treatment, patients with newly treated major depressive episodes can expect their suicidal ideas and psychomotor symptoms to disappear first but sleep disturbances and anergia to linger on.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Interpretable inference on the mixed effect model with the Box-Cox transformation.

We derived results for inference on parameters of the marginal model of the mixed effect model with the Box-Cox transformation based on the asymptotic theory approach. We also provided a robust variance estimator of the maximum likelihood estimator of the parameters of this model in consideration of the model misspecifications. Using these results, we developed an inference procedure for the difference of the model median between treatment groups at the specified occasion in the context of mixed effects models for repeated measures analysis for randomized clinical trials, which provided interpretable estimates of the treatment effect. From simulation studies, it was shown that our proposed method controlled type I error of the statistical test for the model median difference in almost all the situations and had moderate or high performance for power compared with the existing methods. We illustrated our method with cluster of differentiation 4 (CD4) data in an AIDS clinical trial, where the interpretability of the analysis results based on our proposed method is demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Waiting list may be a nocebo condition in psychotherapy trials: a contribution from network meta-analysis.

OBJECTIVE: Various control conditions have been employed in psychotherapy trials, but there is growing suspicion that they may lead to different effect size estimates. The present study aims to examine the differences among control conditions including waiting list (WL), no treatment (NT) and psychological placebo (PP). METHOD: We comprehensively searched for all randomized controlled trials (RCTs) comparing cognitive-behaviour therapies (CBT) against various control conditions in the acute phase treatment of depression, and applied network meta-analysis (NMA) to combine all direct and indirect comparisons among the treatment and control arms. RESULTS: We identified 49 RCTs (2730 participants) comparing WL, NT, PP and CBT. This network of evidence was consistent, and the effect size estimates for CBT were substantively different depending on the control condition. The odds ratio of response for NT over WL was statistically significant at 2.9 (95% CI: 1.3-5.7). However, the quality of evidence, including publication bias, was less than ideal and none of the preplanned sensitivity analyses limiting to high-quality studies could be conducted, while findings of significant differences did not persist in post hoc sensitivity analyses trying to adjust for publication bias. CONCLUSION: There may be important differences in control conditions currently used in psychotherapy trials.

Conjunctival sensitization to hydrolyzed wheat protein in facial soap

No disponible

Prototyping sensor network system for automatic vital signs collection. Evaluation of a location based automated assignment of measured vital signs to patients.

OBJECTIVE: Development of a clinical sensor network system that automatically collects vital sign and its supplemental data, and evaluation the effect of automatic vital sensor value assignment to patients based on locations of sensors. METHODS: The sensor network estimates the data-source, a target patient, from the position of a vital sign sensor obtained from a newly developed proximity sensing system. The proximity sensing system estimates the positions of the devices using a Bluetooth inquiry process. Using Bluetooth access points and the positioning system newly developed in this project, the sensor network collects vital sign and its 4W (who, where, what, and when) supplemental data from any Bluetooth ready vital sign sensors such as Continua-ready devices. The prototype was evaluated in a pseudo clinical setting at Kyoto University Hospital using a cyclic paired comparison and statistical analysis. RESULTS: The result of the cyclic paired analysis shows the subjects evaluated the proposed system is more effective and safer than POCS as well as paper-based operation. It halves the times for vital signs input and eliminates input errors. On the other hand, the prototype failed in its position estimation for 12.6% of all attempts, and the nurses overlooked half of the errors. A detailed investigation clears that an advanced interface to show the system's "confidence", i.e. the probability of estimation error, must be effective to reduce the oversights. CONCLUSIONS: This paper proposed a clinical sensor network system that relieves nurses from vital signs input tasks. The result clearly shows that the proposed system increases the efficiency and safety of the nursing process both subjectively and objectively. It is a step toward new generation of point of nursing care systems where sensors take over the tasks of data input from the nurses.

Pinguecula and contact lenses.

