Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Vagal Nerve Stimulation-Modulation of the Anti-Inflammatory Response and Clinical Outcome in Psoriatic Arthritis or Ankylosing Spondylitis.

OBJECTIVES: The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis. METHODS: Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed. RESULTS: In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described. CONCLUSION: This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.

Minor effect of loss to follow-up on outcome interpretation in the Swedish spine register.

BACKGROUND AND PURPOSE: Loss to follow-up in observational studies may skew results and hamper study reliability. We evaluated the importance of loss to follow-up in the Swedish spine register. PATIENTS: Patients operated in the lumbar spine and scheduled for a postal questionnaire follow-up during part of 2016 were identified. Out of the 351 patients, 203 had responded. After multiple attempts, 115 of the 148 non-responders were reached; 68 returned the complete questionnaire; and 47 answered a brief questionnaire by phone. Analyses were made with the Chi-square test, analysis of covariance or logistic regression. Some analyses were adjusted. RESULTS: At baseline, the non-responders were younger than the responders (55 vs 61 years, p < 0.001) and had higher Oswestry Disability Index (ODI) (54 vs 48, p = 0.003), lower SF-36 physical component summary score (PCS) (36 vs 40, p = 0.011) and lower EQ-5D (0.17 vs 0.27, p = 0.018). Mean back pain, leg pain, ODI, EQ-5D, SF-36 mental component summary score (MCS) improved significantly in both groups (all p < 0.001). SF-36 PCS did not improve in the non-responder group (p = 0.063). Non-responders perceived less improvement in back pain (global assessment back 60% vs 72%, p = 0.002). At follow-up, there were no differences in patient-reported outcome measures between the groups (all p ≥ 0.06), with the exception of a lower SF-36 MCS among the non-responders (p = 0.015). INTERPRETATION: After surgery for lumbar spine degenerative disorders, non-responders achieve similar outcome as responders in the Swedish spine register, with the exception of a lower mental health and less perceived improvement in back pain. These slides can be retrieved under Electronic Supplementary Material.

Discovery of an Exceptionally Strong ß-Decay Transition of

A significant fraction of stars between 7 and 11 solar masses are thought to become supernovae, but the explosion mechanism is unclear. The answer depends critically on the rate of electron capture on ^{20}Ne in the degenerate oxygen-neon stellar core. However, because of the unknown strength of the transition between the ground states of ^{20}Ne and ^{20}F, it has not previously been possible to fully constrain the rate. By measuring the transition, we establish that its strength is exceptionally large and that it enhances the capture rate by several orders of magnitude. This has a decisive impact on the evolution of the core, increasing the likelihood that the star is (partially) disrupted by a thermonuclear explosion rather than collapsing to form a neutron star. Importantly, our measurement resolves the last remaining nuclear physics uncertainty in the final evolution of degenerate oxygen-neon stellar cores, allowing future studies to address the critical role of convection, which at present is poorly understood.

Obesity surgery and risk of cancer.

BACKGROUND: Obesity increases the risk of several types of cancer. Whether bariatric surgery influences the risk of obesity-related cancer is not clear. This study aimed to uncover the risk of hormone-related (breast, endometrial and prostate), colorectal and oesophageal cancers following obesity surgery. METHODS: This national population-based cohort study used data from the Hospital Episode Statistics database in England collected between 1997 and 2012. Propensity matching on sex, age, co-morbidity and duration of follow-up was used to compare cancer risk among obese individuals undergoing bariatric surgery (gastric bypass, gastric banding or sleeve gastrectomy) and obese individuals not undergoing such surgery. Conditional logistic regression provided odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: In the study period, from a cohort of 716 960 patients diagnosed with obesity, 8794 patients who underwent bariatric surgery were matched exactly with 8794 obese patients who did not have surgery. Compared with the no-surgery group, patients who had bariatric surgery exhibited a decreased risk of hormone-related cancers (OR 0·23, 95 per cent c.i. 0·18 to 0·30). This decrease was consistent for breast (OR 0·25, 0·19 to 0·33), endometrium (OR 0·21, 0·13 to 0·35) and prostate (OR 0·37, 0·17 to 0·76) cancer. Gastric bypass resulted in the largest risk reduction for hormone-related cancers (OR 0·16, 0·11 to 0·24). Gastric bypass, but not gastric banding or sleeve gastrectomy, was associated with an increased risk of colorectal cancer (OR 2·63, 1·17 to 5·95). Longer follow-up after bariatric surgery strengthened these diverging associations. CONCLUSION: Bariatric surgery is associated with decreased risk of hormone-related cancers, whereas gastric bypass might increase the risk of colorectal cancer.

Response rate does not affect patient-reported outcome after lumbar discectomy.

