A pilot study of an organised population-based testing programme for prostate cancer.

OBJECTIVE: To determine the feasibility of a digitally automated population-based programme for organised prostate cancer testing (OPT) in Southern Sweden. PATIENTS AND METHODS: A pilot project for a regional OPT was conducted between September 2020 and February 2021, inviting 999 randomly selected men aged 50, 56, or 62 years. Risk stratification was based on prostate-specific antigen (PSA) level, PSA density (PSAD), and bi-parametric prostate magnetic resonance imaging (MRI). Men with a PSA level of 3-99 ng/mL had an MRI, and men with elevated PSA level (≥3 ng/mL) had a urological check-up, including a digital rectal examination and transrectal ultrasonography (TRUS). Indications for targeted and/or systematic transrectal prostate biopsies were suspicious lesions on MRI (Prostate Imaging-Reporting and Data System [PI-RADS] 4-5) and/or PSAD > 0.15 ng/mL/mL. Additional indications for prostate biopsies were palpable tumours, PSA ratio < 0.1, or cancer suspicion on TRUS. Patient selection, mail correspondence, data collection, and algorithm processing were performed by an automated digital management system. Feasibility is reported descriptively. RESULTS: A total of 418 men had a PSA test (42%), with increasing participation rates by age (50 years, 38%; 56 years, 44%; and 62 years, 45%). Among these, 35 men (8%) had elevated PSA levels (≥3 ng/mL: one of 139, aged 50 years; 10/143, aged 56 years; and 24/146, aged 62 years). On MRI, 16 men (48%) had a negative scan (PI-RADS < 3), seven men (21%) had PI-RADS 3, nine men (27%) had PI-RADS 4, and one man (3%) had PI-RADS 5. All men with PI-RADS 4 or 5 underwent prostate biopsies, as well as two men with PI-RADS 3 due to PSAD > 0.15 ng/mL/mL or a suspicious finding on TRUS. Prostate cancer was diagnosed in 10 men. Six men underwent active treatment, whereas four men were assigned to active surveillance. CONCLUSION: Our OPT model is feasible from an operational point of view, but due to the limited scale of this study no conclusions can be made regarding the efficacy of the diagnostic model or outcome.

The Swedish version of the Motivation and Pleasure Scale self-report (MAP-SR): psychometric properties in patients with schizophrenia or depression.

PURPOSE: Negative symptoms are commonly regarded as a symptom dimension belonging to schizophrenia spectrum disorders but are also present in depression. The recently developed Clinical Assessment Interview for Negative Symptoms (CAINS) has shown to be reliable and valid. A corresponding self-report questionnaire has also been developed, named the Motivation and Pleasure Scale - Self Report (MAP-SR). The purpose was to evaluate the psychometric properties of the Swedish version of the MAP-SR in patients with either schizophrenia or depression. MATERIALS AND METHODS: The MAP-SR was translated to Swedish. Participants were 33 patients with schizophrenia spectrum disorders and 52 patients with a depressive disorder and they completed the MAP-SR, the CAINS and other measures assessing adjacent psychopathology, functioning and cognition. RESULTS: The internal consistency for the MAP-SR was adequate in both groups (schizophrenia spectrum α = .93, depressive disorder α = .82). Furthermore, the MAP-SR had a large correlation to the motivation and pleasure subscale of the CAINS in patients with schizophrenia disorders (r = -0.75, p < .001), however among patients with depression this correlation was medium-to-large (r = -0.48, p < 0.001). CONCLUSIONS: Findings suggest that the Swedish version of the MAP-SR shows promise as a useful measure of motivation and pleasure, especially in patients with schizophrenia spectrum disorders. Furthermore, results also suggest that the MAP-SR does not assess negative symptoms specifically, but that there is an overlap between depressive and negative symptoms.

Changes in apparent diffusion coefficient and pathological response in colorectal liver metastases after preoperative chemotherapy.