PURPOSE: To assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers. METHODS: A total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11-60 years and 579 non-wearers aged 10-60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects. RESULTS: There was an age-related increase in the grade of pinguecula among both CL wearers and non-wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001). CONCLUSIONS: This was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula.

Macular microcirculation and macular oedema in branch retinal vein occlusion.

BACKGROUND/AIMS: The relationship between the blood-flow velocity in the perifoveal capillaries and macular oedema was investigated in patients with branch retinal vein occlusion (BRVO). METHODS: This study compared 18 patients with BRVO and 16 healthy volunteers. Perifoveal capillary blood-flow velocity was measured on fluorescein angiograms with a scanning laser ophthalmoscope by the tracing method. Retinal thickness at the central fovea was measured by optical coherence tomography. Then, the relation between perifoveal capillary blood-flow velocity and retinal thickness at the central fovea was investigated. RESULTS: Perifoveal capillary blood-flow velocity was significantly lower in the patients with BRVO (1.08 (SD 0.28) mm/s) than in the healthy volunteers (1.49 (0.11) mm/s) (p<0.0001). Capillary blood-flow velocity showed a negative correlation with the retinal thickness at the central fovea in the two groups (r = -0.8426, p<0.0001). Multivariate linear regression analysis with stepwise variable selection confirmed that capillary blood-flow velocity was an independent determinant of the retinal thickness at the central fovea (p<0.001). CONCLUSION: A reduction in perifoveal capillary blood-flow velocity may be involved in the development of macular oedema in patients with BRVO.

Relationship between refraction and allergic conjunctivitis.

PURPOSE: External allergens are the main causative factor in the pathogenesis of allergic diseases; however, little is known about internal factors such as the biometrical structure of the eye. We investigated the relationship between refractive error and allergic conjunctivitis in order to reveal possible insights into the pathogenesis in 1015 subjects. METHODS: The patients were divided into four groups: contact lens wearers with allergic conjunctivitis (n=73), contact lens wearers without allergic conjunctivitis (n=59), non-contact lens wearers with allergic conjunctivitis (n=224), and non-contact lens wearers without allergic conjunctivitis (n=659). The spherical power, cylindrical power, corneal radius, and minimum and maximum corneal refractive powers were measured in all subjects. RESULTS: In the non-contact lens wearers, the spherical equivalent and spherical power were significantly lower in patients with allergic conjunctivitis than in patients without allergic conjunctivitis (-3.01+/-3.83 D vs-1.36+/-3.08 D, P<0.0001, and -2.64+/-3.63 D vs-1.05+/-2.88 D, P<0.0001, respectively), while there was no significant difference in any of the parameters between the contact lens wearers with and without allergic conjunctivitis. CONCLUSION: Refractive error may be a risk factor for allergic conjunctivitis.

Changes of vascular endothelial growth factor after vitrectomy for macular edema secondary to retinal vein occlusion.

PURPOSE: To examine whether vitrectomy combined with retinal photocoagulation reduces the vitreous level of vascular endothelial growth factor (VEGF) in patients with macular edema associated with retinal vein occlusion (RVO). METHODS: The authors measured VEGF levels in vitreous samples from four eyes of four patients with RVO during vitrectomy and fluid samples obtained during revitrectomy 3 to 9 months postoperatively for complications: an epiretinal membrane in two patients, macular holes in one patient, and vitreous hemorrhage in one patient. During vitrectomy, retinal photocoagulation was performed on the ischemic region of the retina in all cases (mean of 510 shots). RESULTS: In four eyes with RVO, there was a difference in the vitreous VEGF levels between the vitreous samples obtained during vitrectomy (mean of 2692 pg/mL, range of 15.6-9040 pg/mL) and the fluid samples obtained at the time of revitrectomy (mean of 947 pg/mL, range of 15.6-3430 pg/mL). CONCLUSIONS: The results suggest that the vitreous levels of VEGF may be reduced by vitrectomy combined with retinal photocoagulation for macular edema with RVO. It may be important to reduce the vitreous levels of VEGF by vitrectomy and retinal photocoagulation for ischemic retina in macular edema with RVO.

Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion.

AIM: To investigate whether the aqueous levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) are correlated to the vitreous levels of these substances and to the severity of macular oedema in branch retinal vein occlusion (BRVO). METHODS: Aqueous and vitreous samples were obtained during cataract and vitreous surgery from 24 patients (24 eyes) with macular oedema in BRVO. The VEGF and IL-6 levels in aqueous humour, vitreous fluid, and plasma were determined by enzyme-linked immunosorbent assay. The degree of retinal ischaemia was evaluated in terms of the area of capillary nonperfusion using the Scion Image. The severity of macular oedema was evaluated using the OCT. RESULTS: The aqueous level of VEGF was significantly correlated with the vitreous level of VEGF (P<0.0001). Vitreous levels of VEGF and IL-6 were significantly correlated with the nonperfusion area of BRVO (P<0.0001, P=0.0061, respectively), as were the aqueous levels of VEGF and IL-6 (P<0.0001, P=0.0267, respectively). Furthermore, the vitreous levels of VEGF and IL-6 and the aqueous level of VEGF were significantly correlated with the severity of macular oedema of BRVO (P=0.0001, P=0.0331, P=0.0272, respectively). CONCLUSION: Our results suggest that the aqueous level of VEGF may reflect its vitreous level. Measurement of the aqueous level of VEGF may be clinically useful to indicate the severity of macular oedema with BRVO.

Clinical significance of midkine expression in pancreatic head carcinoma.

Midkine (MK) is a heparin-binding growth factor and a product of a retinoic acid-responsive gene. Midkine is overexpressed in many carcinomas and thought to play an important role in carcinogenesis. However, no studies have been focussed on the role of MK in pancreatic carcinoma. This study sought to evaluate the clinical significance of MK expression in pancreatic head carcinoma, including the relationship between immunohistochemical expression and clinicopathologic factors such as prognosis. Immunohistochemical expression of MK and CD34 was evaluated in pancreatic head carcinoma specimens from 75 patients who underwent surgical resection. Midkine was expressed in 53.3% of patients. Midkine expression was significantly correlated with venous invasion, microvessel density, and liver metastasis (P=0.0063, 0.0025, and 0.0153, respectively). The 5-year survival rate was significantly lower for patients positive for MK vs patients negative for MK (P=0.0073). Multivariate analysis revealed that MK expression was an independent prognostic factor (P=0.0033). This is the first report of an association between MK expression and pancreatic head carcinoma. Midkine may play an important role in the progression of pancreatic head carcinoma, and evaluation of MK expression is useful for predicting malignant properties of pancreatic head carcinoma.

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer.

In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy x 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m(-2) day(-1) on days 1-7 and 15-21 (level 1), 1-14 (level 2), and 1-21 (level 3a) and 80 mg m(-2) day(-1) on days 1-21 (level 3b) and 1-28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19-9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m(-2) day(-1) given on days 1-21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

Risk evaluation of outcome of vitreous surgery based on vitreous levels of cytokines.

AIM: To ascertain whether vitreous and plasma levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) and fundus findings could predict the outcome of vitreous surgery in patients with proliferative diabetic retinopathy (PDR). METHODS: Vitreous fluid samples were obtained during vitreoretinal surgery from 73 consecutive eyes with PDR. The levels of VEGF and IL-6 in vitreous fluid and plasma were determined by enzyme-linked immunosorbent assay. Patients were prospectively followed for 6 months and the postoperative outcome was analysed by logistic regression analysis. RESULTS: No improvement and/or progression of PDR occurred in 23 (32%) of the 73 eyes (progression group). The vitreous levels of VEGF and IL-6 were significantly higher in eyes from the progression group than in eyes with regression of PDR (regression group) (P=0.0032 and 0.0088, respectively). Multivariate logistic regression analysis showed that higher vitreous levels of VEGF were associated with the progression of PDR after vitreous surgery (odds ratio 2.72, P=0.0003). CONCLUSIONS: High vitreous levels of VEGF identified as a significant risk factor for the outcome of vitreous surgery in patients with PDR. A model was developed to predict the probability of PDR progression and measurement of the vitreous level of VEGF may be useful for predicting the outcome of surgery.

