Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LaTE study)-a nationwide inverse probability of treatment-weighted registry-based cohort study and survey.

AIM: Stage III colon cancer is routinely treated with adjuvant chemotherapy, which causes significant short-term morbidity. Its effect on long-term quality of life (QoL) is poorly investigated. The aim of this study was to investigate long-term QoL after curative treatment for colon cancer and explore the impact of chemotherapy on general and disease-specific QoL. METHOD: All patients aged under 75 years operated on for colon cancer between 30 September 2007 and 1 October 2019 were identified by the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence, dementia and rectal/rectosigmoid cancer operation. The primary outcome measure was Gastrointestinal Quality of Life Index (GIQLI). Secondary outcome measures included the Short Form Health Survey (SF-36). To achieve balanced groups when assessing differences in outcome measures the analyses were weighted by inverse probability weights based on a multiple logistic regression model with prechosen confounders. RESULTS: A total of 8627 patients were invited and 3109 responded (36% response rate). After exclusions 3025 patients were included, of whom 1148 (38%) had received adjuvant chemotherapy and 1877 (62%) had surgery alone, with mean follow-up of 75.5 versus 74.5 months, respectively. The GIQLI differed significantly between the groups [mean 111.0 (SD 18.4) vs. 115.6 (SD 17.8), respectively; mean difference: -4.6 (95% CI -5.9; -3.2); p < 0.001]. Those with the highest neurotoxicity exhibited the lowest GIQLI. The adjuvant chemotherapy group scored significantly lower in six of eight SF-36 domains compared with the surgery alone group. The main differences were found in social, physical and emotional function. CONCLUSION: Long-term QoL was significantly lower in patients who received adjuvant chemotherapy than in patients who did not. Neurotoxicity was closely related to reduced QoL in these patients. The low response rate limits the generalizability of the results.

Effects of NMDA-receptor blockade by ketamine on mentalizing and its neural correlates in humans: a randomized control trial.

Schizophrenia is associated with various deficits in social cognition that remain relatively unaltered by antipsychotic treatment. While faulty glutamate signaling has been associated with general cognitive deficits as well as negative symptoms of schizophrenia, no direct link between manipulation of glutamate signaling and deficits in mentalizing has been demonstrated thus far. Here, we experimentally investigated whether ketamine, an uncompetitive N-methyl-D-aspartate receptor antagonist known to induce psychotomimetic effects, influences mentalizing and its neural correlates. In a randomized, placebo-controlled between-subjects experiment, we intravenously administered ketamine or placebo to healthy participants performing a video-based social cognition task during functional magnetic resonance imaging. Psychotomimetic effects of ketamine were assessed using the Positive and Negative Syndrome Scale. Compared to placebo, ketamine led to significantly more psychotic symptoms and reduced mentalizing performance (more "no mentalizing" errors). Ketamine also influenced blood oxygen level dependent (BOLD) response during mentalizing compared to placebo. Specifically, ketamine increased BOLD in right posterior superior temporal sulcus (pSTS) and increased connectivity between pSTS and anterior precuneus. These increases may reflect a dysfunctional shift of attention induced by ketamine that leads to mentalizing deficits. Our findings show that a psychotomimetic dose of ketamine impairs mentalizing and influences its neural correlates, a result compatible with the notion that deficient glutamate signaling may contribute to deficits in mentalizing in schizophrenia. The results also support efforts to seek novel psychopharmacological treatments for psychosis and schizophrenia targeting glutamatergic transmission.

Laparoscopic lavage for Hinchey III perforated diverticulitis: factors for treatment failure in two randomized clinical trials.

