An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

A brain model of altered self-appraisal in social anxiety disorder.

The brain's default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, particularly social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modeling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, SAD participants exhibited reduced intrinsic connectivity in the absence of task modulation. This was illustrated by reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD.

High Incidence of Soft Tissue Injury in Pediatric Proximal Tibia Fractures: A Systematic Review.

Purpose: The purpose of this study was to describe the incidence of soft tissue injuries associated with pediatric proximal tibial fractures (PPTF) and the frequency that magnetic resonance imaging (MRI) was used before surgery in this patient population. Methods: A systematic review of English literature, using EMBASE and PubMed, was completed. Articles reporting on soft tissue injury in PPTFs between 1980 and 2021 were identified. Associated pathology (meniscal tear, meniscal entrapment, cruciate ligament injury, extensor mechanism injury, and chondral injury) and use of MRI at time of diagnosis, were assessed in these studies. Twenty-three articles were included. Results: Extraction of data revealed 1046 patients and 1057 fractures, with a mean age of 12.3 ± 1.7 at the time of injury. Most patients were male (n = 757 [72.3%]). Most fractures were tibial eminence fractures (TEF) (n = 747 [70.7%]), followed by tibial tubercle (n = 218 [20.6%]) and then tibial plateau fractures (n = 92 [8.7%]). Associated soft tissue injuries were found in 58.8% (n = 621) of fractures overall. Meniscal entrapment was the most common, occurring in 22.1% (n = 234) of cases. Meniscal tears occurred in 18.6% of cases (n = 197), followed by ligament injury in 9.4% (n = 99), chondral injury in 6.5% (n = 69), and extensor mechanism injury in 2.1% (n = 22) of cases. All cases of tendinous extensor mechanism injury were seen in tibial tubercle fractures, with 22 injuries occurring in 10.1% of tibial tubercle fractures. At time of injury just 24.3% (n = 257) of fractures had an MRI performed before surgery. Conclusions: PPTFs are associated with a high incidence of associated injury (58.8%), particularly in TEFs (63.5%) and TPFs (100%). Level of Evidence: Systematic Review of Level III-IV studies.

RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming.

OPINION STATEMENT: Since the discovery of oncogenes in the 1970s, cancer doctors and researchers alike have understood the promise of discovering drugs to block the dominantly acting function of mutated signaling proteins in cancer. This promise was delivered, first slowly, with early signals inhibiting HER2 and BCR-Abl in the 1990s and 2000s, and then quickly, with kinase inhibitors being approved hand over fist in non-small cell lung cancer, melanoma, and many other malignancies. The RAS proteins, however, remained recalcitrant to chemical inhibition for decades, despite being, by far, the most frequently mutated oncogenes in cancers of all types. Nowhere was this deficit more palpable than in pancreatic ductal adenocarcinoma (PDA), where > 90% of cases are driven by single nucleotide substitutions at a single codon of the KRAS gene. The ice began to crack in 2012 when Ostrem and colleagues (Nature 503(7477): 548-551, 2013) synthesized the first KRAS G12C inhibitors, which covalently bind to GDP-bound G12C-mutated KRAS and lock the oncoprotein in its inactive state. In the last decade, the scientific community has established a new foundation on this and other druggable pockets in mutant KRAS. Here we provide an up-to-date overview of drugs targeting KRAS and other molecular targets in pancreatic cancer.

A New Podcast for Reducing Stigma Against People Living With Complex Mental Health Issues: Co-design Study.

