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Background Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohns disease (CD) are still limited. Aim To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. Methods Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (>= 3-point-decrease of Harvey-Bradshaw index (HBI)) and remission (HBI = 1 and 58 (51%) >= 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. Conclusions In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option. Funding Agencies|Janssen Cilag AB, Sweden

Background Although prostate-specific antigen (PSA) testing is common, little is known about the pattern of retesting by either PSA values or subsequent prostate biopsies. Poor follow-up of high PSA values may lead to delayed diagnosis. Objective To estimate the probabilities of follow-up (including retesting, prostate biopsies, diagnosis, and cause-specific death) for men undergoing prostate cancer testing at a population level. Design, setting, and participants Cohort study design for men living in Stockholm with no previous diagnosis of prostate cancer between 2003 and 2015. Men were linked to the national health and population registries in Sweden. We report follow-up for men aged 50–79 yr at 2003 or at their index PSA test. Outcome measurements and statistical analysis State probabilities with 95% confidence intervals (CIs) were calculated using multistate Markov models. Results and limitations Among men not previously diagnosed with prostate cancer with an initial PSA value of ≥10ng/ml, the proportions at 1 yr with no subsequent testing or only elevated PSA test values >3ng/ml were 21.7% (95% CI: 19.5, 23.9), 25.2% (95% CI: 23.9, 26.6), and 47.7% (95% CI: 46.2, 49.1) for those aged 50–59, 60–69, and 70–79 yr, respectively. No significant changes were noticed when stratifying by comorbidities. Limitations include the lack of detail from patient medical charts. This detail would have allowed for more accurate assessment of appropriate clinical follow-up. Conclusions Regardless of medical history, a large proportion of men with PSA≥10ng/ml were not followed appropriately at 1 yr after the index PSA test. This may partially explain why opportunistic testing is not as effective as screening within trials to reduce prostate cancer mortality. Patient summary For men aged 50–69 yr, who undertake a prostate-specific antigen (PSA) test, a PSA level of >10ng/ml should prompt further investigation. However, we found that one out of 10 of these men did not receive repeat testing within 1 yr of the initial test. This may partially explain why opportunistic prostate cancer testing is less effective than screening trials.

Pathology training resources remain scarce in many parts of the world. With rapid economic development comes the need to educate new pathologists to meet the medical care demands. Our aim was to set up a cost-effective system for training and testing the diagnostic skills of pathologists. Pathologists in nine countries in Asia and South America were invited by the International Society of Urological Pathology (ISUP) to participate in a prostate pathology education course combining image-based tests with lectures and on-line tutorials. The tests and tutorials are available free of charge at the ISUP education website www.edu.isupweb.org . A total of 603 pathologists registered on the website. Of these, 224 completed pre- and post-lecture assessments (tests 1 and 2). Replies were classified as correct/acceptable, when a lesion was accurately classified into clinically relevant categories (benign, cancer, high-grade prostatic intraepithelial neoplasia, intraductal carcinoma of the prostate). The rate of correct/acceptable replies increased from 60.7 to 72.3% in Tests 1 and 2, respectively. In Test 1, pathologists from upper middle, lower middle, and low resource countries gave a correct/acceptable diagnosis in 65.8%, 61.0%, and 47.4%, respectively. Their results improved in Test 2 to 76.4%, 72.5%, and 62.8%, respectively. The greatest improvement in diagnostic ability was achieved in pathologists from the low resource group of countries. The use of web-based testing and training, combined with lectures, is an efficient method for improving diagnostic skills of pathologists in low to middle resource countries.

Background RBC concentrates are commonly stored for up to 42 days but there has been conflicting evidence on the effect of storage duration and clinical outcomes. Most clinical studies have focused on possible associations between duration of storage time and risk for adverse outcomes, including mortality. Recent clinical trials did not find any such associations, but fewer studies have addressed whether storage time affects component efficacy. The main aim of this study was to determine the effect of RBC storage time on hemoglobin increment in transfused patients. Study design and methods Transfusion data on a cohort of patients with myelodysplastic syndromes were linked to hemoglobin measurements taken between 2 days before and 28 days after a transfusion episode. We applied a mixed-effect linear regression model, accounting for patient characteristics and time from transfusion to next hemoglobin measurement, to study the effect of RBC storage on the hemoglobin increment. Results The study population consisted of 225 patients who received 6437 RBC units. Compared to units stored less than 5 days, transfusion of blood units stored 5 to 9, 10 to 19, 20 to 29, or 30 or more days resulted in hemoglobin increases that were 0.83 (95% confidence interval [CI], 0.24-1.41), 0.92 (95% CI, 0.34-1.51), 1.33 (95% CI, 0.65-2.02) and 1.51 (95% CI, 0.58-2.43) g/L lower, respectively, per RBC unit. Results were consistent in sensitivity analyses. Conclusions Longer RBC storage was associated with a smaller increase in hemoglobin concentration after transfusion. Although statistically significant, the effect was modest, and its clinical relevance in subgroups of patients should be investigated in prospective clinical trials.