PURPOSE: Quality registers give unique possibilities to achieve information from large groups of patients, but outcome must be interpreted carefully due to less stringent data collection and lower follow-up rates than in research projects. We tried to quantify any outcome differences between a national spine quality register and a prospective observational study. METHODS: Adult patients treated with lumbar discectomy between 2004 and 2010 were retrieved from the Swedish Spine register (Swespine) (n = 7791) and from the single center lumbar disc herniation study (LDHS) in Stockholm (n = 177). The mean follow-up rates at 1 and 2 years were 73 and 62%, compared to 98 and 99%, respectively. Patient-reported outcome measurements included VAS for back and leg pain, ODI, EQ-5D, patient satisfaction, and global assessment. RESULTS: When comparing the two cohorts at baseline, there were minor differences in the patient-reported outcome measurements, all within reported minimal clinical important differences (MCID). Mean outcome improved significantly in both groups after surgery. All outcomes at 1 and 2 years were similar and within the reported MCID in both groups. Complications and reoperations were similar, except for more surgical site infections in the LDHS group. CONCLUSIONS: Higher response rates than seen in Swespine are not needed to achieve reasonably representative data on patient-reported outcome for large cohorts. Two-year data do not seem to add additional information. These slides can be retrieved under Electronic Supplementary Material.

Saliva testing for human papilloma virus in oropharyngeal squamous cell carcinoma: A diagnostic accuracy study.

BACKGROUND: New cases of oropharyngeal squamous cell carcinoma (OPSCC) are routinely tested for HPV. HPV in saliva can be detected with PCR, but its clinical applicability in the context of OPSCC remains unknown. METHODS: Forty-six consecutive patients diagnosed with OPSCC had pre-treatment saliva specimens collected. PCR for HPV on saliva was compared to p16 IHC and HPV DNA in situ hybridisation (ISH) on surgical biopsies. RESULTS: The sensitivity and specificity of saliva testing when compared to the reference test of p16 IHC and HPV DNA ISH were 72.2% and 90%, and positive and negative predictive values were 96.3% and 47.4%. There were no adverse events. Time from last meal, smoking, alcohol drinking and physical exercise did not impact on results. CONCLUSIONS: Saliva testing is a promising test to detect HPV in patients with OPSCC. A positive result could avoid the need for surgical biopsies, thereby reducing costs, patient morbidity and expedite treatment.

Silexan does not cause withdrawal symptoms even when abruptly discontinued.

OBJECTIVE: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder (GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan after abrupt discontinuation. METHODS: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the original trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist questionnaire (PWC-20). RESULTS: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in placebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation. CONCLUSIONS: Values assessed for the silexan groups indicate the absence of a dependency potential of this preparation.

EPA guidance on improving the image of psychiatry.

This paper explores causes, explanations and consequences of the negative image of psychiatry and develops recommendations for improvement. It is primarily based on a WPA guidance paper on how to combat the stigmatization of psychiatry and psychiatrists and a Medline search on related publications since 2010. Furthermore, focussing on potential causes and explanations, the authors performed a selective literature search regarding additional image-related issues such as mental health literacy and diagnostic and treatment issues. Underestimation of psychiatry results from both unjustified prejudices of the general public, mass media and healthcare professionals and psychiatry's own unfavourable coping with external and internal concerns. Issues related to unjustified devaluation of psychiatry include overestimation of coercion, associative stigma, lack of public knowledge, need to simplify complex mental issues, problem of the continuum between normality and psychopathology, competition with medical and non-medical disciplines and psychopharmacological treatment. Issues related to psychiatry's own contribution to being underestimated include lack of a clear professional identity, lack of biomarkers supporting clinical diagnoses, limited consensus about best treatment options, lack of collaboration with other medical disciplines and low recruitment rates among medical students. Recommendations are proposed for creating and representing a positive self-concept with different components. The negative image of psychiatry is not only due to unfavourable communication with the media, but is basically a problem of self-conceptualization. Much can be improved. However, psychiatry will remain a profession with an exceptional position among the medical disciplines, which should be seen as its specific strength.

[Experiences of stigma and discrimination in patients with first-episode schizophrenia]. / Erleben von Stigma und Diskriminierung bei ersterkrankten Schizophreniepatienten.