BACKGROUND: Mental illness stigma refers to damaging stereotypes and emotional responses around the experience of mental health issues. Media-based interventions have the potential to reduce the public's stigmatizing attitudes by improving mental health literacy, emotional appeal, and the intimacy of address. As audio-based media facilitating storytelling, podcasts show potential for reducing stigma; however, it is unclear what features could make a podcast effective or engaging. OBJECTIVE: The Co-Design and Anti-Stigma Podcast Research (CASPR) study aimed to collaborate with key target audience members to inform the development of a new podcast. This podcast primarily aims to reduce listeners' stigmatizing attitudes toward people living with complex mental health issues. METHODS: This study was adapted from Experience-Based Co-Design methodology. The first part, information gathering, involved a web-based mixed methods survey with 629 Australian podcast listeners to explore their interest and concerns around podcasts. Then, a series of focus groups were held with a purposive sample of 25 participants to explore the potential benefits and challenges of the podcast format. Focus group participants included people with lived experience of complex mental health issues, media and communications professionals, health care professionals, and people interested in workplace mental health. The second part, co-design, constituted 3 meetings of a co-design committee with 10 participants drawn from the focus groups to design the podcast using brainstorming and decision-making activities. RESULTS: Most survey respondents (537/629, 85.3%) indicated a willingness to listen to a podcast about experiences of mental illness stigma; participants indicated preference for semistructured episodes and a mixture of light and serious content. Focus group participants identified potential challenges with appealing to listeners, making the content emotionally resonant and engaging, and translation to listeners' attitude change. The co-design committee collaborated to achieve consensus on the focus of individual episodes: domains where stigma and discrimination are common, such as workplaces and health care settings; the structure of individual episodes: storyboards that centralize guests with lived experience, featuring explicit discussions around stigma and discrimination; and overarching content principles, including a sincere, empathetic, and hopeful tone; using plain language; having clear calls to action; and providing listener resources. CONCLUSIONS: The co-design process informed a podcast design that features lived experience narratives with an explicit focus on stigma and discrimination, highlighting the realities of stigma while acknowledging progress in the space and how listeners can contribute toward social change. This study allowed for an in-depth discussion around the strengths and limitations of such a podcast according to different target audience members. The co-design committee designed key elements of a podcast that has the potential to minimize the limitations of the format while embracing the benefits of podcast-based storytelling. Once produced, the podcast will be evaluated for its impact on attitude change.

Childhood trauma is prevalent and associated with co-occurring depression, anxiety, mania and psychosis in young people attending Australian youth mental health services.

OBJECTIVES: Childhood trauma is common and associated with mental ill health. While high rates of trauma are observed across individual disorders, there is evidence that trauma is associated with an admixture of affective, anxiety and psychotic symptoms in adults. Given that early onset of mental disorder and trauma exposure herald poor outcomes, it is important to examine trauma prevalence rates in youth mental health services and to determine whether this trauma-related clustering is present in help-seeking young people. METHODS: We used data from the Transitions Study, a longitudinal investigation of young people attending headspace youth mental health services in Australia between January 2011 and August 2012. Participants were 775 young people aged 12-25. Childhood trauma was assessed using the Childhood Trauma Questionnaire. Multinomial regression was used to assess whether reported childhood trauma was more strongly associated with the co-occurrence of depression, anxiety, mania and psychosis symptoms than with any one in isolation. RESULTS: Approximately 84% of participants reported some form of abuse (emotional: 68%; physical: 32%; sexual: 22%) or neglect (emotional: 65%; physical: 46%). Exposure to multiple trauma types was common. Childhood trauma was significantly associated with each symptom domain. More severe childhood trauma was more strongly associated with the co-occurrence of symptoms than with any one symptom domain in isolation, such that more severely trauma-exposed young people were more likely to experience increased symptom clustering. CONCLUSIONS: Childhood trauma is pervasive in youth mental health services and associated with a symptom profile that cuts across traditional diagnostic boundaries.

Lessons learned: the first consecutive 1000 patients of the CCCMunichLMU Molecular Tumor Board.