Cure models are used in time-to-event analysis when not all individuals are expected to experience the event of interest, or when the survival of the considered individuals reaches the same level as the general population. These scenarios correspond to a plateau in the survival and relative survival function, respectively. The main parameters of interest in cure models are the proportion of individuals who are cured, termed the cure proportion, and the survival function of the uncured individuals. Although numerous cure models have been proposed in the statistical literature, there is no consensus on how to formulate these. We introduce a general parametric formulation of mixture cure models and a new class of cure models, termed latent cure models, together with a general estimation framework and software, which enable fitting of a wide range of different models. Through simulations, we assess the statistical properties of the models with respect to the cure proportion and the survival of the uncured individuals. Finally, we illustrate the models using survival data on colon cancer, which typically display a plateau in the relative survival. As demonstrated in the simulations, mixture cure models which are not guaranteed to be constant after a finite time point, tend to produce accurate estimates of the cure proportion and the survival of the uncured. However, these models are very unstable in certain cases due to identifiability issues, whereas LC models generally provide stable results at the price of more biased estimates.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68–0.84) and 0.50 (range 0.40–0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.

Vitamin D may reduce mortality from prostate cancer (PC). We examined the associations of post-treatment plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with PC mortality. Participants were PC cases from the New South Wales Prostate Cancer Care. All contactable and consenting participants, at 4.9 to 8.6 years after diagnosis, were interviewed and had plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) measured in blood specimens. Cox regression allowing for left-truncation was used to calculate adjusted mortality hazards ratios (HR) and 95% confidence intervals (95% CI) for all-cause and PC-specific mortality in relation to vitamin D levels and other potentially-predictive variables. Of the participants (n = 111; 75·9% response rate), there were 198 deaths from any cause and 41 from PC in the study period. Plasma 25(OH)D was not associated with all-cause or PC-specific mortality (p-values > 0·10). Plasma 1,25(OH)2D was inversely associated with all-cause mortality (HR for highest relative to lowest quartile = 0·45; 95% CI: 0·29–0·69), and PC-specific mortality (HR = 0·40; 95% CI: 0·14–1·19). These associations were apparent only in men with aggressive PC: all-cause mortality HR = 0·28 (95% CI·0·15–0·52; p-interaction = 0·07) and PC-specific mortality HR = 0·26 (95% CI: 0·07–1.00). Time spent outdoors was also associated with lower all-cause (HR for 4th relative to 1st exposure quartile = 0·42; 95% CI: 0·24–0·75) and PC-specific (HR = 0·48; 95% CI: 0·14–1·64) mortality, although the 95% CI for the latter was wide. The inverse association between post-treatment plasma 1,25(OH)2D levels and all-cause and PC-specific mortality in men with aggressive PC, suggest a possible beneficial effect of vitamin D supplementation in these men.

Purpose To investigate whether herpes zoster vaccine (HZV) was associated with socioeconomic status in Stockholm, when the vaccine was reimbursed in Sweden. Methods This was an observational retrospective case-control study, using population-based health care registers. During the study period, September 2013 to November 2014, the HZV was reimbursed as part of the National Pharmaceutical Benefits Scheme in Sweden and recommended for individuals over 50 years. A case was any person, living in Stockholm County, who received HZV during the study period. For each case, 10 (unvaccinated) controls living in Stockholm County were selected and matched by age and sex. In total, 9099 cases and 89 736 controls were included. Socioeconomic variables investigated included education, income, immigration status, and marital status. We also investigated whether HZV was associated with the Charlson Comorbidity Index (CCI), and/or previous herpes zoster diagnosis. Results Mean age at vaccination was 69.8 years, and 65.8% of vaccinees were women. There was a positive association between vaccination and higher education (OR = 3.4 (95% CI 3.0-3.8) for men and OR = 2.8 (95% CI 2.6-3.0) for women, respectively) in comparison to primary education. Higher income and being married were positively associated with vaccination, particularly for men, whereas being an immigrant was negatively associated. There was a negative association between a higher CCI score and HZV, indicating that healthier individuals were more likely to have been vaccinated. Conclusions Despite the vaccine being part of the National Pharmaceutical Benefit Scheme, receipt of the HZV was significantly associated with socioeconomic factors.

Prostate cancer screening is associated with low specificity, unnecessary biopsies, and overdiagnosis. We have previously shown that the Stockholm-3 model (S3M) can reduce biopsies compared with using prostate-specific antigen (PSA) ≥3ng/ml as an indication for biopsy. Urologists in today's current prostate cancer testing (CPT) have access to numerous variables in addition to PSA (eg, age, ethnicity, family history, free PSA, PSA velocity, digital rectal examination, and prostate volume) to support biopsy decisions. We estimated the number of prostate cancers diagnosed and prostate biopsies performed if S3M replaced CPT in Stockholm, Sweden, by comparing biopsy results in 56 282 men who underwent PSA testing according to CPT in Stockholm in 2011 with the 47 688 men enrolled in the STHLM3 validation cohort 2012–2015. With the same sensitivity as CPT to diagnose Gleason score ≥7 prostate cancer, S3M was estimated to reduce the number of men biopsied by 53% (95% confidence interval [CI]: 41–65%), avoid 76% (95% CI: 67–81%) of negative biopsies, and reduce Gleason score 6 cancers by 23% (95% CI: 6–40%). S3M has the potential to improve prostate cancer diagnostics by better selecting men with high risk of GS ≥7 prostate cancer. Patient summary We modeled the effect the Stockholm-3 model would have on prostate cancer diagnostics if it replaced current clinical practice. We found that Stockholm-3 model may substantially reduce the number of biopsies, while maintaining the same sensitivity to diagnose clinically significant prostate cancer.

