AI Concepts for System of Systems Dynamic Interoperability.

Interoperability is a central problem in digitization and System of Systems (SoS) engineering, which concerns the capacity of systems to exchange information and cooperate. The task to dynamically establish interoperability between heterogeneous cyber-physical systems (CPSs) at run-time is a challenging problem. Different aspects of the interoperability problem have been studied in fields such as SoS, neural translation, and agent-based systems, but there are no unifying solutions beyond domain-specific standardization efforts. The problem is complicated by the uncertain and variable relations between physical processes and human-centric symbols, which result from, e.g., latent physical degrees of freedom, maintenance, re-configurations, and software updates. Therefore, we surveyed the literature for concepts and methods needed to automatically establish SoSs with purposeful CPS communication, focusing on machine learning and connecting approaches that are not integrated in the present literature. Here, we summarize recent developments relevant to the dynamic interoperability problem, such as representation learning for ontology alignment and inference on heterogeneous linked data; neural networks for transcoding of text and code; concept learning-based reasoning; and emergent communication. We find that there has been a recent interest in deep learning approaches to establishing communication under different assumptions about the environment, language, and nature of the communicating entities. Furthermore, we present examples of architectures and discuss open problems associated with artificial intelligence (AI)-enabled solutions in relation to SoS interoperability requirements. Although these developments open new avenues for research, there are still no examples that bridge the concepts necessary to establish dynamic interoperability in complex SoSs, and realistic testbeds are needed.

Uptake of doublet therapy for de novo metastatic castration sensitive prostate cancer: a population-based drug utilisation study in Sweden.

BACKGROUND: Randomised controlled trials have demonstrated prolonged survival with new upfront treatments in addition to standard androgen deprivation therapy (ADT) in men with de novo metastatic castration-sensitive prostate cancer. We describe patient characteristics, time trends and regional differences in uptake of these new treatment strategies in clinical practice. MATERIAL AND METHODS: This descriptive study consisted of men registered in the National Prostate Cancer Register of Sweden from 1 January 2018 to 31 March 2022 with de novo metastatic castration-sensitive prostate cancer defined by the presence of metastases on imaging at the time of diagnosis. Life expectancy was calculated based on age, Charlson Comorbidity Index and a Drug Comorbidity Index. RESULTS: Within 6 months from diagnosis, 57% (1,677/2,959) of men with de novo metastatic castration-sensitive prostate cancer and more than 3 years of life expectancy had received docetaxel, abiraterone, enzalutamide, apalutamide and/or radiotherapy. Over time, there was a 2-fold increase in uptake of any added treatment, mainly driven by a 6-fold increase in use of abiraterone, enzalutamide or apalutamide, with little change in use of other treatments. CONCLUSIONS: Slightly more than half of men diagnosed with de novo metastatic castration-sensitive prostate cancer and a life expectancy of at least 3 years received additions to standard ADT as recommended by national guidelines in 2019-2022 in Sweden. There was a 2-fold increase in use of these treatments during the study period; however, efforts to further increase adherence to guidelines are warranted.

Deep Ontology Alignment Using a Natural Language Processing Approach for Automatic M2M Translation in IIoT.

The technical capabilities of modern Industry 4.0 and Industry 5.0 are vast and growing exponentially daily. The present-day Industrial Internet of Things (IIoT) combines manifold underlying technologies that require real-time interconnection and communication among heterogeneous devices. Smart cities are established with sophisticated designs and control of seamless machine-to-machine (M2M) communication, to optimize resources, costs, performance, and energy distributions. All the sensory devices within a building interact to maintain a sustainable climate for residents and intuitively optimize the energy distribution to optimize energy production. However, this encompasses quite a few challenges for devices that lack a compatible and interoperable design. The conventional solutions are restricted to limited domains or rely on engineers designing and deploying translators for each pair of ontologies. This is a costly process in terms of engineering effort and computational resources. An issue persists that a new device with a different ontology must be integrated into an existing IoT network. We propose a self-learning model that can determine the taxonomy of devices given their ontological meta-data and structural information. The model finds matches between two distinct ontologies using a natural language processing (NLP) approach to learn linguistic contexts. Then, by visualizing the ontological network as a knowledge graph, it is possible to learn the structure of the meta-data and understand the device's message formulation. Finally, the model can align entities of ontological graphs that are similar in context and structure.Furthermore, the model performs dynamic M2M translation without requiring extra engineering or hardware resources.

Penile cancer: long-term infectious and thromboembolic complications following lymph node dissection - a population-based study (Sweden).

