Treatment of a coronal shear injury of the trochlea using a modified hedgehog-based technique through an anterior neurovascular interval approach: A case report.

INTRODUCTION AND IMPORTANCE: Surgical treatment for dislocated trochlear shear injuries is recommended due to its articular nature. However, the surgical exposure is often limited and large cartilaginous fragments with lack of subchondral bone stock makes a stable fixation technically challenging. Rapid swelling of the traumatized cartilage induces a size misfit between the cartilage of the fragment and the defect site. The use of a "modified hedgehog"-based technique might be a solution in these cases. However, this technique has only been described in chondral shear lesions of the knee. CASE PRESENTATION: A fifteen-year-old boy fell out of the still rings during gymnastics at school and suffered trauma to his elbow. A CT-scan of the right elbow showed a coronal shear injury of the trochlea with accompanied lateral condyle fracture of the humerus. The patient was treated throughout an anterior neurovascular approach with a modified hedgehog-based technique with triple fixation by creating an interlocking match of the cartilage, application of fibrin glue and additional screw fixation. CLINICAL DISCUSSION: The anterior neurovascular interval approach provides a clear exposure of the fracture site which is useful for anatomic reduction and triple fixation. The subsequent modified hedgehog-based technique has only been described once in children with shear-off chondral fragments of the knee, without additional screw fixation. Adding a screw fixation of the fragment creates some collateral damage to the cartilage and might not be necessary in future cases. CONCLUSION: The anterior neurovascular approach seems elegant and provides adequate exposure. Furthermore, a modified hedgehog-based technique delivers a stable triple fixation of the osteochondral fragment.

Definitive chemoradiation or surgery in elderly patients with potentially curable esophageal cancer in the Netherlands: a nationwide population-based study on patterns of care and survival.

BACKGROUND: The aim of our study was to describe treatment patterns and the impact on overall survival among elderly patients (75 years and older) with potentially curable esophageal cancer. MATERIAL AND METHODS: Between 2003 and 2013, 13,244 patients from the nationwide population-based Netherlands Cancer Registry (NCR) were diagnosed with potentially curable esophageal cancer (cT2-3, X, any cN, cM0, X) of which 34% were elderly patients (n = 4501). RESULTS: Surgical treatment with or without neoadjuvant treatment remained stable among elderly patients (around the 16% between 2003 and 2013). However, among younger patients, surgical treatment increased from 60.2 to 67.0%. The use of definitive chemoradiation (dCRT) increased in elderly patients from 1.9 to 19.5% and in younger patients from 5.2 to 17.2%. Due to the increase in dCRT, treatment with curative intent doubled in the elderly from 17 to 37.1%. Multivariable Cox regression revealed that elderly patients with an adenocarcinoma receiving surgery alone or dCRT had a significantly worse overall survival compared to those receiving surgery with neoadjuvant chemo (radio) therapy (nCRT/CT) (HR: 1.7 95% CI 1.4-2.0 and HR: 1.9 95% CI 1.5-2.3). However, among elderly with squamous cell carcinoma overall survival was comparable between dCRT, surgery alone and surgery with nCRT/CT. CONCLUSIONS: Survival was comparable among elderly patients with squamous cell carcinoma who underwent surgery with nCRT/CT, surgery alone or received dCRT, while elderly patients with an adenocarcinoma who underwent surgery with nCRT/CT had a better overall survival when compared with surgery alone or dCRT. Therefore, dCRT can be considered as a reasonable alternative for surgery among potentially curable elderly patients with esophageal squamous cell carcinoma. However, in elderly patients with esophageal adenocarcinoma surgery with nCRT/CT is still preferable regarding overall survival.

[Hospital of diagnosis influences the probability of receiving curative treatment for oesophageal and gastric cancer]. / Ziekenhuis van diagnose beïnvloedt kans op curatieve behandeling voor slokdarm- en maagkanker.