BACKGROUND: The pathological response to preoperative chemotherapy of colorectal liver metastases (CRLMs) is predictive of long-term prognosis after liver resection. Accurate preoperative assessment of chemotherapy response could enable treatment optimization. PURPOSE: To investigate whether changes in lesion-apparent diffusion coefficient (ADC) measured with diffusion-weighted magnetic resonance imaging (MRI) can be used to assess pathological treatment response in patients with CRLMs undergoing preoperative chemotherapy. MATERIAL AND METHODS: Patients who underwent liver resection for CRLMs after preoperative chemotherapy between January 2011 and December 2019 were retrospectively included if they had undergone MRI before and after preoperative chemotherapy on the same 1.5-T MRI scanner with diffusion-weighted imaging with b-values 50, 400, and 800 s/mm2. The pathological chemotherapy response was assessed using the tumor regression grade (TRG) by AJCC/CAP. Lesions were divided into two groups: pathological responding (TRG 0-2) and non-responding (TRG 3). The change in lesion ADC after preoperative chemotherapy was compared between responding and non-responding lesions. RESULTS: A total of 27 patients with 49 CRLMs were included, and 24/49 lesions showed a pathological chemotherapy response. After chemotherapy, ADC increased in both pathological responding (pretreatment ADC: 1.26 [95% confidence interval (CI)=1.06-1.37] vs. post-treatment ADC: 1.33 [95% CI=1.13-1.56] × 10-3 mm2/s; P = 0.026) and non-responding lesions (1.12 [95% CI=0.980-1.21] vs. 1.20 [95% CI=1.09-1.43] × 10-3 mm2/s; P = 0.018). There was no difference in median relative difference in ADC after chemotherapy between pathological responding and non-responding lesions (15.8 [95% CI=1.42-26.3] vs. 7.17 [95% CI=-4.31 to 31.2]%; P = 0.795). CONCLUSION: Changes in CRLM ADCs did not differ between pathological responding and non-responding lesions.

Psychometric properties of the Clinical Assessment Interview for Negative Symptoms (CAINS) in patients with depression and its relationship to affective symptoms.

BACKGROUND: There is a conceptual overlap between negative and depressive symptoms, requiring further exploration to advance the understanding of negative symptoms. The aim of this study was to examine psychometric properties of the Clinical Assessment Interview for Negative Symptoms (CAINS) in patients with depression, and to explore the relationship between the negative and affective symptoms domains. METHODS: Fifty-one patients with a depressive episode were included and interviewed with the CAINS and the Brief Psychiatric Rating Scale-Expanded (BPRS-E). Self-reported depressive symptoms were collected with the Montgomery-Asberg Depression Rating Scale (MADRS-S). Inter-rater agreement, internal consistency and validity measures were examined, as were correlations between negative and affective symptoms. RESULTS: The intraclass correlation for the CAINS motivation and pleasure subscale (CAINS-MAP) was 0.98 (95% CI 0.96-0.99) and that for the expressional subscale (CAINS-EXP) was 0.81 (95% CI 0.67-0.89). Cronbach's alpha was 0.71 (95% CI 0.57-0.82) for the CAINS-MAP and 0.86 (95% CI 0.79-0.92) for the CAINS-EXP. The correlation with the negative symptoms subscale of the BPRS-E was 0.35 (p = 0.011, blinded/different raters) or 0.55 (p < 0.001, not blinded/same rater). The CAINS-MAP correlated with the affective symptoms subscale of the BPRS-E (r = 0.39, p = 0.005) and the MADRS-S total score (r = 0.50, p < 0.001), but not with anxiety symptoms. CONCLUSIONS: Negative symptoms in depression can be assessed with the CAINS with good inter-rater agreement and acceptable internal consistency and validity. There are associations between negative and depressive symptoms that call for further exploration.

The role of computed tomography in the assessment of tumour extent and the risk of residual disease after upfront surgery in advanced ovarian cancer (AOC).