BACKGROUND: The Scandinavian Diverticulitis (SCANDIV) trial and the LOLA arm of the LADIES trial randomized patients with Hinchey III perforated diverticulitis to laparoscopic peritoneal lavage or sigmoid resection. The aim of this analysis was to identify risk factors for treatment failure in patients with Hinchey III perforated diverticulitis. METHODS: This was a post hoc analysis of the SCANDIV trial and LOLA arm. Treatment failure was defined as morbidity requiring general anaesthesia (Clavien-Dindo grade IIIb or higher) within 90 days. Age, sex, BMI, ASA fitness grade, smoking status, previous episodes of diverticulitis, previous abdominal surgery, time to surgery, and surgical competence were all tested in univariable and multivariable logistic regression analyses using an interaction variable. RESULTS: The pooled analysis included 222 patients randomized to laparoscopic lavage and primary resection (116 and 106 patients respectively). Univariable analysis found ASA grade to be associated with advanced morbidity in both groups, and the following factors in the laparoscopic lavage group: smoking, corticosteroid use, and BMI. Significant factors for laparoscopic lavage morbidity in multivariable analysis were smoking (OR 7.05, 95 per cent c.i. 2.07 to 23.98; P = 0.002) and corticosteroid use (OR 6.02, 1.54 to 23.51; P = 0.010). CONCLUSION: Active smoking status and corticosteroid use were risk factors for laparoscopic lavage treatment failure (advanced morbidity) in patients with perforated diverticulitis.

Nutrition claims influence expectations about food attributes, attenuate activity in reward-associated brain regions during tasting, but do not impact pleasantness.

INTRODUCTION: Nutrition claims are one of the most common tools used to improve food decisions. Previous research has shown that nutrition claims impact expectations; however, their effects on perceived pleasantness, valuation, and their neural correlates are not well understood. These claims may have both intended and unintended effects on food perception and valuation, which may compromise their effect on food decisions. METHODS: We investigated the effects of nutrition claims on expectations, perceptions, and valuation of milk-mix drinks in a behavioral (n = 110) and an fMRI (n = 39) study. In the behavioral study, we assessed the effects of a "fat-reduced" and a "protein-rich" nutrition claim on expected and perceived food attributes of otherwise equal food products. In the fMRI study, we investigated the effect of a "protein-rich" claim on taste pleasantness perception and valuation, and on their neural correlates during tasting and swallowing. RESULTS: We found that both nutrition claims increased expected and perceived healthiness and decreased expected but not perceived taste pleasantness. The "protein-rich" claim increased expected but not perceived satiating quality ratings, while the "fat-reduced" claim decreased both expected and perceived satiating quality ratings. In the absence vs. presence of the "protein-rich" claim, we observed an increased activity in a cluster extending to the left nucleus accumbens during tasting and an increased functional connectivity between this cluster and a cluster in right middle frontal gyrus during swallowing. CONCLUSION: Altogether, we found that nutrition claims impacted expectations and attenuated reward-related responses during tasting but did not negatively affect perceived pleasantness. Our findings support highlighting the presence of nutrients with positive associations and exposure to foods with nutrition claims to increase their acceptance. Our study offers insights that may be valuable in designing and optimizing the use of nutrition claims.

Animacy and the prediction of behaviour.

To survive, all animals need to predict what other agents are going to do next. We review neural mechanisms involved in the steps required for this ability. The first step is to determine whether an object is an agent, and if so, how sophisticated it is. This involves brain regions carrying representations of animate agents. The movements of the agent can then be anticipated in the short term based solely on physical constraints. In the longer term, taking into account the agent's goals and intentions is useful. Observing goal directed behaviour activates the neural action observation network, and predicting future goal directed behaviour is helped by the observer's own action generating mechanisms. Intentions are critically important in determining actions when interacting with other agents, as several intentions can lie behind an action. Here, interpretation is helped by prior beliefs about the agent and the brain's mentalising system is engaged. Biologically-constrained computational models of action recognition exist, but equivalent models for understanding intentional agents remain to be developed.

Ketamine increases fronto-posterior functional connectivity during meta-perceptual confidence ratings.

