Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial

Importance: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT.

Objective: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients.

Design, Setting, and Participants: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011.

Exposures: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry.

Main Outcomes and Measures: Failure-free survival (FFS) and overall survival.

Results: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]).

Conclusions and Relevance: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease.

Trial Registration: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

Effect of providing free glasses on children's educational outcomes in China: cluster randomized controlled trial

Objective: To assess the effect of provision of free glasses on academic performance in rural Chinese children with myopia. Design: Cluster randomized, investigator masked, controlled trial.Setting 252 primary schools in two prefectures in western China, 2012-13. Participants: 3177 of 19 934 children in fourth and fifth grades (mean age 10.5 years) with visual acuity <6/12 in either eye without glasses correctable to >6/12 with glasses. 3052 (96.0%) completed the study.Interventions Children were randomized by school (84 schools per arm) to one of three interventions at the beginning of the school year: prescription for glasses only (control group), vouchers for free glasses at a local facility, or free glasses provided in class. Main outcome measures: Spectacle wear at endline examination and end of year score on a specially designed mathematics test, adjusted for baseline score and expressed in standard deviations. Results: Among 3177 eligible children, 1036 (32.6%) were randomized to control, 988 (31.1%) to vouchers, and 1153 (36.3%) to free glasses in class. All eligible children would benefit from glasses, but only 15% wore them at baseline. At closeout glasses wear was 41% (observed) and 68% (self reported) in the free glasses group, and 26% (observed) and 37% (self reported) in the controls. Effect on test score was 0.11 SD (95% confidence interval 0.01 to 0.21) when the free glasses group was compared with the control group. The adjusted effect of providing free glasses (0.10, 0.002 to 0.19) was greater than parental education (0.03, −0.04 to 0.09) or family wealth (0.01, −0.06 to 0.08). This difference between groups was significant, but was smaller than the prespecified 0.20 SD difference that the study was powered to detect. Conclusions: The provision of free glasses to Chinese children with myopia improves children’s performance on mathematics testing to a statistically significant degree, despite imperfect compliance, although the observed difference between groups was smaller than the study was originally designed to detect. Myopia is common and rarely corrected in this setting. Trial Registration: Current Controlled Trials ISRCTN03252665.

Label-free human chorionic gonadotropin detection at picogram levels using oriented antibodies bound to graphene screen-printed electrodes

Human chorionic gonadotropin (hCG) is a key diagnostic marker of pregnancy and an important biomarker for cancers in the prostate, ovaries and bladder and therefore of great importance in diagnosis. For this purpose, a new immunosensor of screen-printed electrodes (SPEs) is presented here. The device was fabricated by introducing a polyaniline (PANI) conductive layer, via in situ electropolymerization of aniline, onto a screen-printed graphene support. The PANI-coated graphene acts as the working electrode of a three terminal electrochemical sensor. The working electrode is functionalised with anti-hCG, by means of a simple process that enabled oriented antibody binding to the PANI layer. The antibody was attached to PANI following activation of the –COOH group at the Fc terminal. Functionalisation of the electrode was analysed and optimized using Electrochemical Impedance Spectroscopy (EIS). Chemical modification of the surface was characterised using Fourier transform infrared, and Raman spectroscopy with confocal microscopy. The graphene–SPE–PANI devices displayed linear responses to hCG in EIS assays from 0.001 to 50 ng mL−1 in real urine, with a detection limit of 0.286 pg mL−1. High selectivity was observed with respect to the presence of the constituent components of urine (urea, creatinine, magnesium chloride, calcium chloride, sodium dihydrogen phosphate, ammonium chloride, potassium sulphate and sodium chloride) at their normal levels, with a negligible sensor response to these chemicals. Successful detection of hCG was also achieved in spiked samples of real urine from a pregnant woman. The immunosensor developed is a promising tool for point-of-care detection of hCG, due to its excellent detection capability, simplicity of fabrication, low-cost, high sensitivity and selectivity.

Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group.

BACKGROUND: Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined. METHODS: We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers. RESULTS: Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse. CONCLUSIONS: Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.

Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group.

BACKGROUND: There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). PATIENTS AND METHODS: Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. RESULTS: The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. CONCLUSION: As for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial setting.

On some Density Theorems in Number Theory and Group Theory

Gowers, dans son article sur les matrices quasi-aléatoires, étudie la question, posée par Babai et Sos, de l'existence d'une constante $c>0$ telle que tout groupe fini possède un sous-ensemble sans produit de taille supérieure ou égale a $c|G|$. En prouvant que, pour tout nombre premier $p$ assez grand, le groupe $PSL_2(\mathbb{F}_p)$ (d'ordre noté $n$) ne posséde aucun sous-ensemble sans produit de taille $c n^{8/9}$, il y répond par la négative. Nous allons considérer le probléme dans le cas des groupes compacts finis, et plus particuliérement des groupes profinis $SL_k(\mathbb{Z}_p)$ et $Sp_{2k}(\mathbb{Z}_p)$. La premiére partie de cette thése est dédiée à l'obtention de bornes inférieures et supérieures exponentielles pour la mesure suprémale des ensembles sans produit. La preuve nécessite d'établir préalablement une borne inférieure sur la dimension des représentations non-triviales des groupes finis $SL_k(\mathbb{Z}/(p^n\mathbb{Z}))$ et $Sp_{2k}(\mathbb{Z}/(p^n\mathbb{Z}))$. Notre théoréme prolonge le travail de Landazuri et Seitz, qui considérent le degré minimal des représentations pour les groupes de Chevalley sur les corps finis, tout en offrant une preuve plus simple que la leur. La seconde partie de la thése à trait à la théorie algébrique des nombres. Un polynome monogéne $f$ est un polynome unitaire irréductible à coefficients entiers qui endengre un corps de nombres monogéne. Pour un nombre premier $q$ donné, nous allons montrer, en utilisant le théoréme de densité de Tchebotariov, que la densité des nombres premiers $p$ tels que $t^q -p$ soit monogéne est supérieure ou égale à $(q-1)/q$. Nous allons également démontrer que, quand $q=3$, la densité des nombres premiers $p$ tels que $\mathbb{Q}(\sqrt[3]{p})$ soit non monogéne est supérieure ou égale à $1/9$.

Computation of locally free class groups

We show that the locally free class group of an order in a semisimple algebra over a number field is isomorphic to a certain ray class group. This description is then used to present an algorithm that computes the locally free class group. The algorithm is implemented in MAGMA for the case where the algebra is a group ring over the rational numbers.

Uptake of a free coronary heart disease risk screening programme in community pharmacy: the Healthy Heart Assessment service