PURPOSE: In 2016, the University of Munich Molecular Tumor Board (MTB) was implemented to initiate a precision oncology program. This review of cases was conducted to assess clinical implications and functionality of the program, to identify current limitations and to inform future directions of these efforts. METHODS: Charts, molecular profiles, and tumor board decisions of the first 1000 consecutive cases (01/2016-03/2020) were reviewed. Descriptive statistics were applied to describe relevant findings. RESULTS: Of the first 1000 patients presented to the MTB; 914 patients received comprehensive genomic profiling. Median age of patients was 56 years and 58% were female. The most prevalent diagnoses were breast (16%) and colorectal cancer (10%). Different types of targeted or genome-wide sequencing assays were used; most of them offered by the local department of pathology. Testing was technically successful in 88%. In 41% of cases, a genomic alteration triggered a therapeutic recommendation. The fraction of patients receiving a tumor board recommendation differed significantly between malignancies ranging from over 50% in breast or biliary tract to less than 30% in pancreatic cancers. Based on a retrospective chart review, 17% of patients with an MTB recommendation received appropriate treatment. CONCLUSION: Based on these retrospective analyses, patients with certain malignancies (breast and biliary tract cancer) tend to be more likely to have actionable variants. The low rate of therapeutic implementation (17% of patients receiving a tumor board recommendation) underscores the importance of meticulous follow-up for these patients and ensuring broad access to innovative therapies for patients receiving molecular tumor profiling.

Barriers to young people seeking help for trauma: A qualitative analysis of Internet forums.

OBJECTIVE: Exposure to trauma is common in childhood and adolescence and is associated with significant psychopathology. Despite being amenable to treatment, many young people suffering trauma-related distress do not disclose or seek help. Multiple barriers to young people help seeking for mental health concerns have been identified, but very little research has focused on help seeking after trauma exposure. We undertook a qualitative analysis of Internet forums in which young people discuss trauma, aiming to understand the barriers preventing them from disclosing and seeking help offline. METHOD: Posts about trauma written in 2016 from five Internet forums targeting young people were analyzed by thematic analysis. RESULTS: Barriers to offline help-seeking for trauma aligned with five key themes: questioning the validity of the trauma response; negative emotions and beliefs about the self; fear of a negative response; difficulties trusting others; and not thinking or talking about the trauma. CONCLUSIONS: Young people conceptualized many barriers as consequences of the trauma, such as avoidance of the trauma memory, and difficulties trusting others, indicating there are trauma-specific barriers to help-seeking. Understanding of, and attempts to minimize, these barriers may facilitate provision of services to vulnerable young people. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders.

BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.

The specific phenotype of depression in recent onset schizophrenia spectrum disorders: A symptom profile and network comparison to recent onset major depressive disorder without psychotic features.

The specific phenotype of depression in recent-onset schizophrenia spectrum disorders (SSD) and its relation to non-psychotic depression is unknown. Symptom profile and network analysis are complementary statistical techniques that may provide important insights into the presentation and relative importance of individual symptoms that give rise to depression. The aim of the current study was to characterise the profile and network of depressive symptoms in SSD and compare it to individuals with major depressive disorder (MDD) without psychotic features. This study involved analysis of baseline data pertaining to 109 individuals with comorbid SSD and depression and 283 with MDD without psychotic features. Study cohorts were the Psychosis Recent Onset GRoningen Survey (PROGR-S) and Youth Depression Alleviation (YoDA) trials, respectively. Profile and network analyses revealed that SSD and MDD differed in the profile and relative importance of individual depressive symptoms. While reported sadness was the primary hallmark of depression in both SSD and MDD, individuals with depression in SSD were more likely to sleep more, and have lower lassitude and pessimism. While sadness had great importance in MDD and SSD, in SSD but not MDD lassitude, sleep, appetite, concentration difficulties, and inability to feel were important in the network of depressive symptoms. The specific phenotype of depression might be different in SSD compared to MDD. Symptom inequivalence or underlying functional mechanisms in SSD might result in depression in SSD that is similar to MDD with atypical features.

Does prediction error during exposure relate to clinical outcomes in cognitive behavior therapy for social anxiety disorder? A study protocol.