PURPOSE: To assess the long-term risks of infectious and thromboembolic events following inguinal (ILND) and pelvic (PLND) lymph node dissection in men with penile cancer. MATERIAL AND METHODS: A total of 364 men subjected to ILND with or without PLND for penile cancer between 2000 and 2012 were identified in the Swedish National Penile Cancer Register. Each patient was matched based on age and county of residence with six penile cancer-free men. The Swedish Cancer Register and other population-based registers were used to retrieve information on treatment and hospitalisation for selected infectious and thromboembolic events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models with multiple imputation. RESULTS: The risk of infectious events remained increased for more than five years postoperatively in men with penile cancer compared with matched controls. The palpable nodal disease was the only predictor of these events, with risk increasing with the cN stage. The HR at one, three and five years and six months postoperatively was 8.60 (95% CI 5.16-14.34), 4.02 (95% CI 2.65-6.09) and 1.93 (95% CI 1.11-3.38), respectively. An increased risk of thromboembolic events persisted for three years postoperatively. The HR at one and three years postoperatively was 13.51 (95% CI 6.53-27.93) and 2.12 (95% CI 1.07-4.20). The results correspond well with the over-prescription of anticoagulants observed during this period. An association with bulky disease (cN3) was observed. CONCLUSIONS: Lymph node dissection for penile cancer is associated with an increased risk of infectious and thromboembolic events. The findings of this population-based study show that the risks of these events remain increased more than five years for infectious and three years for thromboembolic events. Improved awareness of long-term complications following ILND is of importance both among patients and care givers to ensure early detection and treatment.

Integration of neuromorphic AI in event-driven distributed digitized systems: Concepts and research directions.

Increasing complexity and data-generation rates in cyber-physical systems and the industrial Internet of things are calling for a corresponding increase in AI capabilities at the resource-constrained edges of the Internet. Meanwhile, the resource requirements of digital computing and deep learning are growing exponentially, in an unsustainable manner. One possible way to bridge this gap is the adoption of resource-efficient brain-inspired "neuromorphic" processing and sensing devices, which use event-driven, asynchronous, dynamic neurosynaptic elements with colocated memory for distributed processing and machine learning. However, since neuromorphic systems are fundamentally different from conventional von Neumann computers and clock-driven sensor systems, several challenges are posed to large-scale adoption and integration of neuromorphic devices into the existing distributed digital-computational infrastructure. Here, we describe the current landscape of neuromorphic computing, focusing on characteristics that pose integration challenges. Based on this analysis, we propose a microservice-based conceptual framework for neuromorphic systems integration, consisting of a neuromorphic-system proxy, which would provide virtualization and communication capabilities required in distributed systems of systems, in combination with a declarative programming approach offering engineering-process abstraction. We also present concepts that could serve as a basis for the realization of this framework, and identify directions for further research required to enable large-scale system integration of neuromorphic devices.

Association of surgeon and hospital volume with short-term outcomes after robot-assisted radical prostatectomy: Nationwide, population-based study.

BACKGROUND AND OBJECTIVE: Few studies have investigated the association between surgical volume and outcome of robot-assisted radical prostatectomy (RARP) in an unselected cohort. We sought to investigate the association between surgical volume with peri-operative and short-term outcomes in a nation-wide, population-based study group. METHODS: 9,810 RARP's registered in the National Prostate Cancer Register of Sweden (2015-2018) were included. Associations between outcome and volume were analyzed with multivariable logistic regression including age, PSA-density, number of positive biopsy cores, cT stage, Gleason score, and extent of lymph node dissection. RESULTS: Surgeons and hospitals in the highest volume group compared to lowest group had shorter operative time; surgeon (OR 9.20, 95% CI 7.11-11.91), hospital (OR 2.16, 95% CI 1.53-3.06), less blood loss; surgeon (OR 2.58. 95% CI 2.07-3.21) hospital (no difference), more often nerve sparing intention; surgeon (OR 2.89, 95% CI 2.34-3.57), hospital (OR 2.02, 95% CI 1.66-2.44), negative margins; surgeon (OR 1.90, 95% CI 1.54-2.35), hospital (OR 1.28, 95% CI 1.07-1.53). There was wide range in outcome between hospitals and surgeons with similar volume that remained after adjustment. CONCLUSIONS: High surgeon and hospital volume were associated with better outcomes. The range in outcome was wide in all volume groups, which indicates that factors besides volume are of importance. Registration of surgical performance is essential for quality control and improvement.

Prostate cancer diagnosis, staging, and treatment in Sweden during the first phase of the COVID-19 pandemic.