OBJECTIVE: The aim of these studies was to examine the influence of hospital of diagnosis on the probability of receiving curative treatment and its impact on survival among oesophageal and gastric cancer. DESIGN: Although oesophageal and gastric cancer surgery is centralised in the Netherlands, the disease is often diagnosed in hospitals that do not perform this procedure. METHOD: Patients with potentially curable oesophageal or gastric cancer tumours diagnosed between 2005 and 2013 were selected from the Netherlands Cancer Registry. The probability to undergo curative treatment was examined for each hospital of diagnosis after adjustment for case-mix. Effects of variation in probability of undergoing curative treatment among these hospitals on survival were investigated Cox regression. RESULTS: All 13,017 patients with potentially curable oesophageal and 5,620 patients with potentially curable gastric cancer, diagnosed in 91 hospitals, were included. After adjustment, the proportion of oesophageal cancer patients receiving curative treatment ranged from 50% to 82% and from 48% to 78% for patients with gastric cancer in 2010-2013, depending on hospital of diagnosis (both P < 0.001). Furthermore, patients diagnosed in hospitals with a low probability of undergoing curative treatment had a worse overall survival in the period 2010-2013 (oesophageal cancer hazard ratio (HR): 1,15; 95%-CI: 1,07-1,24; gastric cancer HR: 1,21; 95%-CI: 1,04-1,41). CONCLUSION: The variation in probability of undergoing potentially curative treatment for oesophageal and gastric cancer between hospitals of diagnosis and its impact on survival indicates that treatment decision-making for these patients may be improved. Regional expert multidisciplinary team meetings in this field may improve the selection of patients for curative treatment.

Influence of the Extent and Dose of Radiation on Complications After Neoadjuvant Chemoradiation and Subsequent Esophagectomy With Gastric Tube Reconstruction With a Cervical Anastomosis.

PURPOSE: To determine, in a large series, the influence of the extent and dose of radiation to the fundus of the stomach and mediastinum on the development and severity of anastomotic complications in patients with esophageal cancer treated with neoadjuvant chemoradiation followed by esophagectomy with cervical anastomosis. METHODS AND MATERIALS: Between 2005 and 2012, 364 consecutive patients with esophageal cancer treated with neoadjuvant chemoradiation (41.4 Gy combined with chemotherapy) followed by esophagectomy were included. The future anastomotic region in the fundus was determined, and the mean dose, V20-V40, and upper planning target volume border in relation to mediastinal length, expressed as the mediastinal ratio, were calculated. RESULTS: Anastomotic leakage occurred in 22% and anastomotic stenosis in 41%. Logistic regression analysis revealed no influence of age, comorbidity, mean fundus dose, V20-V40, or the mediastinal ratio on the incidence of anastomotic leakage or anastomotic stenosis. In 28% of the patients severe complications (Clavien-Dindo score of ≥IIIB) occurred. The presence of multiple comorbidities (hazard ratio 2.4 [95% confidence interval 1.3-4.5], P=.006) and a mediastinal ratio of 0.5 to 1.0 (hazard ratio 1.9 [95% confidence interval 1.0-3.5], P=.036) were both independent predictors of severe complications. CONCLUSION: With a mean radiation dose of 24.2 Gy to the future anastomotic region of the gastric fundus, the radiation dose was not associated with the incidence of anastomotic leakage or anastomotic stenosis. The incidence of severe complications was associated with a high superior mediastinal planning target volume border.

Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.

BACKGROUND: A better understanding of factors underlying antidepressant non-response may improve the prediction of which patients will respond to what treatment. Major depressive disorder (MDD) is associated with alterations in fatty acid metabolism, (neuro)inflammation and amygdala-reactivity. However, their mutual relations, and the extent to which they are associated with prospective antidepressant-response, remain unknown. PURPOSE: To test (I) alterations in (neuro)inflammation and its associations with fatty acid metabolism and amygdala-reactivity in MDD-patients compared to controls, and (II) whether these alterations are associated with prospective paroxetine response. METHODS: We compared 70 unmedicated MDD-patients with 51 matched healthy controls at baseline, regarding erythrocyte membrane omega-6 arachidonic acid (AA), inflammation [serum (high-sensitivity) C-reactive protein (CRP)], and in a subgroup amygdala-reactivity to emotional faces using functional magnetic resonance imaging (fMRI) (N=42). Subsequently, we treated patients with 12 weeks paroxetine, and repeated baseline measures after 6 and 12 weeks to compare non-responders, early-responders (response at 6 weeks), and late-responders (response at 12 weeks). RESULTS: Compared to controls, MDD-patients showed higher CRP (p=0.016) and AA (p=0.019) after adjustment for confounders at baseline. AA and CRP were mutually correlated (p=0.043). In addition, patients showed a more negative relation between AA and left amygdala-reactivity (p=0.014). Moreover, AA and CRP were associated with antidepressant-response: early responders showed lower AA (p=0.018) and higher CRP-concentrations (p=0.008) than non-responders throughout the study. CONCLUSION: Higher observed CRP and AA, their mutual association, and relation with amygdala-reactivity, are corroborative with a role for (neuro)inflammation in MDD. In addition, observed associations of these factors with prospective antidepressant-response suggest a potential role as biomarkers. Future studies in independent samples are needed to replicate and test the clinical applicability of these biological predictors for treatment response to result in a precision/personalized medicine approach for treatment.