Correlation between reduction of syndecan-1 expression and clinico-pathological parameters in squamous cell carcinoma of tongue.

We examined expression of syndecan-1 in squamous cell carcinoma (SCC) of tongue using immunohistochemistry. Forty-three cases of SCC arising in lateral border of tongue were investigated. From the immunohistochemical staining pattern, the cases were divided into two groups based on expression of syndecan-1 at the supra-peripheral cells of the tumor nest: Group A, completely or mainly positive; Group B, sporadically positive or negative. Most poorly differentiated SCC cases were classified into Group B (81.8%). The number of Group B cases in T1-2 was different from that in T3-4. The number of cases where syndecan-1 expression was reduced was much greater in T3-4, and represented the majority of Group B (86.7%). More than 80% of Grade 4D cases were in Group B (83.3%) based on the Yamamoto-Kohama criteria. These results indicate that reduction of syndecan-1 correlates to histological grade, tumor size and mode of invasion in tongue SCC.

A study of osteoclast-related cytokines in mandibular invasion by squamous cell carcinoma.

The purpose of this study was to analyze the mechanism of bone invasion in carcinoma of the mandibular gingiva. We investigated 38 specimens of lower gingival carcinoma and histopathologically classified them into an invasion group (23 cases) and a non-invasion group (15 cases) on the basis of light microscopy evidence. These specimens were examined using immunohistochemical techniques involving antibodies of parathyroid hormone-related protein (PTHrP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, -1beta, -6, -11, -18 and transforming growth factor (TGF)-beta. The invasion group showed a high level of expression of PTHrP, TNF-alpha, IL-6 and IL-11 positive cells (P<0.01 versus non-invasion group). The difference in the levels of expression of IL-1alpha, -1beta, -18 and TGF-beta positive cells was not significant between these two groups. Our results suggest that various cancer-derived cytokines, such as PTHrP, TNF-alpha, IL-6 and IL-11, play an important role in the mechanism of bone invasion associated with lower gingival squamous cell carcinoma.

Risk evaluation of outcome of vitreous surgery for proliferative diabetic retinopathy based on vitreous level of vascular endothelial growth factor and angiotensin II.

AIMS: To ascertain whether measurement of the vitreous fluid levels of vascular endothelial growth factor (VEGF) or angiotensin II (Ang II) could predict the outcome of vitreous surgery in patients with proliferative diabetic retinopathy (PDR). METHODS: A prospective observational case study was performed in 61 consecutive patients (61 eyes) with PDR who underwent vitreoretinal surgery. Vitreous fluid samples were obtained during surgery. The VEGF level in vitreous fluid and plasma was determined by enzyme linked immunosorbent assay, while the Ang II level was measured by radioimmunoassay. Patients were prospectively followed for 6 months and the postoperative outcome was analysed by logistic regression analysis. RESULTS: No improvement and/or progression of PDR was seen in 15 (25%) of the 61 eyes. Vitreous levels of VEGF and Ang II were significantly higher in eyes with progression of PDR than in eyes with regression of PDR (p = 0.0044, and p = 0.0178, respectively). Multivariate logistic regression analysis showed that the vitreous VEGF level increased along with the progression of PDR after vitreous surgery (odds ratio 2.48, p = 0.0008). CONCLUSION: A high vitreous fluid VEGF level is associated with a significant risk of postoperative progression of PDR. The vitreous level of VEGF at the time of surgery may be a useful predictor of the outcome.