INTRODUCTION: The first case of COVID-19 in Sweden was diagnosed in late January 2020, the first recommendations against the spread of the virus were released in mid-March, and the peak of the first wave of the pandemic was reached in March-June. The aim of this cross-sectional study was to assess the short-term effects of the first wave of the COVID-19 pandemic on prostate cancer (PCa) diagnosis, staging, and treatment. MATERIALS AND METHODS: Data in the National Prostate Cancer Register (NPCR) of Sweden on newly diagnosed PCa cases and on the number of diagnostic and therapeutic procedures performed between 18 March 2020 and 2 June 2020 were compared with those in the corresponding time periods in 2017-2019, as reported until January 31 of the year after each study period. RESULTS: During the study period in 2020, 36% fewer PCa cases were registered in NPCR compared with the corresponding time period in previous years: 1458 cases in 2020 vs a mean of 2285 cases in 2017-2019. The decrease in new PCa registrations was more pronounced in men above age 75 years, down 51%, than in men aged 70-75, down 37%, and in men below age 70, down 28%. There was no decrease in the number of radical prostatectomies and number of radical radiotherapy courses increased by 32%. CONCLUSIONS: During the peak of the first phase of the COVID-19 pandemic, the number of men diagnosed with PCa in Sweden decreased by one third compared with previous years, whereas there was no decrease in the number of curative treatments.

Successful tyrosine kinase inhibitor discontinuation outside clinical trials - data from the population-based Swedish chronic myeloid leukaemia registry.

Clinical trials show that tyrosine kinase inhibitor (TKI) treatment can be discontinued in selected patients with chronic myeloid leukaemia (CML). Although updated CML guidelines support such procedure in clinical routine, data on TKI stopping outside clinical trials are limited. In this retrospective study utilising the Swedish CML registry, we examined TKI discontinuation in a population-based setting. Out of 584 patients diagnosed with chronic-phase CML (CML-CP) in 2007-2012, 548 had evaluable information on TKI discontinuation. With a median follow-up of nine years from diagnosis, 128 (23%) discontinued TKI therapy (≥1 month) due to achieving a DMR (deep molecular response) and 107 (20%) due to other causes (adverse events, allogeneic stem cell transplant, pregnancy, etc). Among those stopping in DMR, 49% re-initiated TKI treatment (median time to restart 4·8 months). In all, 38 patients stopped TKI within a clinical study and 90 outside a study. After 24 months 41·1% of patients discontinuing outside a study had re-initiated TKI treatment. TKI treatment duration pre-stop was longer and proportion treated with second-generation TKI slightly higher outside studies, conceivably affecting the clinical outcome. In summary we show that TKI discontinuation in CML in clinical practice is common and feasible and may be just as successful as when performed within a clinical trial.

Estimates of lung and pancreatic cancer survival in Sweden with and without inclusion of death certificate initiated (DCI) cases.

INTRODUCTION: International differences in cancer incidence and survival may partly reflect differences in cancer registration practices. As opposed to most other National Cancer Registries, Death Certificate Initiated (DCI) cases are not included in the Swedish Cancer Register. We characterized cases not reported to the Swedish Cancer Register and assessed the impact of inclusion of DCI cases on the completeness and estimates of one-year lung and pancreatic cancer survival. METHODS: We used information in the Swedish Cause of Death Register to identify individuals in two Health Care Regions (West and Uppsala Örebro) with lung or pancreatic cancer as cause of death in 2013. These records were cross-linked to the Cancer Register to identify individuals without a corresponding cancer registration, i.e. Death Certificate Notified (DCN) cases. DCN cases were cross-linked to the Patient Register to retrieve hospital discharge information to confirm the diagnosis. In a separate step, trace-back of DCN cases was performed to access medical records to validate the diagnosis. RESULTS: Following validity checks, an estimated 16% and 34% of individuals with a diagnosis of lung or pancreatic cancer, respectively, had not been reported to the SCR. Non-reported patients were older and had a considerable poorer survival than those included in the SCR. Inclusion of DCI cases decreased one-year lung cancer overall survival from 45% to 41%. The corresponding decrease for pancreatic cancer was five percentage points, from 29% to 24%. CONCLUSIONS: Lung and pancreatic cancers are underreported to the SCR yielding too low incidence rates and upward biased survival estimates. We conclude that implementation of systematic death certificate processing with trace-back is feasible also within the Swedish system with regionalized cancer reporting. Verifying registrability by use of information in the Patient Register provided a good approximation of "corrected" survival estimates based on chart review.