Aims: Harvesting of unfixed tissue from radical prostatectomy specimens for research purposes is challenging. Many prostate cancers cannot be identified at gross inspection, and this tumour is notoriously multifocal and heterogeneous. We aimed to develop a technique to allow detailed topographic analysis and the sampling of a sufficient amount of tumour without jeopardising clinical reporting. Methods and results: A custom-made double-bladed knife was utilised for cutting a 4-mm-thick horizontal section of the prostate. The slices were split into segments that were frozen in gel, cryosections were cut, and RNA integrity numbers (RINs) were analysed. Sections were cut from all blocks of 20 cases, and the cutting time was monitored. Slides were scanned, and the slices were digitally reconstructed. Cutting frozen sections of an entire slice took 79-253 min (mean 162 min). Tumour was detected in frozen sections of 85% (17/20) of cases and in 46% (72/155) of blocks. The morphological quality was determined to be excellent, and RIN values were high (mean 8.9). Conclusions: This novel protocol for biobanking of fresh tissue from prostatectomy specimens provides sufficient tumour material for research purposes, while also enabling reporting of histopathology. The harvesting of a full tissue slice facilitates studies of tumour multifocality and heterogeneity.

Objectives We present a novel approach to identify critical exposure levels or health-based benchmarks of job control using the benchmark dose (BMD) method. This method provides benchmarks for risk assessment of psychosocial risks, similar to benchmarks used for other occupational health hazards such as chemicals. Methods Two staged (bivariate and adjusted) BMD modelling was conducted using epidemiological data from an age-cohort study in south-eastern Australia. The adjusted BMD model incorporated age, gender, education, personality traits and mental health status at baseline. Results Depression is a more sensitive (health compromising) outcome for job control compared to anxiety in both types of BMD modelling. For an excess risk of 5% for depression, the adjusted benchmark dose was 0.49 and the critical exposure level, being the lower one sided 95% confidence limit of the adjusted BMD, was 0.37. If workplace guidelines are based on this critical exposure level, workers need to have a minimum of ten out of 15 aspects of job control measured in this study to reduce the excess risk of depression. Conclusions The BMD approach can identify critical exposure levels for job control. This suggests a similar approach can be used for other psychosocial risks for which no critical exposure levels are currently available. Critical exposure levels can provide guidance needed to assess risk and address psychosocial risks, similar to other health hazards. Benchmarks or critical exposure levels of psychosocial risks can assist the inspectorate and employers to conduct risk assessment of workplaces and identify areas for intervention.

This study aimed to investigate the expression of programmed death receptor ligand 1 (PD-L1) and deficient mismatch repair (dMMR) in ductal adenocarcinoma of the prostate. A tissue microarray of 32 ductal and 42 grade-matched acinar adenocarcinomas was used. Slides were stained for PD-L1, PD-L2, MMR proteins, CD4 and CD8. PD-L1 expression in tumor cells was only seen in 3% (1/34) of ductal and 5% (2/42) of acinar adenocarcinomas (p = 1.0), while PD-L1 expression in tumor-infiltrating immune cells was seen in 29% (10/34) of ductal and 14% (6/42) of acinar adenocarcinomas (p = 0.16). dMMR, as defined by loss of one or more of the MMR proteins, was identified in 5% (4/73) of cases, including 1 ductal and 3 acinar adenocarcinomas. There was a suggested association between infiltration of CD8+ lymphocytes and ductal subtype (p = 0.04) but not between CD4+ lymphocytes and tumor type (p = 0.28). The study shows that both dMMR and PD-L1 expression is uncommon in tumor cells of both ductal and acinar adenocarcinoma of the prostate, while PD-L1 expression in tumor-infiltrating immune cells is a more common finding.

Background Active surveillance (AS) is increasingly utilized for low-risk prostate cancers, to delay or avoid treatment. Objective To (1) describe uptake and surveillance intensity of real-world use of AS and compare with national guidelines, and (2) describe transitions from conservative to curative treatment by different indications of disease progression. Design, setting, and participants A population-based cohort study of men diagnosed with low-risk prostate cancer, in Stockholm County, Sweden, during 2008–2017. Follow-up was up to 10 yr, with a median of 3.5 yr. Outcome measurements and statistical analysis Poisson regression was used to estimate incidence rate ratios of prostate-specific antigen (PSA) testing and biopsies. Cox regression was used to estimate hazard ratios of starting curative treatment. Results and limitations A total of 6021 men with low-risk prostate cancer were included in the analysis; 3116 (52%) had AS recorded as the intended primary management (AS cohort). During 1, 2, and 3 yr after diagnosis, the frequencies of at least one PSA test were 90%, 92%, and 88%, respectively, and those of postdiagnostic surveillance biopsies were 42%, 19% and 18%, respectively. During surveillance, 13% of men in the AS cohort were upgraded on rebiopsy, with Gleason upgrading being the strongest factor for starting curative treatment. One limitation is the generalizability to other populations because of differences between surveillance protocols and clinical settings. Conclusions Our results show that AS is underutilized and that monitoring differs from current guidelines. Optimization of AS protocols is important in order to increase adherence and avoid overtreatment. Patient summary Active surveillance has the potential to reduce overtreatment and avoid treatment-related side effects. Our results show that few men receive the recommended monitoring.