Recent advances in the neuropsychopharmacology of metacognition indicate a constituent role of glutamate for the integrity of metamnestic processes. However, the extent to which previous results can be generalized across functional domains to characterize the relationship between glutamate and metacognition remains unclear. Here, in a randomized, double-blind, placebo-controlled, preregistered fMRI study, we tested the effects of a psychotomimetic dose (target plasma concentration 100 ng/mL) of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine on metacognition in a perceptual decision-making framework. We collected trial-by-trial metacognitive reports as participants performed a two-alternative forced-choice perceptual task during functional magnetic resonance imaging (fMRI). Results indicated ketamine-induced deterioration in metacognitive performance, whereas no significant effects were observed for perceptual performance, response times and - unexpectedly - metacognitive bias. Whilst there were no detectable ketamine effects on mean BOLD activation, exploratory psychophysiological interaction (PPI) analysis revealed alterations in functional connectivity during metacognitive confidence ratings under ketamine. Specifically, there was increased task-specific connectivity for ketamine compared to placebo between right anterior dorsolateral prefrontal cortex and left middle temporal, supramarginal and precentral gyrus, as well as between right insula/inferior frontal gyrus and left lingual gyrus, possibly indicating re-representations of object-level features supplied for metacognitive evaluations. Overall, these findings contribute towards the emerging picture of the substructures underlying metacognitive operations at the neurotransmitter level and may shed light on a neural pattern characteristic of pharmacologically challenged metacognition.

Behavioral and Neural Dissociation of Social Anxiety and Loneliness.

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety (SA), cognitive-behavioral interventions targeting SA might be adopted to reduce loneliness. However, whether SA and loneliness share the same underlying neurocognitive mechanisms is still an elusive question. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in SA are evident in loneliness. We used a prestratified approach involving 42 (21 females) participants with high loneliness (HL) and 40 (20 females) participants with low loneliness (LL) scores. During fMRI, participants completed a social gambling task to measure the subjective value of engaging in social situations and responses to social feedback. Univariate and multivariate analyses of behavioral and neural data replicated known task effects. However, although HL participants showed increased SA, loneliness was associated with a response pattern clearly distinct from SA. Specifically, contrary to expectations based on SA differences, Bayesian analyses revealed moderate evidence for equal subjective values of engaging in social situations and comparable amygdala responses to social decision-making and striatal responses to positive social feedback in both groups. Moreover, while explorative analyses revealed reduced pleasantness ratings, increased striatal activity, and decreased striatal-hippocampal connectivity in response to negative computer feedback in HL participants, these effects were diminished for negative social feedback. Our findings suggest that, unlike SA, loneliness is not associated with withdrawal from social interactions. Thus, established interventions for SA should be adjusted when targeting loneliness.SIGNIFICANCE STATEMENT Loneliness can cause serious health problems. Adapting well-established cognitive-behavioral therapies targeting social anxiety might be promising to reduce chronic loneliness given a close link between both constructs. However, a better understanding of behavioral and neurobiological factors associated with loneliness is needed to identify which specific mechanisms of social anxiety are shared by lonely individuals. We found that lonely individuals show a consistently distinct pattern of behavioral and neural responsiveness to social decision-making and social feedback compared with previous findings for social anxiety. Our results indicate that loneliness is associated with a biased emotional reactivity to negative events rather than social avoidance. Our findings thus emphasize the distinctiveness of loneliness from social anxiety and the need for adjusted psychotherapeutic protocols.

Management of acute uncomplicated diverticulitis without antibiotics: compliance and outcomes -a retrospective cohort study.

METHODS: Recent randomized control trials (RCTs) have confirmed that antibiotics in acute uncomplicated diverticulitis (AUD) neither accelerate recovery nor prevent complications or recurrences. A retrospective cohort study was conducted, including all consecutive AUD patients hospitalized 2015- 2018 at Helsingborg Hospital (HH) and Skåne University Hospital (SUS), Sweden. HH had implemented a non-antibiotic treatment protocol in 2014 while SUS had not. Main outcomes were proportion of patients treated with antibiotics, complications, recurrences, and adherence to routinely colon evaluation. RESULTS: A total of 583 AUD patients were enrolled, 388 at SUS and 195 at HH. The diagnosis was CT-verified in 320 (83%) vs. 186 (95%) patients respectively (p < 0.001). Forty-three (11%) and 94 (48%) of patients respectively did not receive antibiotics during hospitalization (p < 0.001). CRP was higher in the antibiotic group compared to the non-antibiotic group, both at admission and peak (90 mg/L vs 65 mg/L; p = 0.016) and (138 mg/L and 97 mg/L; p < 0.001). There were no significant differences in recurrences (22.0% vs. 22.6%; p = 0.87) and complications (2.5% vs. 2.9%; p = 0.77) between the antibiotic/non-antibiotic groups. CONCLUSION: The structured treatment protocol led to reduced antibiotic use and a higher standard of care in terms of CT-verification. Clinicians' compliance to the treatment protocol and best clinical practice was poor and warrants further studies.