Synaptic Delays for Insect-Inspired Temporal Feature Detection in Dynamic Neuromorphic Processors.

Spiking neural networks are well-suited for spatiotemporal feature detection and learning, and naturally involve dynamic delay mechanisms in the synapses, dendrites, and axons. Dedicated delay neurons and axonal delay circuits have been considered when implementing such pattern recognition networks in dynamic neuromorphic processors. Inspired by an auditory feature detection circuit in crickets, featuring a delayed excitation by post-inhibitory rebound, we investigate disynaptic delay elements formed by inhibitory-excitatory pairs of dynamic synapses. We configured such disynaptic delay elements in the DYNAP-SE neuromorphic processor and characterized the distribution of delayed excitations resulting from device mismatch. Interestingly, we found that the disynaptic delay elements can be configured such that the timing and magnitude of the delayed excitation depend mainly on the efficacy of the inhibitory and excitatory synapses, respectively, and that a neuron with multiple delay elements can be tuned to respond selectively to a specific pattern. Furthermore, we present a network with one disynaptic delay element that mimics the auditory feature detection circuit of crickets, and we demonstrate how varying synaptic weights, input noise and processor temperature affect the circuit. Dynamic delay elements of this kind open up for synapse level temporal feature tuning with configurable delays of up to 100 ms.

High efficacy of hypofractionated proton therapy with 4 fractions of 5 Gy as a boost to 50 Gy photon therapy for localized prostate cancer.

PURPOSE: We report the outcome of hypofractionated proton boost as an alternative to high dose-rate brachytherapy boost, aimed at an equivalent dose exceeding 86 Gy in 2 Gy fractions, for patients with localized prostate cancer and all risk groups. METHODS: Proton boost of 20 Gy given in 4 daily fractions to the prostate was followed after a one-week rest by photon therapy to 50 Gy in 2 Gy fractions. Outcomes are presented per risk group according to both NCCN and ISUP classifications. Advanced imaging was performed for adequate staging, and at an early stage of rising PSA, to identify the relapse site. Endpoints were PSA relapse-free-, locoregional relapse-free-, and distant metastasis-free- survival. Prostate cancer-specific-, metastasis-free-, and overall survival were also estimated. Genitourinary (GU) and gastrointestinal (GI) toxicity were based on patients' questionnaires and physicians' records. RESULTS: We treated 531 patients between 2002 and 2015; 504 had localized disease. The cohort included 180 patients with T3/T4 disease (36%). The majority of the 50% with high-/very high-risk disease received ADT, 9-24 months; 92 had adjuvant pelvic node treatment. Median follow-up was 113 months (43-193). For low-, intermediate-, high-, and very high-risk patients, the 5-year PSA relapse-free survival was 100%, 94%, 82%, and 72%, respectively. Prolonged ADT improved biochemical control and nodal treatment regional control. The NCCN classification had higher predictive discrimination than the ISUP classification. The 5-year prevalence grade 3+ was 2% for GU and 0% for GI toxicity in pre-treatment symptom-free patients, and not worsened by nodal treatment. CONCLUSION: Dose escalation with hypofractionated proton boost was as effective as reported with high dose-rate brachytherapy boost, and the GU and GI toxicity profile was very similar. The proton boost was also appropriate for patients with larger prostate volume, higher T-stage, and high-risk disease encompassing elective regional node photon therapy.

Clinical characteristics and survival in non-small cell lung cancer patients by smoking history: a population-based cohort study.

Introduction: Approximately, 10-15% of lung cancer patients have never smoked. Previous epidemiological studies on non-tobacco associated lung cancer have been hampered by selected data from a small number of hospitals or limited numbers of patients. By use of data from large population-based registers with national coverage, this study aims to compare characteristics and survival of patients with non-small cell lung cancer (NSCLC) with different smoking histories.Methods: Swedish national population-based registers were used to retrieve data on patients diagnosed with primary NSCLC between 2002 and 2016. The Kaplan-Meier method and Cox proportional hazard models were used to estimate overall survival and lung cancer-specific survival by smoking history.Results: In total, 41,262 patients with NSCLC were included. Of those, 4624 (11%) had never smoked. Never-smokers were more often women and older compared to ever smokers (current and former). Adenocarcinoma was proportionally more common in never-smokers (77%) compared to current (52%) and former smokers (57%). Stage IV disease was more common in never-smokers (57%) than in current (48%) and former smokers (48%). Epidermal growth factor receptor mutation was observed more in never-smokers (37%) compared to current (5%) and former smokers (9%). Both lung cancer-specific and overall survival were higher for never-smokers compared to current smokers.Conclusions: The observed differences in characteristics between never-smokers and smokers, and the higher survival in never-smokers compared to smokers from this large population-based study provide further evidence that lung cancer in never-smokers is clinically different to tobacco-associated lung cancer. The findings from this study emphasise the need for an improved understanding of genetics, pathogenesis, mechanisms and progression of non-tobacco associated lung cancer that may help prevent lung cancer or identify individually targeted treatments.

Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era: population-based data from the Swedish CML registry.

Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TKI resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at <65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score >2 and reduced intensity conditioning, and for death, CP > 2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.

Good prognosis following a PSA bounce after high dose rate brachytherapy and external radiotherapy in prostate cancer.

BACKGROUND: PSA kinetics after curative radiotherapy for prostate cancer is an important part of the posttreatment evaluation. We analysed PSA bounce occurrence after combined high dose rate brachytherapy (HDR-BT) and external radiotherapy (ERT). MATERIAL & METHODS: We analysed 623 patients treated from 1995 to 2008. The median age was 66 years (47-79). The median initial PSA was 12 ng/ml (0.1-224). Neoadjuvant endocrine therapy was given to 429 patients. ERT was given with 2 Gy fractions to 50 Gy and HDR-BT in two 10 Gy fractions. The median follow-up was 11 years (range 2-266 months). PSA bounce was defined as a temporary rise in PSA >0.2 ng/ml. PSA failure was defined according to the Phoenix definition. RESULTS: PSA bounce occurred in 159 patients (26%), where 56 patients had a bounce amplitude >2 ng/ml and 31 patients had multiple bounces. Median time to bounce peak was 15 (3-103) months with a median bounce value of 1.5 (0.3-12)ng/ml. Younger age and lower Gleason scores were associated with PSA bounce. In a Cox regression analysis with PSA bounce as a time-dependent covariate and adjusted for other prognostic factors, PSA bounce was associated with a lower risk for PSA failure (HR = 0.42; 95% confidence interval 0.26-0.70). CONCLUSION: PSA bounce after HDR-BT combined with ERT is common and associated with a good prognosis. As the relapse risk after an early bounce is very low, the findings should alert clinicians not to initiate salvage treatment too early. Research in prospective identification of PSA bounce is clinically relevant.

Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer.

BACKGROUND: High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience. MATERIAL AND METHODS: The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2-266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy. RESULTS: The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent GU complication with a 10-year actuarial incidence of 10%. Treatment without dose constraints for the urethra conferred a higher incidence 18%, compared to 5% after 2003 (p < 0.001). Sixteen patients experienced grade 4 GU toxicity, of which 13 were treated before 2003. No grade 4 rectal toxicity was seen. CONCLUSION: The combination of EBRT and HDR-BT with adequate dose constraints to risk organs provides satisfactory long-term tumour control even in high-risk patients. GI toxicity stabilised but GU toxicity progressed during the 10-year follow up.

Patient education-level affects treatment allocation and prognosis in esophageal- and gastroesophageal junctional cancer in Sweden.

BACKGROUND: Low socioeconomic status and poor education elevate the risk of developing esophageal- and junctional cancer. High education level also increases survival after curative surgery. The present study aimed to investigate associations, if any, between patient education-level and treatment allocation after diagnosis of esophageal- and junctional cancer and its subsequent impact on survival. METHODS: A nation-wide cohort study was undertaken. Data from a Swedish national quality register for esophageal cancer (NREV) was linked to the National Cancer Register, National Patient Register, Prescribed Drug Register, Cause of Death Register and educational data from Statistics Sweden. The effect of education level (low; ≤9 years, intermediate; 10-12 years and high >12 years) on the probability of allocation to curative treatment was analyzed with logistic regression. The Kaplan-Meier-method and Cox proportional hazard models were used to assess the effect of education on survival. RESULTS: A total of 4112 patients were included. In a multivariate logistic regression model, high education level was associated with greater probability of allocation to curative treatment (adjusted OR: 1.48, 95% CI: 1.08-2.03, p = 0,014) as was adherence to a multidisciplinary treatment-conference (adjusted OR: 3.13, 95% CI: 2.40-4.08, p < 0,001). High education level was associated with improved survival in the patients allocated to curative treatment (HR: 0.82, 95% CI: 0.69-0.99, p = 0,036). DISCUSSION: In this nation-wide cohort of esophageal- and junctional cancer patients, including data regarding many confounders, high education level was associated with greater probability of being offered curative treatment and improved survival.