ObjectiveGiven a man’s current prostate- specific antigen (PSA) level, age and family history of prostate cancer, what are the benefits (decreased risk of higher Gleason score [GS] cancer at diagnosis) and harms (increased risk of false-positive biopsy recommendation) of waiting 1, 2, 3, 4 or 5–8 years until the next PSA test?DesignProspective cohort.SettingAll PSA tested men in Stockholm, Sweden, between 2003 and 2015.ParticipantsMen aged 50–74 years with at least two PSA tests between 2003 and 2015 (n=174 636).Main outcome measuresLog-binomial regression to calculate the risk ratio (RR) of GS ≥7 and GS 6 versus benign outcome at prostate biopsy and 12-year cumulative probability of experiencing a false-positive biopsy by testing interval, age, PSA level and first-degree family history.ResultsMen with PSA ≤1 ng/mL had low risk of GS ≥7 prostate cancer irrespective of testing interval; 3 at the next testing occasion, and of the 663 men biopsied after the next PSA test only 32 (5%) had GS ≥7 cancer. Men with PSA >1 ng/mL had increased risk of being diagnosed with GS ≥7 prostate cancer when screened with longer than annual intervals (RRs ranged from 1.4 to 3.2 depending on PSA level and testing interval). The results were consistent across age groups and family history status. This benefit needs to be balanced against the increased risk for false-positive biopsy recommendation with shorter testing intervals (twofold for annual vs biennial and threefold for annual vs triennial).ConclusionsMen aged 50–74 years with PSA ≤1 ng/mL can wait 3–4 years before having a new PSA test. For men with PSA >1 ng/mL, we observed an increased risk of being diagnosed with GS ≥7 prostate cancer with longer than annual testing intervals. This benefit needs to be balanced against the markedly increased risks for false-positive biopsy recommendations with shorter testing intervals recommendations.

Background: Bone fractures may have an impact on prognosis of breast cancer. The long-term risks of bone fracture in breast cancer patients have not been thoroughly studied. Methods: Poisson regression was used to investigate the incidence of hospitalisation due to bone fracture comparing women with and without breast cancer based on Swedish National registers. Cox regression was used to investigate the risk of being hospitalised with bone fracture, and subsequent risk of death, in a regional cohort of breast cancer patients. Results: For breast cancer patients, the 5-year risk of bone fracture hospitalisation was 4.8% and the 30-day risk of death following a bone fracture hospitalisation was 2.0%. Compared with the general population, breast cancer patients had incidence rate ratios of 1.25 (95% CI: 1.23–1.28) and 1.18 (95% CI: 1.14–1.22) for hospitalisation due to any bone fracture and hip fracture, respectively. These ratios remained significantly increased for 10 years. Comorbidities (Charlson Comorbidity Index ⩾1) were associated with the risk of being hospitalised with bone fracture. Women taking aromatase inhibitors were at an increased risk as compared with women taking tamoxifen (HR=1.48; 95% CI: 0.98–2.22). Breast cancer patients hospitalised for a bone fracture showed a higher risk of death (HR=1.83; 95% CI: 1.50–2.22) compared with those without bone fracture. Conclusions: Women with a previous breast cancer diagnosis are at an increased risk of hospitalisation due to a bone fracture, particularly if they have other comorbidities.

We describe generalized survival models, where g( S( t| z)), for link function g, survival S, time t, and covariates z, is modeled by a linear predictor in terms of covariate effects and smooth time effects. These models include proportional hazards and proportional odds models, and extend the parametric Royston–Parmar models. Estimation is described for both fully parametric linear predictors and combinations of penalized smoothers and parametric effects. The penalized smoothing parameters can be selected automatically using several information criteria. The link function may be selected based on prior assumptions or using an information criterion. We have implemented the models in R. All of the penalized smoothers from the mgcv package are available for smooth time effects and smooth covariate effects. The generalized survival models perform well in a simulation study, compared with some existing models. The estimation of smooth covariate effects and smooth time-dependent hazard or odds ratios is simplified, compared with many non-parametric models. Applying these models to three cancer survival datasets, we find that the proportional odds model is better than the proportional hazards model for two of the datasets.

Summary Objectives Infections are a common cause of hospitalization in breast cancer patients. We studied the risk, clinical characteristics and outcomes of infection-related hospitalizations in this patient population. Methods A Swedish registry-based study including 8338 breast cancer patients diagnosed between 2001 and 2008, followed prospectively for infection-related hospitalizations until 2010. Standardized incidence ratios (SIRs) were calculated using background rates from the general female population. Associations with clinical characteristics and mortality were analyzed using flexible parametric survival models. Results In total, 720 patients experienced an infection-related hospitalization during a median follow-up of 4.9 years. Infection rates were highest within the first year of diagnosis (SIR = 5.61, 95% CI; 4.98–6.32), and site-specific risks were most pronounced for sepsis (SIR = 3.14, 95% CI; 2.66–3.71) and skin infections (SIR = 2.80, 95% CI; 2.24–3.50). Older age at diagnosis, comorbidities, markers of tumor aggressiveness, chemotherapy and axillary node dissection were independent predictors of infectious disease risk. Infection-related hospitalizations were also independently associated with overall and breast cancer-specific death. Conclusions A significant number of breast cancer patients are hospitalized with an infection following diagnosis, which in turn predicts poor prognosis. The risk profile of infection-related hospitalizations is multifactorial, including patient, tumor and treatment-related factors.