BACKGROUND: Patients with mental illnesses, especially with schizophrenia, suffer from stigma and discrimination. In addition, the stigma is a barrier to recognising and treating patients with first-episode psychosis; however, a self-rating instrument that assesses the general burden due to stigma experiences is still lacking. MATERIAL AND METHODS: A total of N = 48 patients with first-episode schizophrenia who were participants in the multicenter first-episode (long-term) study within the German Research Network on Schizophrenia, completed a newly developed self-rating questionnaire to assess the burden due to stigma experiences (B-STE). The following variables were analyzed as possible correlates: psychopathology (CGI, PANSS, CDSS and HAM-D), global functioning (GAF), social adjustment (SAS), self-esteem (FSKN), as well as quality of life (LQLP), subjective well-being under neuroleptic treatment (SWN) and anticipated stigma (PDDQ). RESULTS: Of the participants 25 % showed an increased burden due to stigma experiences, which correlated with a lower quality of life, lower subjective well-being under neuroleptic treatment, lower self-esteem and higher anticipated stigma. The results indicate that patients rated higher on the CGI scale who are at the same time better socially adjusted (SAS), are more intensely affected by the burden due to stigma experiences. CONCLUSION: The short self-rating instrument burden due to stigma experiences (B-STE) can help to identify patients who might benefit from therapeutic or educational interventions to support coping with stigma experiences.

[Concept and results of the German Research Network on Schizophrenia]. / Konzept und Ergebnisse des Kompetenznetzes Schizophrenie.

BACKGROUND: The German Research Network on Schizophrenia (GRNS) was funded by the Federal Ministry of Education and Research (BMBF) from 1999 to 2011. The aim was to obtain a better horizontal and vertical networking of German research and care facilities on schizophrenia, in order to investigate open research questions, to transfer the results into clinical practice and improve care and quality of life in patients with schizophrenia. OBJECTIVES/METHODS: This paper describes the concept and operations of the GRNS as well as its results on the basis of selected research projects. RESULTS: The GRNS comprised about 25 clinical trials of high practical relevance, which were closely interrelated regarding content, methodology and organization. The trials primarily served the development and evaluation of new and established diagnostic and therapeutic approaches, the assessment of the status quo of clinical care, as well as its improvements, together with the investigation of basic scientific questions. Many substantial results to highly relevant issues were obtained, which led or will lead to an improvement in mental health care. CONCLUSIONS: Quantitative and qualitative evaluation parameters, such as scientific publications and obtaining additional grants, as well as promotion of young scientists, public relations activities, congress activities and the foundation of a European Schizophrenia Association, document the successful work of the network. Successful funding requests will allow us to continue cooperative schizophrenia research in Germany as initiated by the GRNS, without necessarily always binding these activities formally to the GRNS.

Who are the cancer survivors? A nationwide study in Denmark, 1943-2010.

BACKGROUND: No nationwide studies on social position and prevalence of comorbidity among cancer survivors exist. METHODS: We performed a nationwide prevalence study defining persons diagnosed with cancer 1943-2010 and alive on the census date 1 January 2011 as cancer survivors. Comorbidity was compared by social position with the non-cancer population. RESULTS: Cancer survivors composed 4% of the Danish population. Somatic comorbidity was more likely among survivors (OR 1.59, 95% CI 1.57-1.60) and associated with higher age, male sex, short education, and living alone among survivors. CONCLUSIONS: Among cancer survivors, comorbidity is common and highly associated with social position.

Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort.

BACKGROUND: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score. METHODS: Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort. RESULTS: In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ(2)=89.0, P<10(-20)) and captured virtually all available prognostic information. CONCLUSIONS: The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.

Soluble CD163 levels are elevated in cerebrospinal fluid and serum in people with Type 2 diabetes mellitus and are associated with impaired peripheral nerve function.

AIMS: To measure soluble CD163 levels in the cerebrospinal fluid and serum of people with Type 2 diabetes, with and without polyneuropathy, and to relate the findings to peripheral nerve function. METHODS: A total of 22 people with Type 2 diabetes and 12 control subjects without diabetes were included in this case-control study. Participants with diabetes were divided into those with neuropathy (n = 8) and those without neuropathy (n = 14) based on clinical examination, vibratory perception thresholds and nerve conduction studies. Serum and cerebrospinal fluid soluble CD163 levels were analysed using an enzyme-linked immunosorbent assay. RESULTS: Soluble CD163 levels were significantly higher in the cerebrospinal fluid and serum of the participants with Type 2 diabetes compared with the control participants [cerebrospinal fluid: median (range) 107 (70-190) vs 84 (54-115) µg/l, P < 0.01 and serum: 2305 (920-7060) vs 1420 (780-2740) µg/l, P < 0.01). Cerebrospinal fluid soluble CD163 was positively related to impaired peripheral nerve conduction (nerve conduction study rank score: r = 0.42; P = 0.0497) and there was a trend for higher levels of soluble CD163 in the cerebrospinal fluid and serum in participants with neuropathy than in those without neuropathy [cerebrospinal fluid: median (range) 131 (86-173) vs 101 (70-190) µg/l, P = 0.08 and serum: 3725 (920-7060) vs 2220 (1130-4780), P = 0.06). CONCLUSIONS: Cerebrospinal fluid soluble CD163 level is associated with impaired peripheral nerve function. Higher levels of soluble CD163 in people with diabetic polyneuropathy suggest that inflammation plays a role in the development of neural impairment. The relationship between cerebrospinal fluid soluble CD163 level and peripheral nerve conduction indicates that soluble CD163 may be a potential biomarker for the severity of diabetic polyneuropathy.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Soluble CD163, a specific macrophage activation marker, is decreased by anti-TNF-α antibody treatment in active inflammatory bowel disease.