Delaying surgery after neoadjuvant chemoradiotherapy does not significantly influence postoperative morbidity or oncological outcome in patients with oesophageal adenocarcinoma.

BACKGROUND: Patients with resectable oesophageal cancer are treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery within 3-8 weeks. In practice, surgery is often delayed for various reasons. The aim of this study was to evaluate whether delaying surgery beyond 8 weeks has an effect on postoperative morbidity, long-term survival, and pathologic response in patients treated for oesophageal ADC. METHODS: Patients who underwent nCRT followed by surgery, for cT1-3, N0-3, M0 ADC between 2001 and 2014 were retrospectively included from a prospectively obtained database. Patients with a time from the end of nCRT to surgery (TTS) ≤8 weeks were compared with patients with a TTS >8 weeks. RESULTS: Of 190 patients, 65 had a TTS ≤8 weeks, and 125 had a TTS >8 weeks. Patient characteristics were comparable for both groups, but patients with TTS >8 weeks exhibited higher ASA scores (p = 0.013) and more comorbidities (p = 0.007). Multivariate analysis revealed that TTS did not significantly influence postoperative morbidity, pathologic complete response rates, and five-year survival rates (42% in patients with TTS ≤8 weeks and 37% in patients with TTS >8 weeks). CONCLUSIONS: Delaying surgery beyond 8 weeks after nCRT did not significantly influence postoperative morbidity, pathologic response, and survival in patients with non-metastatic ADC. Therefore, it appears reasonable to postpone surgery beyond 8 weeks in patients who have not yet recovered from nCRT. However, if the patient is fit for surgery, postponing surgery does not have any additional advantages.

Visuospatial planning in unmedicated major depressive disorder and bipolar disorder: distinct and common neural correlates.

BACKGROUND: Cognitive impairments are an important feature of both remitted and depressed major depressive disorder (MDD) and bipolar disorder (BD). In particular, deficits in executive functioning may hamper everyday functioning. Identifying the neural substrates of impaired executive functioning would improve our understanding of the pathophysiology underlying these disorders, and may eventually aid in discriminating between MDD and BD, which is often difficult during depression and remission. To date, mostly medicated MDD and BD subjects have been investigated, which may have influenced results. Therefore, we investigated executive functioning in medication-free depressed and remitted MDD and BD subjects. METHOD: We used the Tower of London (ToL) visuospatial planning task to assess behavioural performance and blood oxygen-level dependent responses in 35 healthy controls, 21 remitted MDD, 23 remitted BD, 19 depressed MDD and nine depressed BD subjects. RESULTS: Visuospatial planning per se was associated with increased frontostriatal activity in depressed BD compared to depressed MDD. In addition, post-hoc analyses indicated that visuospatial planning load was associated with increased parietal activity in depressed compared to remitted subjects, and BD compared to MDD subjects. Task performance did not significantly differ between groups. CONCLUSIONS: More severely affected, medication-free mood disorder patients require greater parietal activity to perform in visuospatial planning, which may be compensatory to maintain relatively normal performance. State-dependent frontostriatal hyperactivity during planning may be a specific BD characteristic, providing clues for further characterization of differential pathophysiology in MDD v. BD. This could potentially provide a biomarker to aid in the differentiation of these disorders.