To investigate the contribution of direct electron transfer mechanisms to electricity production in microbial fuel cells by physically retaining Shewanella oneidensis cells close to or away from the anode electrode. A maximum power output of 114 ± 6 mWm−2 was obtained when cells were retained close to the anode using a dialysis membrane. This was 3.5 times more than when the cells were separated away from the anode. Without the membrane the maximum power output was 129 ± 6 mWm−2. The direct mechanisms of electron transfer contributed significantly to overall electron transfer from S. oneidensis to electrodes, a result that was corroborated by another experiment where S. oneidensis cells were entrapped in alginate gels. S. oneidensis transfers electrons primarily by direct electron transfer as opposed to mediated electron transfer.

Background Risk prediction models and magnetic resonance imaging (MRI) of the prostate can reduce unnecessary biopsies and overdiagnosis of low-risk prostate cancer. However, it is unclear how these tools should be used in concert. Objective To develop a unified risk prediction model (S3M-MRI) that combines the Stockholm3 score (based on protein and genetic markers and clinical variables) and Prostate Imaging-Reporting and Data System v.2 scores modified for MRI without contrast (modPI-RADS). Design, setting, and participants We used data for 532 men from the prospective multicentre STHLM3-MRI diagnostic study to construct S3M-MRI. We compared S3M-MRI to Stockholm3 and modPI-RADS alone with respect to model discrimination, calibration, and net benefit. We also compared clinical outcomes for five diagnostic strategies according to the use of combinations of the three models. Results and limitations The area under the receiver operating characteristic curve (AUC) was 0.88 (95% confidence interval [CI] 0.85–0.91) for S3M-MRI, which was significantly higher (p = 0.04) than for Stockholm3 (0.86, 95% CI 0.83–0.89) and modPI-RADS (0.83, 95% CI 0.79–0.87). S3M-MRI had a higher net benefit on decision curve analysis for clinically relevant probability thresholds for biopsy recommendation in comparison to Stockholm3 and modPI-RADS. However, for different diagnostic strategies, sequential use of Stockholm3 followed by MRI only for Stockholm3-positive men resulted in a similar number of unnecessary biopsies (64 vs 69) and diagnosed International Society of Urological Pathology (ISUP) grade group 1 cancers (56 vs 51) at similar sensitivity for ISUP grade group ≥2 cancers, while avoiding 38% of MRI scans. Limitations include the ethnically homogeneous study population. Conclusions The unified S3M-MRI model was superior to the Stockholm3 model and modPI-RADS alone. However, the S3M-MRI improvement was marginal compared to sequential use of Stockholm3 followed by MRI, and resulted in 60% more MRI scans. Patient summary A new risk prediction model combining clinical variables, genetic and protein biomarkers, and results from prostate magnetic resonance imaging improved the clinical outcome performance of prostate cancer diagnostics.

Continuous glucose monitoring (CGM) has been demonstrated in randomized trials to improve glucose control in patients with type 1 diabetes (1), but until recently only a minority of participants in the German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registry and the U.S.-based T1D Exchange (T1DX) registry were using CGM (2,3). Over the past decade, both the accuracy and usability of CGM devices have improved considerably with expanded cost coverage of CGM by government statutory and private insurance. Some CGM devices are regulatory body approved for determining insulin dose in most circumstances, thereby reducing the number of fingersticks needed to monitor blood glucose. To assess change in CGM use over time across the age spectrum, we analyzed data from the T1DX and DPV registries for the years 2011, 2013, 2015, and 2017. CGM use (including both real-time and intermittent scanning CGM) at each data collection time point were obtained from clinic medical records. The number of participants with available data on CGM usage varied slightly depending on the calendar year for both registries. In DPV, the cohort size ranged from 17,632 to 21,707 for youth (aged 2 to

Ductal adenocarcinoma of the prostate (DAC) has morphological similarities to adenocarcinomas of other organs. DAC behaves in an aggressive manner and may present with metastases. These metastases may occur at unusual sites, which itself may cause diagnostic difficulties. It is important for therapeutic decisions that a prostatic origin of these metastases be established. Our aim was to compare the protein expression of DAC and adenocarcinomas of colon, endometrium, lung, pancreas, stomach and urinary bladder. A tissue microarray was constructed using 60 DAC, 6 colonic, 7 endometrial, 7 lung, 5 pancreatic, 5 gastric, and 9 urinary bladder adenocarcinomas. Slides were stained for estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-Myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, and PAX-8. Androgen receptor, prostein, PSA, and PSAP were almost invariably expressed in DAC. Ki-67-labeling index was lower in DAC than in other adenocarcinomas. The expression patterns of intestinal markers and cytokeratins in DAC were less specific and may lead to diagnostic errors if not combined with prostate-specific markers.