Facing your fears, or exposure therapy, is an effective psychological intervention for anxiety disorders that is often thought to work through fear extinction learning. Fear extinction learning is a type of associative learning where fear reduces through repeated encounters with a feared situation or stimulus in the absence of aversive outcomes. Laboratory research suggests fear extinction learning is driven by threat prediction errors, defined as when fearful predictions do not eventuate. Threat prediction error and its relationship to exposure therapy outcomes haven't been studied enough in actual therapy settings. It remains unclear whether prediction error and extinction learning are central mechanisms of exposure therapy. We are conducting a longitudinal and observational study of how threat prediction error during exposure in social anxiety disorder (SAD) treatment relates to session-by-session symptom change and treatment outcome in addition to exposure surprise and learning outcome. We aim to recruit 65 adults with a primary diagnosis of SAD through an outpatient psychology clinic. Participants will receive 12 sessions of individual manualized cognitive behavioral therapy (CBT), adapted from an efficacious group protocol, that includes graded exposure. Exposure processes, including self-report measures of anxiety, threat prediction, threat outcomes, surprise, and learning outcome, will be measured with smartphone-based event-contingent ecological momentary assessments (EMAs) of all behavioral experiments completed during treatment. Clinical outcomes include self-reported social anxiety symptoms and social threat appraisals, at each session, post and 3-months after treatment. Prediction error will be operationalized as the mismatch between the threat prediction and threat outcome. The joint effect of threat prediction and threat outcome on session-by-session symptom change, treatment outcome, exposure surprise, and learning outcome will be explored using multilevel modeling. The present study will help determine whether threat prediction error during exposures in SAD treatment is related to theoretically implied clinical outcomes. This would contribute to the larger research aim of clarifying exposure therapy mechanisms.

Cognitive strengths in first episode psychosis: a thematic analysis of clinicians' perspectives.

BACKGROUND: Cognitive deficits are associated with poor functional outcomes in individuals recovering from a first episode of psychosis (FEP). Existing treatments that target cognitive deficits in FEP may enhance cognitive function, but improvements to real-world functioning are less consistent. Furthermore, these treatments may not adequately address the personal recovery goals of young people attending FEP services. A novel cognitive strengths-based approach may overcome these shortcomings. METHODS: This qualitative study used semi-structured interviews to explore clinicians' (N = 12) perspectives toward the potential development of a cognitive strengths-based assessment or treatment in FEP. The interviews were analysed using thematic analysis. RESULTS: Five higher-order themes emerged: (1) pro-strengths attitude despite unfamiliarity and minimal use, (2) default to a cognitive deficit lens, (3) potential benefits of a cognitive strengths approach, (4) potential risks and barriers, and (5) considerations for successful implementation. While clinicians acknowledged their current deficit approach, they supported implementing a cognitive strengths assessment or treatment and highlighted their potential benefits for the personal recovery needs of young people with FEP. CONCLUSIONS: These findings suggest that a deficit-focused approach to cognitive function amongst clinicians may be common practice in FEP services. Nevertheless, a cognitive strengths approach was viewed favourably by clinicians and may represent a novel method of supporting personal recovery. Thus, the design and implementation of a cognitive strengths approach may be worthwhile. Future exploration of other stakeholder perspectives, such as young people with FEP, is essential.

Interrelationships between depressive symptoms and positive and negative symptoms of recent onset schizophrenia spectrum disorders: A network analytical approach.