PURPOSE: Epithelial ovarian cancer is usually diagnosed in the advanced stages. To choose the best therapeutic approach, an accurate preoperative assessment of the tumour extent is crucial. This study aimed to determine whether the peritoneal cancer index (PCI), the amount of ascites, and the presence of cardiophrenic nodes (CPLNs) visualized by computed tomography (CT) can assess the tumour extent (S-PCI) and residual disease (RD) for advanced ovarian cancer (AOC) patients treated with upfront surgery. METHODS: In total, 118 AOC cases were included between January 2016 and December 2018 at Skåne University Hospital, Lund, Sweden. Linear regression and interclass correlation (ICC) analyses were used to determine the relationship between CT-PCI and S-PCI. The patients were stratified in complete cytoreductive surgery (CCS) with no RD or to non-CCS with RD of any size. The amount of ascites on CT (CT-ascites), CA-125 and the presence of radiological enlarged CPLNs (CT-CPLN) were analysed to evaluate their impact on estimating RD. RESULTS: CT-PCI correlated well with S-PCI (0.397; 95% CI 0.252-0.541; p < 0.001). The risk of RD was also related to CT-PCI (OR 1.069 (1.009-1.131), p < 0.023) with a cut-off of 21 for CT-PCI (0.715, p = 0.000). The sensitivity, specificity, positive predictive value and negative predictive value were 58.5, 70.3, 52.2 and 75.4%, respectively. CT-ascites above 1000 ml predicted RD (OR 3.510 (1.298-9.491) p < 0.013). CONCLUSION: CT is a reliable tool to assess the extent of the disease in advanced ovarian cancer. Higher CT-PCI scores and large volumes of ascites estimated on CT predicted RD of any size.

A blinded validation of the Swedish version of the Clinical Assessment Interview for Negative Symptoms (CAINS).

PURPOSE: The Clinical Assessment Interview for Negative Symptoms (CAINS) was developed in order to advance the assessment of negative symptoms. The aim of this study was to validate the Swedish version of the CAINS. MATERIALS AND METHODS: Thirty-four out-patients with a schizophrenia spectrum disorder were recruited. All patients were videotaped while interviewed with the CAINS and the Brief Psychiatric Rating Scale (BPRS). Another rater watched the video recordings in the reverse order, enabling a blinded design. The patients also filled in self-reported measures of depression, quality of life, and social and vocational functioning. We calculated inter-rater agreement and internal consistency for the CAINS. We also calculated validity measures by correlating the subscales Motivation and Pleasure (CAINS-MAP) and Expression (CAINS-EXP) to subscales of the BPRS. RESULTS: The blinded inter-rater agreement for the CAINS total score was high (ICC = 0.92) but slightly lower for the expression subscale (ICC = 0.76). Cronbach's alpha was 0.84 for the total score. Convergent validity with the negative symptoms subscale of BPRS was different for the blinded and the unblinded data, with a CAINS-MAP correlation of 0.10 (p = 0.580) and a CAINS-EXP correlation of 0.48 (p = 0.004) in the blinded data. The unblinded data had a CAINS-MAP correlation of 0.38 (p = 0.026) and a CAINS-EXP correlation of 0.87 (p < 0.001). Self-rated measures of anhedonia correlated to CAINS-MAP with a coefficient of 0.68 (p < 0.001), while the CAINS-EXP only had a correlation of 0.16 (p = 0.366) to these measures. CONCLUSION: The Swedish version of the CAINS displays adequate psychometric properties in line with earlier validation studies.

Ambulatory Heart Rate Variability in Schizophrenia or Depression: Impact of Anticholinergic Burden and Other Factors.

BACKGROUND: Heart rate variability (HRV) has been found reduced in patients with schizophrenia and depression. However, there is a lack of knowledge on how demographic, lifestyle, and pharmacological factors contribute to the reduction in HRV in these patients. METHODS: We recruited 37 patients with schizophrenia, 43 patients with unipolar depression, and 64 healthy controls. A combined chest-worn HRV and accelerometer device was used in an ambulatory measurement. Age, sex, anticholinergic burden of medication, nicotine use, body mass index, and ongoing physical activity were assessed in multiple regression models regarding their influence on HRV, measured as the standard deviation of all the RR intervals (SDNN). RESULTS: In the fully adjusted model, schizophrenia (ß = -0.23, P = 0.019), depression (ß = -0.18, P = 0.028), age (ß = -0.34, P < 0.000), ongoing physical activity (ß = -0.23, P = 0.001), and anticholinergic burden (ß = -0.19, P = 0.025) influenced SDNN negatively. Sex, nicotine use, and BMI had negligible effects on SDNN. CONCLUSIONS: We show for the first time that a quantified score of anticholinergic burden of medication has a negative relationship to HRV in patients with schizophrenia or depression, but that the diagnoses themselves still exhibit an effect on HRV.

Uterine artery embolization in a sheep model: biodegradable versus non-degradable microspheres.