New technologies such as human papillomavirus (HPV) testing and vaccination necessitate comprehensive policy analyses to optimize cervical cancer prevention. To inform future Scandinavian-specific policy analyses, we aimed to provide an overview of cervical cancer epidemiology and existing prevention efforts in Denmark, Norway and Sweden. We compiled and summarized data on current prevention strategies, population demography and epidemiology (for example, age-specific HPV prevalence and cervical cancer incidence over time) for each Scandinavian country by reviewing published literature and official guidelines, performing registry-based analyses using primary data and having discussions with experts in each country. In Scandinavia, opportunistic screening occurred as early as the 1950s and by 1996, all countries had implemented nationwide organized cytology-based screening. Prior to implementation of widespread screening and during 1960-66, cervical cancer incidence was considerably higher in Denmark than in Norway and Sweden. Decades of cytology-based screening later (i.e. 2010-2014), cervical cancer incidence has been considerably reduced and has converged across the countries since the 1960s, although it still remains lowest in Sweden. Generally, Scandinavian countries face similar cervical cancer burdens and utilize similar prevention approaches; however, important differences remain. Future policy analyses will need to evaluate whether these differences warrant differential prevention policies or whether efforts can be streamlined across Scandinavia.

Aims: Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results: The International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62-0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two-thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non-members are able to access a limited number of cases. Conclusions: It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

The synthesis of cDNA from RNA is challenging due to the inefficiency of reverse transcription (RT). In order to address this, an RT-Bst method was developed for sequential RT of RNA and Bst DNA polymerase amplification for enrichment of cDNA in a single-tube reaction. Using genomic RNA from bacteriophage MS2, the yield of cDNA produced by RT alone and RT-Bst were compared by analysis of polymerase chain reaction (PCR)-amplified products. A superior performance was observed when amplifying MS2 cDNA with random primers following RT-Bst compared to RT alone, indicating greater quantities of cDNA were present after RT-Bst. RT-Bst was also compared with RT alone for their relative ability to produce sufficient cDNA to amplify eight target regions spanning the respiratory syncytial virus (RSV) genome. Six out of eight targets were amplified consistently by PCR subsequent to RT-Bst amplification, whereas only three out of eight targets could be amplified after RT alone. The RSV sequences were selectively amplified using RSV-specific primers from a mixed template containing an excess of MS2 RNA without amplifying MS2 sequences. This suggests that RT-Bst can be used to amplify RNA sequences non-specifically using random primers and specifically using sequence-specific primers, and enhances the yield of cDNA when compared to RT alone.

BackgroundKnowledge about the relationship between PSA, age and ISUP grade group (ISUP) 1 prostate cancer can improve clinical and biological understanding of prostate cancer. We aimed to investigate the associations between PSA and age and the risk of ISUP 1 and ISUP ≥ 2 prostate cancer, respectively.MethodsWe included 6 083 men aged 50-69 biopsied with a total of 72 996 individual biopsy cores from the prospective and population based Stockholm3 diagnostic study. We computed the risk of ISUP 1 and ISUP ≥ 2 prostate cancer and their respective associations with PSA and age. Since lower Gleason grades often are masked by higher grades in the overall Gleason score, we compared associations both for overall Gleason score and for Gleason on individual biopsy cores.ResultsISUP 1 prostate cancer was not significantly associated with PSA at diagnosis: odds ratios ranged from 0.82 (95%CI: 0.68-1.00) for PSA 3-4 ng/mL, 0.96 (95%CI: 0.79-1.16) for PSA 4-6 ng/mL, 0.95 (95%CI: 0.75-1.21) for PSA 6-10 ng/mL, and 0.92 (95%CI: 0.58-1.45) for PSA 10-15 ng/mL compared with PSA 2-3 ng/mL. Age was not significantly associated with risk of ISUP 1 cancer. This contrasts to the strong relationship between ISUP ≥ 2 prostate cancer and its respective associations with PSA and age.ConclusionsWe find no significant association between the risk of ISUP 1 prostate cancer and PSA and age at diagnosis indicating that PSA contribution from ISUP 1 prostate cancer is closer to that of benign prostate tissue than to that of ISUP ≥ 2 prostate cancer.

Aims: Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. Methods and results: The International Society of Urological Pathology (ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non-public database. The remaining 23 experts were asked to vote from a multiple-choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two-thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at www.isupweb.org. Non-members may access a selected number of cases. Conclusions: It is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases.

Microsimulation with stochastic life histories is an important tool in the development of public policies. In this article, we use microsimulation to evaluate policies for prostate cancer testing. We implemented the microsimulations as an R package, with pre- and post-processing in R and with the simulations written in C++. Calibrating a microsimulation model with a large population can be computationally expensive. To address this issue, we investigated four forms of parallelism: (i) shared memory parallelism using R; (ii) shared memory parallelism using OpenMP at the C++ level; (iii) distributed memory parallelism using R; and (iv) a hybrid shared/distributed memory parallelism using OpenMP at the C++ level and MPI at the R level. The close coupling between R and C++ offered advantages for ease of software dissemination and the use of high-level R parallelisation methods. However, this combination brought challenges when trying to use shared memory parallelism at the C++ level: the performance gained by hybrid OpenMP/MPI came at the cost of significant re-factoring of the existing code. As a case study, we implemented a prostate cancer model in the microsimulation package. We used this model to investigate whether prostate cancer testing with specific re-testing protocols would reduce harms and maintain any mortality benefit from prostate-specific antigen testing. We showed that four-yearly testing would have a comparable effectiveness and a marked decrease in costs compared with two-yearly testing and current testing. In summary, we developed a microsimulation package in R and assessed the cost-effectiveness of prostate cancer testing. We were able to scale up the microsimulations using a combination of R and C++, however care was required when using shared memory parallelism at the C++ level.