OBJECTIVE: There is a need to better understand the interrelationships between positive and negative symptoms of recent-onset schizophrenia spectrum disorders (SSD) and co-occurring depressive symptoms. Aims were to determine: (1) whether depressive symptoms are best conceptualised as distinct from, or intrinsic to, positive and negative symptoms; and (2) bridging symptoms. METHODS: Network analysis was applied to data from 198 individuals with depressive and psychotic symptoms in SSD from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures were: Montgomery-Åsberg Depression Rating Scale and Positive and Negative Syndrome Scale. RESULTS: Positive symptoms were just as likely to be associated with depressive and negative symptoms, and had more strong associations with depressive than negative symptoms. Negative symptoms were more likely to be associated with depressive than positive symptoms, and had more strong associations with depressive than positive symptoms. Suspiciousness and stereotyped thinking bridged between positive and depressive symptoms, and apparent sadness and lassitude between negative and depressive symptoms. CONCLUSIONS: Depressive symptoms might be best conceptualised as intrinsic to positive and negative symptoms pertaining to deficits in motivation and interest in the psychotic phase of SSD. Treatments targeting bridges between depressive and positive symptoms, and depressive and such negative symptoms, might prevent or improve co-occurring depressive symptoms, or vice-versa, in the psychotic phase of SSD.

The psychometric validity of the Montgomery-Åsberg Depression Rating Scale (MADRS) in recent onset schizophrenia spectrum disorders.

Earlier recognition and accurate assessment of depressive symptoms is important to improving outcomes in individuals with recent-onset schizophrenia spectrum disorders (termed SSD hereafter)-regardless of whether positive psychotic symptoms are present or have resolved. The Montgomery-Åsberg Depression Rating Scale (MADRS) is frequently used to assess depressive symptoms in SSD, but no study has examined the psychometric validity of MADRS scores in individuals exclusively with SSD and sub-grouped by those with and without positive psychotic symptoms. This study involved baseline data from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures used were: MADRS, depressive and negative subscales of Positive and Negative Syndrome Scale (PANSSD, PANSSN), and Schedules for Clinical Assessment in Neuropsychiatry (SCAN). The MADRS total score had sufficient concurrent validity with PANSSD (evidence by ρ≥0.70), and insufficient divergent validity with PANSSN (evidenced by ρ ≥0.30), in the full cohort and when sub-grouped by positive psychotic symptoms. In symptom networks, divergent communities comprising either MADRS or PANSSN items were found, except the MADRS item inability to feel overlapped with PANSSN items. The most divergent MADRS items were sadness, pessimism, and suicidal thoughts. The MADRS total score had sufficient predictive validity for determining caseness for MDD based on SCAN, but the optimal cut-off differed in those with and without positive psychotic symptoms (MADRS≥18 versus MADRS≥11). The MADRS has sufficient validity for assessing depressive symptoms in SSD. Since scores might depend upon symptoms of SSD, MADRS≥11 and the presence of sadness, pessimism, or suicidal ideation might be the best indicator of MDD in SSD.

"I'm tired of being pulled from pillar to post": A qualitative analysis of barriers to mental health care for trauma-exposed young people.

AIM: Traumatic experiences in childhood are pervasive and associated with a range of deleterious mental health outcomes. Despite this, trauma-exposed young people often do not seek help from mental health services. While barriers to care for general mental health concerns are well established, less is known about those specifically facing young people who have experienced trauma. The present paper sought to examine the barriers in seeking mental health care faced by trauma-exposed young people through a qualitative analysis of online forums where individuals discuss and seek informal support for trauma. METHODS: This study used a qualitative, netnographic design, following the six-step LiLEDDa framework, developed for the analysis of online forums. Posts about trauma written in 2016 from five Internet forums targeting young people were included and analysed via thematic analysis. RESULTS: Barriers to mental health care for trauma-exposed young people were categorized into two interrelated themes: (a) structural and (b) relational barriers. Structural barriers related to practical challenges faced when accessing and engaging with mental health services. Relational barriers focused on interpersonal relationships with mental health service providers and how these influenced experiences of, and consequent engagement with, services. CONCLUSIONS: Trauma-exposed young people appear to experience multiple barriers to mental health care, whereby interactions between structural and relational barriers determine ongoing engagement. Service-wide reform including trauma-informed mental health training for practitioners is urgently needed to improve access to care and engagement for this vulnerable group.

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial.

BACKGROUND: Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes. METHODS: The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated. RESULTS: Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours. CONCLUSIONS: FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS. GOV IDENTIFIER: NCT00433927.