Background Transarterial embolization with particles is a relatively common treatment method in both malignant and benign disorders. Permanent occlusion of the uterine arteries may sometimes be disadvantageous. Purpose To compare the local tissue effects, possible side effects, and extent of recanalization following uterine artery embolization, using either degradable or non-degradable microspheres in a sheep model. Material and Methods In 22 female sheep, the uterine artery (UA) was unilaterally, superselectively embolized, with either degradable starch microspheres-DSM (group A) or calibrated gelatin coated spherical shape tris-acryl microspheres-TGMS (group B). The completion of embolization was confirmed by angiography. The animals were kept in the animal research facilities for 14 days and sacrificed following new angiographic evaluation. Gross and histological examination of the uterus and other organs was performed. Results The procedure was successful in all animals. At final angiographic evaluation recanalization was found in 82% of the ewes in group A and in 18% in group B. At histopathological examination, tissue impairment was similar in both groups, whereas vascular changes were more pronounced in the TGMS-group. Conclusion Embolization with DSM was associated with significantly higher degree of recanalization, than after embolization with TGMS.

The effects of uterine artery embolization with a new degradable microsphere in an experimental study.

Background Transarterial particle embolization is a common treatment of uterine fibroids, aiming to obtain ischemia resulting in shrinking of the fibroid with preservation of normal uterine tissue. Embolization with non-degradable microspheres is established, but causes permanent occlusion of the arteries, affecting both the uterus as well as the fibroids. Purpose To evaluate in vivo degradation, local tissue effects, and possible recanalization following intra-arterial deposition of the new, degradable starch microspheres (DSM), in a short-term experimental pilot study. Material and Methods Under general anesthesia, unilateral transarterial embolization of the uterine artery (UA) with DSM 500-700 µm was performed in five female sheep. The animals underwent renewed angiography at different intervals after embolization (19-65 h) and were subsequently sacrificed. Histological examination was performed. Results Embolization with absent flow in the UA could be completed in five of six animals. At final angiographic evaluation, recanalization of the embolized arteries was evident in three sheep. At the gross postmortem examination, edema and discoloration indicating ischemia of the uterus at the embolized side, was observed in all the sheep. At histopathological examination, different stages of DSM degradation in the arterial branches were observed in both endometrium and myometrium. Mild-to-moderate vasculitis and mild-to-extensive ischemic changes were present along with degeneration of the uterine glands. Conclusion This short-term pilot study proved efficacy of embolization with DSM causing ischemic changes in the embolized organ, but also degradation of the DSM with subsequent recanalization of the embolized arteries.

Web-Based STAR E-Learning Course Increases Empathy and Understanding in Dementia Caregivers: Results from a Randomized Controlled Trial in the Netherlands and the United Kingdom.

BACKGROUND: The doubling of the number of people with dementia in the coming decades coupled with the rapid decline in the working population in our graying society is expected to result in a large decrease in the number of professionals available to provide care to people with dementia. As a result, care will be supplied increasingly by untrained informal caregivers and volunteers. To promote effective care and avoid overburdening of untrained and trained caregivers, they must become properly skilled. To this end, the European Skills Training and Reskilling (STAR) project, which comprised experts from the domains of education, technology, and dementia care from 6 countries (the Netherlands, Sweden, Italy, Malta, Romania, and the United Kingdom), worked together to create and evaluate a multilingual e-learning tool. The STAR training portal provides dementia care training both for informal and formal caregivers. OBJECTIVE: The objective of the current study was to evaluate the user friendliness, usefulness, and impact of STAR with informal caregivers, volunteers, and professional caregivers. METHODS: For 2 to 4 months, the experimental group had access to the STAR training portal, a Web-based portal consisting of 8 modules, 2 of which had a basic level and 6 additional modules at intermediate and advanced levels. The experimental group also had access to online peer and expert communities for support and information exchange. The control group received free access to STAR after the research had ended. The STAR training portal was evaluated in a randomized controlled trial among informal caregivers and volunteers in addition to professional caregivers (N=142) in the Netherlands and the United Kingdom. Assessments were performed with self-assessed, online, standardized questionnaires at baseline and after 2 to 4 months. Primary outcome measures were user friendliness, usefulness, and impact of STAR on knowledge, attitudes, and approaches of caregivers regarding dementia. Secondary outcome measures were empathy, quality of life, burden, and caregivers' sense of competence. RESULTS: STAR was rated positively by all user groups on both usefulness and user friendliness. Significant effects were found on a person-centered care approach and on the total score on positive attitudes to dementia; both the experimental and the control group increased in score. Regarding empathy, significant improvements were found in the STAR training group on distress, empathic concern, and taking the perspective of the person with dementia. In the experimental group, however, there was a significant reduction in self-reported sense of competence. CONCLUSIONS: The STAR training portal is a useful and user-friendly e-learning method, which has demonstrated its ability to provide significant positive effects on caregiver attitudes and empathy.