ObjectivesTo develop and validate a prediction model for short-term mortality in Australian men aged ≥45years, using age and self-reported health variables, for use when implementing the Australian Clinical Practice Guidelines for Prostate-Specific Antigen (PSA) Testing and Early Management of Test-Detected Prostate Cancer. Implementation of one of the Guideline recommendations requires an estimate of 7-year mortality.DesignProspective cohort study using questionnaire data linked to mortality data.SettingMen aged ≥45years randomly sampled from the general population of New South Wales, Australia, participating in the 45 and Up Study.Participants123 697 men who completed the baseline postal questionnaire (distributed from 1 January 2006 to 31 December 2008) and gave informed consent for follow-up through linkage of their data to population health databases.Primary outcome measuresThe primary outcome was all-cause mortality.Results12 160 died during follow-up (median=5.9 years). Following age-adjustment, self-reported health was the strongest predictor of all-cause mortality (C-index: 0.827; 95% CI 0.824 to 0.831). Three prediction models for all-cause mortality were validated, with predictors: Model-1: age group and self-rated health; Model-2: variables common to the 45 and Up Study and the Australian Health Survey and subselected using stepwise regression and Model-3: all variables selected using stepwise regression. Final predictions calibrated well with observed all-cause mortality rates. The 90th percentile for the 7-year mortality risks ranged from 1.92% to 83.94% for ages 45–85 years.ConclusionsWe developed prediction scores for short-term mortality using age and self-reported health measures and validated the scores against national mortality rates. Along with age, simple measures such as self-rated health, which can be easily obtained without physical examination, were strong predictors of all-cause mortality in the 45 and Up Study. Seven-year mortality risk estimates from Model-3 suggest that the impact of the mortality risk prediction tool on men’s decision making would be small in the recommended age (50–69 years) for PSA testing, but it may discourage testing at older ages.

Inefficiency of RT-PCR can be associated with the suboptimal process of reverse transcription as only 40-80% of RNA is converted to cDNA. We employed a novel method, RT-Bst, to enrich the concentration of cDNA for subsequent multiplex PCR detection of selected RNA viruses. The RT-Bst method amplifies cDNA through reverse transcription of viral RNA using reverse transcriptase and amplification of cDNA using Bst DNA polymerase. Viral RNA was extracted from 25 nasopharyngeal samples for detection of influenza A, B and C; parainfluenza 1-4; human coronaviruses 229E and OC43; respiratory syncytial virus (RSV) and rhinovirus. Both multiplex one-step RT-PCR and RT-Bst PCR were used to compare their performances for detection of virus sequences. These findings were compared with routine laboratory detection. When using RT-Bst PCR, 28% of samples yielded a viral pathogen compared to 20% with RT-PCR and 12% using routine diagnostic tests. RT-Bst PCR was shown to have particular utility in the detection of RSV RNA as this was present in 20% of the samples studied compared to 8% when using RT-PCR. For one patient, RT-Bst PCR was able to detect RSV five days earlier than conventional hospital diagnostic testing. RT-Bst and RT-Bst PCR can be used as alternative approaches to reverse transcription and one-step RT-PCR, respectively, for sequence-independent amplification of RNA virus sequences and a larger scale analysis of this new diagnostic approach is warranted.

5050The Stockholm-3 (STHLM3) Model can improve prostate cancer testing in men 50-69 years compared to current clinical practiceBackground: The Stockholm-3 model (STHLM3) is a combination of 6 plasm...

Background The National Cervical Screening Program in Australia currently recommends that women aged 18–69 years are screened with conventional cytology every 2 years. Publicly funded HPV vaccination was introduced in 2007, and partly as a consequence, a renewal of the screening program that includes a review of screening recommendations has recently been announced. This study aimed to provide a baseline for such a review by quantifying screening program resource utilisation and costs in 2010. Methods A detailed model of current cervical screening practice in Australia was constructed and we used data from the Victorian Cervical Cytology Registry to model age-specific compliance with screening and follow-up. We applied model-derived rate estimates to the 2010 Australian female population to calculate costs and numbers of colposcopies, biopsies, treatments for precancer and cervical cancers in that year, assuming that the numbers of these procedures were not yet substantially impacted by vaccination. Results The total cost of the screening program in 2010 (excluding administrative program overheads) was estimated to be A$194.8M. We estimated that a total of 1.7 million primary screening smears costing $96.7M were conducted, a further 188,900 smears costing $10.9M were conducted to follow-up low grade abnormalities, 70,900 colposcopy and 34,100 histological evaluations together costing $21.2M were conducted, and about 18,900 treatments for precancerous lesions were performed (including retreatments), associated with a cost of $45.5M for treatment and post-treatment follow-up. We also estimated that $20.5M was spent on work-up and treatment for approximately 761 women diagnosed with invasive cervical cancer. Overall, an estimated $23 was spent in 2010 for each adult woman in Australia on cervical screening program-related activities. Conclusions Approximately half of the total cost of the screening program is spent on delivery of primary screening tests; but the introduction of HPV vaccination, new technologies, increasing the interval and changing the age range of screening is expected to have a substantial impact on this expenditure, as well as having some impact on follow-up and management costs. These estimates provide a benchmark for future assessment of the impact of changes to screening program recommendations to the costs of cervical screening in Australia.