Preserved metacognition despite impaired perception of intentionality cues in schizophrenia.

Social cognition and metacognition are frequently impaired in schizophrenia, and these impairments complicate recovery. Recent work suggests that different aspects of metacognition may not be impaired to the same degree. Furthermore, metacognition and the cognitive capacity being monitored need not be similarly impaired. Here, we assessed performance in detecting cues of intentional behaviour as well as metacognition about detecting those cues in schizophrenia. Thirty patients and controls categorized animations of moving dots into those displaying a dyadic interaction demonstrating a chase or no chase and indicated their confidence in these judgments. Perception and metacognition were assessed using signal detection theoretic measures, which were analysed using frequentist and Bayesian statistics. Patients showed a deficit compared to controls in detecting intentionality cues, but showed preserved metacognitive performance into this task. Our study reveals a selective deficit in the perception of intentionality cues, but preserved metacognitive insight into the validity of this perception. It thus appears that impairment of metacognition in schizophrenia varies across cognitive domains - metacognition should not be considered a monolithic stone that is either impaired or unimpaired.

Fracture of the Dens Axis Due to Spinal Manifestation of Sarcoidosis: Treatment Option and Review of the Literature.

STUDY DESIGN: Case report and literature review. OBJECTIVE: We present a case of a pathologic unstable fracture of the odontoid process due to vertebral osseous sarcoidosis. The surgical management of this unreported pathology is described and a review of the literature is given. SUMMARY OF BACKGROUND DATA: Sarcoidosis is a chronic inflammatory systemic disease of unknown etiology, characterized by multiorgan noncaseating granulomatous infiltrations. It affects primarily the lungs, lymphatic system, eyes, skin, heart, and nervous system. Osseous sarcoidosis is usually clinically asymptomatic and therefore frequently under-diagnosed. When it does affect the skull or vertebral column, specific surgical therapy is only necessary in cases with nonmanageable pain or where structural integrity is threatened. METHODS: Our patient underwent a so-called semiconservative approach, consisting of a minimally invasive transoral-transpharyngeal approach, surgical debridement of the lytic bony lesion, transplantation of cancellous homologous bone, and carbon chest halo-immobilization. Halo-immobilization was left for 8 weeks, followed by a further 6 weeks with a hard cervical collar. RESULTS: Routine computed tomography scans 3 days, 6, 12, 18 weeks, and 1 year after surgery showed good filling of the original defect with cancellous bone, correct alignment of the upper cervical spine, and progressive fracture consolidation and stability. Surgical site infection (SSI) was not observed. The patient had no neurological postoperative deficits. After initial dysphagia, swallowing was not permanently impaired. CONCLUSION: Sarcoidosis-induced odontoid fractures can be managed successfully using a semiconservative approach, consisting of transoral-transmucosal, minimally invasive surgical procedure for debridement of the lesion and transplantation of cancellous bone with additional halo-immobilization. Permanent fusion of C1-2 with loss of the cervical range of motion is avoided. Despite performing bone surgery in a potentially markedly contaminated site, bacterial infection was not an issue, possibly supported by the temporary discontinuation of immunosuppressive agents and the prudent use of antibiotics.Level of Evidence: 4.

Sex differences in economic decision-making: Exogenous estradiol has opposing effects on fairness framing in women and men.