Blinding integrity of dorsomedial prefrontal intermittent theta burst stimulation in depression.

Background: The antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) is partly placebo, making blinding integrity important. Blinding of high-frequency rTMS and intermittent theta burst stimulation (iTBS) has been reported as successful at study end. However, blinding integrity at study start is rarely reported. The aim of this study was to investigate blinding integrity during a treatment course of iTBS over the dorsomedial prefrontal cortex (DMPFC) in depression. Methods: Forty-nine patients with depression from a double-blind-designed randomized controlled trial (NCT02905604) were included. Patients received either active or sham iTBS over the DMPFC with a placebo coil. The sham group received iTBS-synchronized transcutaneous electrical nerve stimulation. Results: After one session, 74% of participants were able to correctly guess their treatment allocation. This was above chance level (p = 0.001). The percentage dropped to 64% and 56% after the fifth and last sessions. Belonging to the active group influenced the choice to guess "active" (odds ratio: 11.7, 95% CI 2.5-53.7). A higher treatment intensity of the sham treatment increased the probability to guess "active", but pain did not influence the choice. Conclusions: Blinding integrity in iTBS trials must be investigated at study start to avoid uncontrolled confounding. Better sham methods are needed.

No effects on heart rate variability in depression after treatment with dorsomedial prefrontal intermittent theta burst stimulation.

Background: The purpose of this study was to investigate whether treatment of a depressive episode with intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) had any effects on heart rate variability (HRV). We also investigated if changes in HRV covaried with symptom change after iTBS and if HRV could predict symptom change. Methods: We included 49 patients with a current depressive episode. All were randomized to receive a double-blind treatment course with active or sham iTBS over the DMPFC. HRV data were obtained from 1 h of night data before and after the iTBS. The standard deviation of the RR interval (SDNN) was chosen as primary outcome measure. Depressive, negative, and anxiety symptoms as well as self-rated health were assessed by clinicians or by self-report. Results: The group×time linear mixed model revealed no effect of iTBS on SDNN (estimate = -1.8, 95% confidence interval [CI]: -19.9 to 16.2). There were neither correlations between HRV and depressive, negative, or anxiety symptom change after iTBS nor with self-assessed health. No predictive value of HRV was found. Conclusions: Treatment for depression with dorsomedial iTBS had neither negative nor positive effects on the cardiac autonomic nervous system.

Correlation between ADC, ADC ratio, and Gleason Grade group in prostate cancer patients undergoing radical prostatectomy: Retrospective multicenter study with different MRI scanners.

Background: MRI is an important tool in the prostate cancer work-up, with special emphasis on the ADC sequence. This study aimed to investigate the correlation between ADC and ADC ratio compared to tumor aggressiveness determined by a histopathological examination after radical prostatectomy. Methods: Ninety-eight patients with prostate cancer underwent MRI at five different hospitals prior to radical prostatectomy. Images were retrospectively analyzed individually by two radiologists. The ADC of the index lesion and reference tissues (contralateral normal prostatic, normal peripheral zone, and urine) was recorded. Absolute ADC and different ADC ratios were compared to tumor aggressivity according to the ISUP Gleason Grade Groups extracted from the pathology report using Spearman's rank correlation coefficient (ρ). ROC curves were used to evaluate the ability to discriminate between ISUP 1-2 and ISUP 3-5 and intra class correlation and Bland-Altman plots for interrater reliability. Results: All patients had prostate cancer classified as ISUP grade ≥ 2. No correlation was found between ADC and ISUP grade. We found no benefit of using the ADC ratio over absolute ADC. The AUC for all metrics was close to 0.5, and no threshold could be extracted for prediction of tumor aggressivity. The interrater reliability was substantial to almost perfect for all variables analyzed. Conclusions: ADC and ADC ratio did not correlate with tumor aggressiveness defined by ISUP grade in this multicenter MRI study. The result of this study is opposite to previous research in the field.