The publicity surrounding the first successful derivation of a human embryonic stem (hES) cell line in 1998 raised the expectation that stem cells will be the panacea for all diseases as well as provoking an ethical debate with respect to the way in which human embryos are used in research. ‘Human Embryonic Stem Cells’ is the first book solely dedicated to this field, covering all aspects of hES biology, providing a balanced discussion of ethical issues, as well as a detailed description of the progress that has been made in understanding how these cells function. The book is arranged as a compilation of chapters, written by experts in the field. The first three chapters deal with both the ethical and policy issues, while the remaining 15 chapters describe methods for HES cell isolation, their propagation and differentiation, and the potential therapeutic application of this research. There is enough breadth to be informative both to the novice as well as established researchers in the field. Human embryonic stem cells can only be isolated from the blastocyst stage embryo and hence is an ethically contentious issue. The first chapter of the book describes both sides of the ethical debate, which is mainly centred on defining the point at which life begins during development and balancing this against the potential benefits that using surplus embryos could provide to society. It explains the position of different religions and describes the national policies that various countries have implemented to regulate this research. The book also discusses the alternative sources of stem cells (both pluripotent and adult cells), explaining in this context the characteristics that make hES cells so unique. A chapter is also dedicated to the controversial subject of therapeutic cloning and provides a very balanced discussion of the ethical and technical issues involved. Overall, the sections of the book dealing with ethical issues are very well written and balanced, leaving the reader to draw their own conclusions about the morality of hES cell research. For researchers in the US, there is a particularly useful chapter written as a researcher's guide to federally funded cell research in the US. In August 2001, President Bush banned the derivation of new human ES lines using public funds and restricted research to existing hES line. This chapter explains succinctly what research is allowed and prohibited with public funds, and also has an important section explaining the restrictions that also apply to research outside the US when performed in collaboration with US researchers. A surprising point raised in this chapter is the fact that embryo research performed with private money in the US is basically unregulated. The book also has a section on patents that infringe on hES cell research and has a great introduction to patent law for the uninitiated. This is particularly relevant for researchers who are interested in commercially exploiting hES cell technologies and explains how restrictive the original US patent is to the development of hES-based therapies. The stance of the European Patent office is also discussed and how its regulation is much more flexible, opening up greater competition than is possible in the US. Only one chapter of the book is dedicated to detailed protocols describing the methods for deriving hES cells and the complex methods required for maintaining the cells in an undifferentiated state. It is especially useful since the original publications describing hES derivation contain very little methodological detail. This is the only chapter of the book containing detailed protocols and so anyone purchasing this book with the expectation that it will contain detailed protocols covering all aspects of hES research will be disappointed. Nevertheless, the book does contain five very comprehensive chapters describing the approaches used by different groups to differentiate hES cells to specific cell types. These chapters are up to date and very well referenced, allowing the reader to access easily the original research articles for the methodological detail. The authors draw useful comparisons between the signalling events that are known to occur in vivo during early embryonic development and the attempts to recreate these conditions in vitro. They also highlight the different responses of mouse and human ES cells to similar differentiation stimuli. When reading the book, one is struck by how much this field is in its infancy, as demonstrated by the fact that many of the chapters are based on only one or two publications describing the initial attempts to differentiate human ES cells. This is due in part to the limited number of labs that have had access to hES cell lines since their isolation in 1998. This situation is rapidly changing as the cell lines become more widely distributed around the world. The last section of the book deals with the potential therapeutic development of hES cells. The clinical use of hES cells is still many years away, particularly since we are yet to understand the mechanisms that control the differentiation process. The authors highlight the potential barriers to using hES cells for treating a variety of diseases and discuss the various approaches being used to resolve these problems. Such barriers include immune rejection, uncontrolled proliferation and poor long-term survival of graft tissue. This section of the book gives a clear outline of the FDA regulations relevant to the development hES cell-based therapies and presents a case study of a first clinical trails using human neurone-like cell line derived from a human embryonic carcinoma line for the treatment of stroke and spinal cord injury. In summary, this is a very comprehensive text on all aspects of hES cell biology. The book covers all of the latest developments in the field, and is very timely due to the explosion of interested in hES cells. As a consequence of the way the book has been compiled, many topics are repeated throughout the text, but since each chapter has been written by a different author, one gets many different perspectives. As access to human ES cell lines becomes more wide spread, this field will rapidly move forward and in a very short span of time this book will become outdated. However, this still remains the most comprehensive review of all aspects of the hES cell biology, and is a must for anyone planning to break into the field.