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (ß=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (ß=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (ß=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

[Working effectively towards rehabilitation goals: long-term outcome of a randomised controlled trial of the Boston psychiatric rehabilitation approach]. / Effectiever werken aan rehabilitatiedoelen: langetermijnuitkomsten van een gerandomiseerde studie naar individuele rehabilitatiebenadering.

BACKGROUND: In the Netherlands the Boston psychiatric rehabilitation approach (bpr) is one of the most widely implemented rehabilitation methods. So far, little research has been done on the efficacy of this approach. AIM: To investigate the effect of bpr on the attainment of personal rehabilitation goals, social functioning and empowerment and on care requirements and quality of life in persons with severe mental illness (smi) in the Netherlands. METHOD: In a multicentre randomised controlled trial (rct: CLINICAL TRIAL REGISTRATION NUMBER: isrctn73683215) patients with smi were randomly assigned to bpr (n = 80) or 'care as usual' (cau; n = 76). The primary outcome was the attainment of the rehabilitation goal as formulated by the patient. The secondary outcomes were a change in the work situation and in the degree of independent living, in care requirements (Camberwell Assessment of Needs), in empowerment (Personal Empowerment Scale) and in the quality of life (who-qol). The effects were tested at 12 and 24 months. RESULTS: The degree of goal attainment was substantially higher in bpr at both 12 months (adjusted risk difference: 16%; 95%ci, 2 to 31; nnt = 7) and 24 months (adjusted risk difference: 21%, 95%ci, 4% to 38%; nnt = 5). The approach was also more effective in the area of societal participation (bpr: 21% adjusted increase, cau: 0% adjusted increase; nnt = 5), but not in the other secondary outcome measures. CONCLUSION: The results suggest that bpr is effective in supporting patients with smi to reach self-formulated rehabilitation goals and in enhancing their societal participation.

Determinants in decision making for curative treatment and survival in patients with resectable oesophageal cancer in the Netherlands: a population-based study.

BACKGROUND: Preferred treatment for resectable oesophageal cancer is surgery with or without neoadjuvant treatment. However, oesophageal surgery has high morbidity and in vulnerable patients with co-morbidity other treatment modalities can be proposed. We examined determinants in decision making for surgery and factors affecting survival in patients with resectable oesophageal cancer in southern Netherlands. METHODS: All patients with resectable (T1-3, N0-1, M0-1A) oesophageal cancer (n=849) diagnosed between 2003 and 2010 were selected from the population-based data of the Eindhoven Cancer Registry. Logistic regression analysis and multivariable Cox survival analysis were conducted to examine determinants of surgery and survival. RESULTS: Forty-five percent of the patients underwent surgery. In multivariable survival analysis only surgery, chemoradiation alone and tumour stage influenced overall survival (OS). Patients aged ≥ 70 yrs, a low socioeconomic status (SES), one or more co-morbidities, cT1-tumours, cN1-tumours, a squamous-cell carcinoma, and those with a proximal tumour were significantly less often offered surgical resection. Older patients and patients with cT1 tumours were less likely to receive chemoradiation alone. Patients with clinically positive lymph nodes or a proximal tumour were more likely to receive chemoradiation alone. CONCLUSION: Treatment modalities including surgery and chemoradiation alone as well as stage of disease were independent predictors of a better OS in patients with potentially resectable oesophageal cancer. Therefore, the decision to perform potentially curative treatment is of crucial importance to improve OS for patients with potentially resectable oesophageal cancer. Although age and SES had no significant influence on overall survival, a higher age and low SES negatively influenced the probability to propose potentially curative treatment.

Net gain analysis, an addition to responder analysis--The case of antipsychotic treatment of acute mania.

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA.

DHEAS and cortisol/DHEAS-ratio in recurrent depression: State, or trait predicting 10-year recurrence?