Usability of a new electronic assistive device for community-dwelling persons with mild dementia.

OBJECTIVE: To evaluate a newly developed integrated digital prosthetic, the COGKNOW Day Navigator (CDN), to support persons with mild dementia in their daily lives, with memory, social contacts, daily activities and safety. METHODS: A user participatory method was applied in the development process, which consisted of three iterative 1-year cycles with field tests in Amsterdam, Belfast and Luleå. In the successive cycles 16, 14 and 12 persons with dementia and their carers participated. Data on usability were collected by means of interviews, observations, questionnaires, logging and diaries. The CDN prototype consists of a touch screen, a mobile device, sensors and actuators. RESULTS: The evaluation showed that persons with dementia and carers valued the CDN overall as user-friendly and useful. Conclusions regarding the effectiveness of the system in daily life were limited due to insufficient duration of the testing period caused by delays in development and some instability of the final prototype. CONCLUSION: With the suggested adaptations, the CDN is expected to be a useful tool for supporting community-dwelling persons with mild dementia and their carers.

Prognostic Value of Peritoneal Cancer Index After Complete Cytoreductive Surgery in Advanced Ovarian Cancer.

BACKGROUND/AIM: Residual disease (RD) after primary debulking surgery (PDS) is a prognostic factor for survival in advanced ovarian cancer (AOC). This study aimed to examine whether the tumor extent affects overall survival (OS) and progression-free survival (PFS) in AOC patients treated with PDS. PATIENTS AND METHODS: A total of 118 patients treated with PDS were included. Age, ECOG score, AOC International Federation of Gynecology and Obstetrics (FIGO) stage, CA-125, RD, peritoneal cancer index (PCI), preoperative imaging (CT-PCI) and macroscopic visualization at the surgery start (S-PCI) were analyzed. Tumor extent was quantified using the PCI, and by CT-PCI and S-PCI. Cox regression, Kaplan-Meier and receiver operating curves (ROC) were performed for survival analyses. RESULTS: S-PCI correlated with both OS (1.067, 95%CI=1.018-1.119, p<0.007) and PFS. Patients exhibiting S-PCI≥18.5, adjusted to age, performance status, and RD, had a two-fold risk of dying (HR=2.070, 95%CI=1.061-4.038, p=0.033) compared those with PCI<18.5. CT-PCI correlated with OS in crude data (1.037, 95%CI=1.005-1.071, p=0.025), but this was not sustained in multivariate analyses. RD of any size doubled the risk of dying (2.177, 95%CI=1.235-3.838, p=0.007). CONCLUSION: The tumor extent at the beginning of surgery seemed to affect OS in patients with AOC, regardless of the extent of RD at the end of the surgery. PCI above 18.5 doubled the risk of dying of the disease. No difference in major complications was noted in the two groups of patients. CT-PCI seemed to play a prognostic role for PFS; however, it is still to be investigated as a prognostic factor for OS.

Designing and Implementing a Population-based Organised Prostate Cancer Testing Programme.

BACKGROUND: European guidelines recommend that well-informed men at elevated risk of having prostate cancer (PCa) should be offered prostate-specific antigen (PSA) testing with risk-stratified follow-up. The Swedish National Board of Health and Welfare recommends against screening for PCa but supports regional implementation of organised prostate cancer testing (OPT). OBJECTIVE: To report the process for designing and implementing OPT programmes. DESIGN, SETTING, AND PARTICIPANTS: Population-based OPT programmes in two Swedish regions, designed to include men aged between 50 and 74 yr, launched in September 2020 for 50-yr-old men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The number of men invited, the participation rate, and the numbers of magnetic resonance imaging (MRI) scans, urological visits, and biopsies from September 2020 to June 2021 were recorded. RESULTS AND LIMITATIONS: Two Swedish regions co-designed an OPT programme with a risk-stratified diagnostic algorithm based on prostate-specific antigen (PSA), PSA density, MRI findings, and age. An automated administrative system was developed on a nationwide web-based platform. Invitation letters and test results are automatically generated and sent out by post. Men with PSA ≥3ng/ml, a suspicious MRI lesion, and/or PSA density ≥0.15 ng/ml/cm3 are referred for a prostate biopsy. Test results are registered for quality control and research. By June 2021, a total of 16 515 men were invited, of whom 6309 (38%) participated; 147 had an MRI scan and 39 underwent prostate biopsy. The OPT framework, algorithm, and diagnostic pathways have been working well. CONCLUSIONS: We designed and implemented a framework for OPT with a high grade of automation. The framework and organisational experiences may be of value for others who plan a programme for early detection of PCa. PATIENT SUMMARY: We describe the implementation of an organised testing programme for early detection of prostate cancer in two Swedish regions. This model is the first of its kind and may serve as a template for similar programmes.