Effect of a novel DNA vaccine against pancreas disease caused by salmonid alphavirus subtype 3 in Atlantic salmon (Salmo salar).

Pancreas disease (PD) caused by salmonid alphavirus subtype 3 (SAV3) is a serious disease with large economic impact on farmed Norwegian Atlantic salmon production despite years of use of oil-adjuvanted vaccines against PD (OAVs). In this study, two commercially available PD vaccines, a DNA vaccine (DNAV) and an OAV, were compared in an experimental setting. At approximately 1040° days (dd) at 12 °C post immunization, the fish were challenged with SAV3 by cohabitation 9 days after transfer to sea water. Sampling was done prior to challenge and at 19, 54, and 83 days post-challenge (dpc). When compared to the OAV and control (Saline) groups, the DNAV group had significantly higher SAV3 neutralizing antibody titers after the immunization period, significantly lower SAV3 viremia levels at 19 dpc, significantly reduced transmission of SAV3 to naïve fish in the latter part of the viremic phase, significantly higher weight gain post-challenge, and significantly reduced prevalence and/or severity of SAV-induced morphologic changes in target organs. The DNAV group had also significantly higher post-challenge survival compared to the Saline group, but not to the OAV group. The data suggest that use of DNAV may reduce the economic impact of PD by protecting against destruction of the pancreas tissue and subsequent growth impairment which is the most common and costly clinical outcome of this disease.

Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials.

PURPOSE: Although biomarkers for patients with metastatic colorectal cancer exist, the benefit patients with RAS mutated tumors derive from established regimens is unclear. METHODS: Efficacy of therapeutic strategies available for RAS mutated patients (addition of chemotherapeutic agents and/or anti angiogenic agents) were investigated in fourteen randomized controlled phase III trials at trial level by meta-analysing individual study hazard ratios and 95% confidence intervals (95% CI) for overall survival (OS) and progression free survival (PFS). RESULTS: 6810 of 10,748 patients (63.3%) were available (48.5% RAS wildtype, 51.5% RAS mutated). Across all treatment lines, additional treatment efficacy (chemotherapy and/or anti angiogenic agents) was significantly smaller in RAS mutated compared to wildtype tumors for OS and PFS. In detail, patients with RAS mutated metastatic colorectal cancer derived significant benefit in PFS but not in OS by the addition of either chemotherapy or anti angiogenic agents to the respective comparator. In patients with RAS wildtype metastatic colorectal cancer, PFS and OS were improved by the addition of chemotherapy or anti angiogenic agent. CONCLUSION: The therapeutic benefit of additional substances is less distinct in patients with RAS mutated as compared to RAS wildtype metastatic colorectal cancer, especially with regard to OS.

Maladaptive Perfectionism and Depression: Testing the Mediating Role of Self-Esteem and Internalized Shame in an Australian Domestic and Asian International University Sample.

OBJECTIVES: To assess whether maladaptive perfectionism (parental and intrapersonal), mediated by self-esteem and internalized shame, lead to depressive symptoms, and to identify whether this model was invariant (i.e., structurally unchanged) across groups of Australian domestic and Asian international students. METHODS: A total of 624 (308 Australian domestic and 316 Asian international undergraduate university students) completed a questionnaire on the variables of interest. RESULTS: Australian domestic and Asian international students did not significantly differ in reported levels of study variables apart from parental maladaptive perfectionism, on which Australian domestic students scored significantly higher. The proposed path-model differed across student groups, with findings indicating that intrapersonal maladaptive perfectionism impacted indirectly on depressive symptoms through internalized shame in both groups, however, indirectly through self-esteem in only the Asian international student group. CONCLUSION: Intrapersonal maladaptive perfectionism may be a culturally independent process, capable of predisposing all university students to develop depressive symptoms, but that self-esteem may be a particularly relevant mediator of this relationship among Asian international students.