Burgeoning evidence indicates that women are more sensitive to the context of an offer and show a stronger propensity to adjust their behavior with changing fairness frames. We evaluated whether the sex hormone estradiol and associated stereotypical beliefs contribute to fairness framings by administering topical estradiol (2 mg) to 108 healthy women and 104 heathy men in a randomized, double-blind, placebo-controlled between-subject study design. Participants played the role of the responder in a modified version of the Ultimatum Game (UG), in which identical offers for the division of a given amount of money were framed as either fair or unfair. Furthermore, participants completed an unframed UG and a delayed discounting task to probe possible effects of estradiol on altruistic preferences and delay gratification. Our results show that women were more sensitive to fairness frames than men. Intriguingly, however, estradiol had sex-specific effects on fairness sensitivity by increasing the acceptance rate of proposals with a fair frame in men and reducing it in women. Furthermore, the mere belief of receiving estradiol treatment significantly increased the acceptance of unfair-framed offers in both sexes, but estradiol did not significantly alter the response to unframed offers and impulsive decision-making. Collectively, our findings indicate that estradiol has opposing effects on the sensitivity to the perceived fairness of economic offers in women and men. The profound effects of estradiol treatment and stereotypical beliefs provide support for the notion that sex differences in fairness framing are rooted in both biological and environmental factors.

Effects of ketamine on brain function during metacognition of episodic memory.

Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N-methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d') and led to larger metacognitive bias, with retrieval performance (d') and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d'/d'). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness.

Simultaneous Resection of Primary Colorectal Cancer and Synchronous Liver Metastases: Contemporary Practice, Evidence and Knowledge Gaps.

The timing of surgical resection of synchronous liver metastases from colorectal cancer has been debated for decades. Several strategies have been proposed, but high-level evidence remains scarce. Simultaneous resection of the primary tumour and liver metastases has been described in numerous retrospective audits and meta-analyses. The potential benefits of simultaneous resections are the eradication of the tumour burden in one procedure, overall shorter procedure time, reduced hospital stay with the likely benefits on quality of life and an expected reduction in the use of health care services compared to staged procedures. However, concerns about accumulating complications and oncological outcomes remain and the optimal selection criteria for whom simultaneous resections are beneficial remains undetermined. Based on the current level of evidence, simultaneous resection should be restricted to patients with a limited liver tumour burden. More high-level evidence studies are needed to evaluate the quality of life, complication burden, oncological outcomes, as well as overall health care implications for simultaneous resections.

Stratification of Stage III colon cancer may identify a patient group not requiring adjuvant chemotherapy.

PURPOSE: Adjuvant chemotherapy for colon cancer with lymph node involvement (Stage III) has been the standard of care since the 1990s. Meanwhile, considerable evolvement of surgery combined with dedicated histopathological examinations may have led to stage migration. Furthermore, prognostic factors other than lymph node involvement have proven to affect overall survival. Thus, adjuvant chemotherapy in Stage III colon cancer should be reconsidered. The objective was to compare recurrence rates and survival in stage III colon cancer patients treated with or without adjuvant chemotherapy. Further, to assess the impact of extensive mesenterectomy, lymph node stage and vascular invasion on outcome. METHODS: Consecutive patients operated for Stage III colon carcinoma between 31 December 2005 and 31 December 2015 were identified in the pathological code register by matching colon (T67) and either adenocarcinoma (M81403) or mucinous adenocarcinoma (M84803), with lymph node (T08) and metastasis of adenocarcinoma (M81406 or M84806). Medical records of all identified patients were reviewed. RESULTS: Of 216 identified patients, 69 received no postoperative adjuvant chemotherapy (group NC), 69 insufficient adjuvant chemotherapy (FLV or < minimum recommended 6 cycles FLOX, group IC), and 78 sufficient adjuvant chemotherapy (≥ 6 cycles FLOX, group SC). When adjusted for age and comorbidity, 5-year overall survival did not differ statistically significant between groups (76% vs. 83% vs. 85%, respectively). Vascular invasion and a high lymph node ratio significantly reduced overall survival. CONCLUSION: The findings imply that subgroups of Stage III colon cancer patients have good prognosis also without adjuvant chemotherapy. For definite conclusions about necessity of adjuvant chemotherapy, prospective trials are needed.