BACKGROUND: Major depressive disorder (MDD) has been associated with low dehydroepiandrosterone-sulphate (DHEAS), - particularly relative to high cortisol - although conflicting findings exist. Moreover, it is unclear whether low DHEAS is only present during the depressive state, or manifests as a trait that may reflect vulnerability for recurrence. Therefore, we longitudinally tested whether low DHEAS and high cortisol/DHEAS-ratio in recurrent MDD (I) reflects a trait, and/or (II) varies with depressive state. In addition, we tested associations with (III) previous MDD-episodes, (IV) prospective recurrence, and (V) effects of cognitive therapy. METHODS: At study-entry, we cross-sectionally compared morning and evening salivary DHEAS and molar cortisol/DHEAS-ratio of 187 remitted recurrent MDD-patients with 72 matched controls. Subsequently, patients participated in an 8-week randomized controlled cognitive therapy trial. We repeated salivary measures after 3 months and 2 years. We measured clinical symptoms during a 10-year follow-up. RESULTS: Remitted patients showed steeper diurnal DHEAS-decline (p<.005) and a flatter diurnal profile of cortisol/DHEAS-ratio (p<.001) than controls. We found no state-effect in DHEAS or cortisol/DHEAS-ratio throughout follow-up and no association with number of previous episodes. Higher morning cortisol/DHEAS-ratio predicted shorter time till recurrence over the 10-year follow-up in interaction with the effects of cognitive therapy (p<.05). Finally, cognitive therapy did not influence DHEAS or cortisol/DHEAS-ratio. CONCLUSIONS: Diurnal profiles of DHEAS and cortisol/DHEAS-ratio remain equally altered in between depressive episodes, and may predict future recurrence. This suggests they represent an endophenotypic vulnerability trait rather than a state-effect, which provides a new road to understand recurrent depression and its prevention. TRIAL REGISTRATION: www.isrctn.com/ISRCTN68246470.

Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies.

Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062-0.344; odds ratio (OR) 1.406, 95% CI 0.998-1.980) than in Europe (g = 0.476, 95% CI 0.200-0.672; OR 2.380, 95% CI 1.682-3.368) or other regions (g = 0.533, 95% CI 0.399-0.667; OR 2.300, 95% CI 1.800-2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions.

Motivational interviewing and interaction skills training for parents of young adults with recent-onset schizophrenia and co-occurring cannabis use: 15-month follow-up.

BACKGROUND: There is a clear need for effective interventions to reduce cannabis use in patients with first-episode psychosis. This follow-up of a randomized trial examined whether an intervention for parents, based on motivational interviewing and interaction skills (Family Motivational Intervention, FMI), was more effective than routine family support (RFS) in reducing cannabis use in patients with recent-onset schizophrenia. METHOD: In a single-blind trial with 75 patients in treatment for recent-onset schizophrenia, 97 parents were randomly assigned to either FMI or RFS. Assessments were conducted at baseline and at 3 and 15 months after the interventions had been ended. Analyses were performed on an intention-to-treat basis using mixed-effect regression models. RESULTS: From baseline to the 15-month follow-up, there was a significantly greater reduction in FMI compared to RFS in patients' quantity (p = 0.01) and frequency (p < 0.01) of cannabis use. Patients' craving for cannabis use was also significantly lower in FMI at 15 months follow-up (p < 0.01). Both groups improved in parental distress and sense of burden; however, only FMI parents' appraisal of patients' symptoms showed further improvement at the 15-month follow-up (p < 0.05). CONCLUSIONS: The results support the sustained effectiveness of FMI in reducing cannabis use in patients with recent-onset schizophrenia at 15 months follow-up. Findings were not consistent with regard to the long-term superiority of FMI over RFS in reducing parents' distress and sense of burden.

Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis.

We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥ 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. METHOD: A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. RESULTS: A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. CONCLUSION: These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.

Adapted cognitive-behavioural therapy required for targeting negative symptoms in schizophrenia: meta-analysis and meta-regression.