Development of a prognostic MRCP-score (DiStrict) for individuals with large-duct primary sclerosing cholangitis.

Background & Aims: Magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis and follow-up of individuals with primary sclerosing cholangitis (PSC). The aim of our study is to develop an MRCP-score based on cholangiographic findings previously associated with outcomes and assess its reproducibility and prognostic value in PSC. Methods: The score (DiStrict score) was developed based on the extent and severity of cholangiographic changes of intrahepatic and extrahepatic bile ducts (range 0-8) on 3D-MRCP. In this retrospective, multicentre study, three pairs of radiologists with different levels of expertise from three tertiary centres applied the score independently. MRCP examinations of 220 consecutive individuals with PSC from a prospectively collected PSC-cohort, with median follow-up of 7.4 years, were reviewed. Inter-reader and intrareader agreements were assessed via intraclass correlation coefficient (ICC). After consensus, the prognostic value of the score was assessed using Cox-regression and outcome-free survival rates were assessed via Kaplan-Meier estimates. Harrell's C-statistic was calculated. Results: Forty patients developed outcomes (liver transplantation or liver-related death). Inter-reader agreement between experienced radiologists was good (ICC 0.82; 95% CI 0.74-0.87, and ICC 0.81; 95% CI 0.70-0.87, respectively) and better than the agreement for the pair of experienced/less-experienced radiologists (ICC 0.48; 95% CI 0.05-0.72). Agreement between radiologists from the three centres was good (ICC 0.76; 95% CI 0.57-0.89). Intrareader agreement was good to excellent (ICC 0.85-0.93). Harrell's C was 0.78. Patients with a DiStrict score of 5-8 had 8.2-fold higher risk (hazard ratio 8.2; 95% CI 2.97-22.65) of developing outcomes, and significantly worse survival (p <0.001), compared to those with a DiStrict score of 1-4. Conclusions: The novel DiStrict score is reproducible and strongly associated with outcomes, indicating its prognostic value for individuals with PSC in clinical practice. Impact and implications: The diagnosis of primary sclerosing cholangitis (PSC) is based on magnetic resonance cholangiopancreatography (MRCP). However, the role of MRCP in the prognostication of PSC is still unclear. We developed a novel, simple, and reproducible risk-score, based on MRCP findings, that showed a strong association with prognosis in individuals with PSC (DiStrict score). This score can be easily used in clinical practice and thus has the potential to be useful in clinical trials and in patient counselling and management.

Metaxa: a software tool for automated detection and discrimination among ribosomal small subunit (12S/16S/18S) sequences of archaea, bacteria, eukaryotes, mitochondria, and chloroplasts in metagenomes and environmental sequencing datasets.

The ribosomal small subunit (SSU) rRNA gene has emerged as an important genetic marker for taxonomic identification in environmental sequencing datasets. In addition to being present in the nucleus of eukaryotes and the core genome of prokaryotes, the gene is also found in the mitochondria of eukaryotes and in the chloroplasts of photosynthetic eukaryotes. These three sets of genes are conceptually paralogous and should in most situations not be aligned and analyzed jointly. To identify the origin of SSU sequences in complex sequence datasets has hitherto been a time-consuming and largely manual undertaking. However, the present study introduces Metaxa ( http://microbiology.se/software/metaxa/ ), an automated software tool to extract full-length and partial SSU sequences from larger sequence datasets and assign them to an archaeal, bacterial, nuclear eukaryote, mitochondrial, or chloroplast origin. Using data from reference databases and from full-length organelle and organism genomes, we show that Metaxa detects and scores SSU sequences for origin with very low proportions of false positives and negatives. We believe that this tool will be useful in microbial and evolutionary ecology as well as in metagenomics.

BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.