Activated macrophages shed the haemoglobin-haptoglobin scavenger receptor CD163 into the circulation as soluble(s)-CD163. We measured sCD163 as an in vivo macrophage activation marker in patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving antitumour necrosis factor (TNF)-α antibody or prednisolone treatment. We also investigated the CD163 expression on circulating monocytes. 58 patients with CD, 40 patients with UC and 90 healthy controls (HC) were included. All patients had active disease at inclusion and were followed for 6 weeks of anti-TNF-α antibody or prednisolone treatment. We measured plasma sCD163 levels at baseline, 1 day, 1 week and 6 weeks after initiating treatment. CD163 expression on circulating CD14(+) monocytes was measured in 21 patients with CD receiving anti-TNF-α antibody treatment. Baseline sCD163 levels were elevated in patients with CD [1.99 (1.80-2.18) mg/l] and in patients with UC [2.07 (1.82-2.32) mg/l] compared with HC [1.51 (1.38-1.63) mg/l] (P < 0.001). Anti-TNF-α antibody treatment induced a rapid decrease in sCD163 levels in patients with CD and in patients with UC 1 day after treatment initiation (P < 0.05). One week of prednisolone treatment did not induce a reduction in sCD163 levels. Anti-TNF-α treatment normalized sCD163 levels in patients with UC, whereas patients with CD exhibited sustained increased sCD163 levels. In patients with CD, CD163 expression on CD14(+) monocytes was increased compared with HC. This study highlights that active CD and UC are associated with increased macrophage activation, as indicated by elevated sCD163 levels and monocytic CD163 expression. Anti-TNF-α antibody treatment induced a rapid decrease in sCD163 levels, suggesting a specific effect on macrophage activation in inflammatory bowel diseases.

History, background, concepts and current use of comedication and polypharmacy in psychiatry.

Based on a careful literature search a review is presented of the history, background, concepts and current use of comedication and polypharmacy in psychiatry. The pros and cons of comedication and polypharmacy are presented, as well as their apparent increase in recent times. Possible reasons for the increase of comedication/polypharmacy are described. Both the potential advantages as well as the potential risks are discussed. The one sided view that all comedication/polypharmacy is nothing but problematic is questioned. Comedication/polypharmacy seems to be, among others, the current answer to the well-known limited efficacy and effectiveness of current monotherapy treatment strategies.

Pattern recognition in long­term Sooty Shearwater data: applying machine learning to create a harvest index.

Rakiura Maori (New Zealand's southernmost group of indigenous peoples) have harvested the chicks of burrow-nesting Sooty Shearwaters (Titi; Puffinus griseus) for generations. As part of the harvest process, some families have maintained annual harvest diaries, some dating back to the 1950s. We used generalized boosted regression models, a machine-learning algorithm, to calculate a harvest index that takes into account factors that could impact the numbers of birds taken on any given hunt. For predicted vs. observed values, r2 was between 0.59 and 0.90 for the nanao (first half of the season, when chicks are harvested from burrows during the day) and 0.67 and 0.88 for the rama (second half of the season, during which chicks are harvested from the surface at night). Exploration of the controlling factors of the models revealed that "day of season" plays an important role in predicting daily harvest during the second half of the season (the rama). The nightly tally in the rama peaked approximately halfway through (10­15 days in), which is probably related to the timing of birds emerging from burrows to fledge. The models also suggested that data from the rama (when chicks are 100­120 days old) may be the most suitable for long-term monitoring of populations of Sooty Shearwaters due to consistencies in calculated harvest indices between diaries. Nanao harvest indices, although less consistent, showed patterns similar to those of the rama. When comparing these data to the harvest indices calculated by general linear models by Clucas and colleagues, we found that the agreement between both indices was r2 = 0.31 and r2 = 0.59 for the nanao and rama, respectively. The use of machine learning to correct for extraneous factors (e.g., hunting effort, skill level, or weather) and to create standardized measures could be applied to other systems such as fisheries or terrestrial resource management.