BACKGROUND: There is an increasing interest in cognitive-behavioural therapy (CBT) interventions targeting negative symptoms in schizophrenia. To date, CBT trials primarily focused on positive symptoms and investigated change in negative symptoms only as a secondary outcome. To enhance insight into factors contributing to improvement of negative symptoms, and to identify subgroups of patients that may benefit most from CBT directed at ameliorating negative symptoms, we reviewed all available evidence on these outcomes. METHOD: A systematic search of the literature was conducted in PsychInfo, PubMed and the Cochrane register to identify randomized controlled trials reporting on the impact of CBT interventions on negative symptoms in schizophrenia. Random-effects meta-analyses were performed on end-of-treatment, short-term and long-term changes in negative symptoms. RESULTS: A total of 35 publications covering 30 trials in 2312 patients, published between 1993 and 2013, were included. Our results showed studies' pooled effect on symptom alleviation to be small [Hedges' g = 0.093, 95% confidence interval (CI) -0.028 to 0.214, p = 0.130] and heterogeneous (Q = 73.067, degrees of freedom = 29, p < 0.001, τ 2 = 0.081, I 2 = 60.31) in studies with negative symptoms as a secondary outcome. Similar results were found for studies focused on negative symptom reduction (Hedges' g = 0.157, 95% CI -0.10 to 0.409, p = 0.225). Meta-regression revealed that stronger treatment effects were associated with earlier year of publication, lower study quality and with CBT provided individually (as compared with group-based). CONCLUSIONS: The co-occurring beneficial effect of conventional CBT on negative symptoms found in older studies was not supported by more recent studies. It is now necessary to further disentangle effective treatment ingredients of older studies in order to guide the development of future CBT interventions aimed at negative symptom reduction.

The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state?

BACKGROUND: An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD. METHODS: We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). RESULTS: First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=-2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components. CONCLUSIONS: Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population.

Hospital of diagnosis and probability to receive a curative treatment for oesophageal cancer.

BACKGROUND: Surgical treatment of oesophageal cancer in the Netherland is performed in high volume centres. However, the decision to refer patients for curative surgery is made in the referring hospital of diagnosis. The objective of this study was to determine the influence of hospital of diagnosis on the probability of receiving a curative treatment and survival. MATERIAL AND METHOD: All patients with resectable oesophageal cancer (cT1-3, cN0-3, cM0-1A) diagnosed between 2003 and 2010 (n = 849) were selected from the population-based Eindhoven Cancer Registry, an area with ten non-academic hospitals. Multivariate logistic regression analysis was conducted to examine the independent influence of hospital of diagnosis on the probability to receive curative treatment. Furthermore, the effect of hospital of diagnosis on overall survival was examined using multivariate Cox regression analysis. RESULTS: 849 patients were included in the study. A difference in proportion of patients referred for surgery was observed ranging from 33% to 67% (p = 0.002) between hospitals of diagnosis. Multivariate logistic regression analysis confirmed the effect of hospital of diagnosis on the chance of undergo curative treatment (OR 0.1, 95% CI 0.1-0.4). Multivariate Cox regression analysis showed that hospital of diagnosis also had an effect on overall survival, up to hazard ratio (HR) 2.2 (95% CI 1.3-3.7). CONCLUSION: There is a strong relation between hospital of diagnosis and the chance of referring patients with oesophageal cancer for a curative treatment as well as overall survival. Patients diagnosed with oesophageal cancer should be discussed within a regional multidisciplinary expert panel.

The impact of non-adherence to medication in patients with schizophrenia on health, social care and societal costs. Analysis of the QUATRO study.

Aims. For people with schizophrenia, non-adherence to antipsychotic medications may result in high use of health and other services. The objective of our research was to examine the economic consequences of non-adherence in patients with schizophrenia taking antipsychotic medication. Methods. Data were taken from QUATRO, a randomized controlled trial that drew a sample of adults with schizophrenia receiving psychiatric services in four European cities: Amsterdam, Leipzig, London and Verona. Trial inclusion criteria were a clinical diagnosis of schizophrenia, requiring on-going antipsychotic medication for at least 1-year following baseline assessment, and exhibiting evidence of clinical instability in the year prior to baseline. The patient-completed Medication Adherence Questionnaire (MAQ) was used to calculate the 5-point Morisky index of adherence. Generalized linear models (GLM) were developed to determine the effect of adherence on (i) health and social care and (ii) societal costs before and after treatment, taking into account other potential cost-influencing factors. Results. The effect of non-adherence on costs was mixed. For different groups of services, and according to treatment group assignment, non-adherence was both negatively and positively associated with costs. Conclusions. The impact of non-adherence on costs varies across the types of services used by individuals with schizophrenia.