Introduction Health promotion (HP) aims to enhance good health while preventing ill-health at three levels of activity; primary (preventative), secondary (diagnostic) and tertiary (management).1 It can range from simple provision of health education to ongoing support, but the effectiveness of HP is ultimately dependent on its ability to influence change. HP as part of the Community Pharmacy Contract (CPC) aims to increase public knowledge and target ‘hard-to-reach’ individuals by focusing mainly on primary and tertiary HP. The CPC does not include screening programmes (secondary HP) as a service. Coronary heart disease (CHD) is a significant cause of morbidity and mortality in the UK. While there is evidence to support the effectiveness of some community pharmacy HP strategies in CHD, there is paucity of research in relation to screening services.2 Against this background, Alliance Pharmacy introduced a free CHD risk screening programme to provide tailored HP advice as part of a participant–pharmacist consultation. The aim of this study is to report on the CHD risk levels of participants and to provide a qualitative indication of consultation outcomes. Methods Case records for 12 733 people who accessed a free CHD risk screening service between August 2004 and April 2006 offered at 217 community pharmacies were obtained. The service involved initial self-completion of the Healthy Heart Assessment (HHA) form and measurement of height, weight, body mass index, blood pressure, total cholesterol and highdensity lipoprotein levels by pharmacists to calculate CHD risk.3 Action taken by pharmacists (lifestyle advice, statin recommendation or general practitioner (GP) referral) and qualitative statements of advice were recorded, and a copy provided to the participants. The service did not include follow-up of participants. All participants consented to taking part in evaluations of the service. Ethical committee scrutiny was not required for this service development evaluation. Results Case records for 10 035 participants (3658 male) were evaluable; 5730 (57%) were at low CHD risk (<15%); 3636 (36%) at moderate-to-high CHD risk (≥15%); and 669 (7%) had existing heart disease. A significantly higher proportion of male (48% versus 30% female) participants were at moderate- to-high risk of CHD (chi-square test; P < 0.005). A range of outcomes resulted from consultations. Lifestyle advice was provided irrespective of participants’ CHD risk or existing disease. In the moderate-to-high-risk group, of which 52% received prescribed medication, lifestyle advice was recorded for 62%, 16% were referred and 34% were advised to have a re-assessment. Statin recommendations were made in 1% of all cases. There was evidence of supportive and motivational statements in the advice recorded. Discussion Pharmacists were able to identify individuals’ level of CHD risk and provide them with bespoke advice. Identification of at-risk participants did not automatically result in referrals or statin recommendation. One-third of those accessing the screening service had moderate-to-high risk of CHD, a significantly higher proportion of whom were men. It is not known whether these individuals had been previously exposed to HP but presumably by accessing this service they may have contemplated change. As effectiveness of HP advice will depend among other factors on ability to influence change, future consultations may need to explore patients’ attitude towards change in relation to the Trans Theoretical Model4 to better tailor HP advice. The high uptake of the service by those at moderate-to-high CHD risk indicates a need for this type of screening programme in community pharmacy, perhaps specifically to reach men who access medical services less.

Dry matter intake is decreased more by abomasal infusion of unsaturated free fatty acids than by unsaturated Triglycerides

Previous experiments from our group have demonstrated that abomasal infusion of unsaturated free fatty acids (FFA) markedly decreases dry matter intake (DMI) in dairy cows. In contrast, experiments from other groups have noted smaller decreases in DMI when unsaturated triglycerides (TG) were infused postruminally. Our hypothesis was that unsaturated FFA would be more potent inhibitors of DMI than an equivalent amount of unsaturated TG. Four Holstein cows in late lactation were used in a single reversal design. Cows were fed a total mixed ration containing (DM basis) 23% alfalfa silage, 23% corn silage, 40.3% ground shelled corn, and 10.5% soybean meal. Two cows received soy FFA (UFA; 0, 200, 400, 600 g/d) and 2 received soy oil (TG) in the same amounts; cows then were switched to the other lipid source. Cows were abomasally infused with each amount for 5-d periods. The daily amount of lipid was pulse-dosed in 4 equal portions at 0600, 1000, 1700, and 2200 h; no emulsifiers were used and there was no sign of digestive disturbance. Both lipid sources linearly decreased DMI, with a significant interaction between lipid source and amount. Slope-ratio analysis indicated that UFA were about 2 times more potent in decreasing DMI than were TG. Decreased DMI led to decreased milk production. Milk fat content was increased linearly by lipid infusion. Milk fat yield decreased markedly for UFA infusion but was relatively unaffected by infusion of TG. Contents of short- and medium-chain fatty acids in milk fat decreased as the amount of either infusate increased. Contents of C-18:2 and C18: 3 in milk fat were increased linearly by abomasal infusion of either fat source; cis-9 C-18:1 was unaffected. Transfer of infused C18: 2 to milk fat was 35.6, 42.5, and 27.8% for 200, 400, and 600 g/d of UFA, and 34.3, 39.6, and 34.0% for respective amounts of TG. Glucagon-like peptide-1 (7-36) amide (GLP-1) concentration in plasma significantly increased as DMI decreased with increasing infusion amount of UFA or TG. Plasma concentration of cholecystokinin-octapeptide (CCK-8) was unaffected by lipid infusion. These results indicate that unsaturated FFA reaching the duodenum are more potent inhibitors of DMI than are unsaturated TG; the effect may be at least partially mediated by GLP-1.

Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues

GP catalyzes the phosphorylation of glycogen to Glc-1-P. Because of its fundamental role in the metabolism of glycogen, GP has been the target for a systematic structure-assisted design of inhibitory compounds, which could be of value in the therapeutic treatment of type 2 diabetes mellitus. The most potent catalytic-site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan). In this work, we employ MD free energy simulations to calculate the relative binding affinities for GP of hydan and two spirohydantoin analogues, methyl-hydan and n-hydan, in which a hydrogen atom is replaced by a methyl- or amino group, respectively. The results are compared with the experimental relative affinities of these ligands, estimated by kinetic measurements of the ligand inhibition constants. The calculated binding affinity for methyl-hydan (relative to hydan) is 3.75 +/- 1.4 kcal/mol, in excellent agreement with the experimental value (3.6 +/- 0.2 kcal/mol). For n-hydan, the calculated value is 1.0 +/- 1.1 kcal/mol, somewhat smaller than the experimental result (2.3 +/- 0.1 kcal/mol). A free energy decomposition analysis shows that hydan makes optimum interactions with protein residues and specific water molecules in the catalytic site. In the other two ligands, structural perturbations of the active site by the additional methyl- or amino group reduce the corresponding binding affinities. The computed binding free energies are sensitive to the preference of a specific water molecule for two well-defined positions in the catalytic site. The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated. The results provide insights into the role of water molecules in modulating ligand binding affinities. A comparison of the interactions between a set of ligands and their surrounding groups in X-ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands. For the systems in this work, such an approach fails to estimate the order of relative binding strengths, in contrast to the rigorous free energy treatment.

Deficient acquisition and consolidation: intertrial free recall performance in Alzheimer's disease and mild cognitive impairment

Previous research demonstrates that dementia of the Alzheimer type (DAT) is characterised by deficits of episodic memory, especially in the acquisition of new material. As well as this deficit in acquisition, some researchers have also argued for a deficit in consolidation in DAT. We examined acquisition and consolidation by measuring the intertrial gained and lost access in DAT, Mild Cognitive Impairment (MCI) and controls. We report findings from a study of clinical data based on assessment of patients using three free recall trials of a word list. We found that both DAT and MCI groups showed a deficit in acquisition and consolidation of items between trials relative to controls. Moreover, the DAT group was significantly impaired relative to the MCI group for both acquisition and consolidation. Correlations within each group showed that there were strong relationships between intertrial measures and standard measures of memory function. Importantly in no group was there a significant correlation between our measures of acquisition and consolidation: we argue that these measures reflect different underlying processes, and the failure to consolidate in DAT and MCI is not related to the deficit in acquisition. Finally, we showed strong correlations between our measure and dementia severity, suggesting that acquisition and consolidation both get worse as the dementia progresses.

Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects

A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (>1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (<1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (<1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P<0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r=-0.57; P<0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.

Approaches to the synthesis of novel photoactive side chain liquid crystalline polymers containing analogues of the cinnamate ester group

A series of chain liquid crystalline copolymers of 4-cyanophenyl 4′-(6-methacryloyloxyhexyloxy)benzoate and 2-methacryloyloxyethyl β-(1-naphthyl)-propenoate were prepared by free radical polymerization. The corresponding polyacrylates could not be prepared in the same way and an alternative method was used for their preparation involving the synthesis of copolymers of the mesogenic monomer and 2-hydroxyethyl acrylate followed by treatment of the resulting polymers with β-(1-naphthyl)propenoyl chloride. The materials are of interest as photoactive liquid crystalline polymers. The effect of introducing a bulky nonmesogenic group into a liquid crystalline copolymer generally lowers the clearing temperature and raises Tg but also gives rise to contrasting phase behaviour in these two series of polymers. Polymethacrylates which show mesomorphism have sharp transitions and continue to exhibit a highly ordered smectic phase over the bulk of their liquid crystal range. Polyacrylates, on the other hand, exhibit a weakening and broadening-out of their thermal transitions consistent with a lowering of order. These results emphasize the effect of the polymer backbone on phase behaviour.

Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: abnormal salience circuitry and relations to positive emotionality

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n=25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject’s connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic-cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.