Integrated noninvasive diagnostics for prediction of survival in immunotherapy.

Background: Integrating complementary diagnostic data sources promises enhanced robustness in the predictive performance of artificial intelligence (AI) models, a crucial requirement for future clinical validation/implementation. In this study, we investigate the potential value of integrating data from noninvasive diagnostic modalities, including chest computed tomography (CT) imaging, routine laboratory blood tests, and clinical parameters, to retrospectively predict 1-year survival in a cohort of patients with advanced non-small-cell lung cancer, melanoma, and urothelial cancer treated with immunotherapy. Patients and methods: The study included 475 patients, of whom 444 had longitudinal CT scans and 475 had longitudinal laboratory data. An ensemble of AI models was trained on data from each diagnostic modality, and subsequently, a model-agnostic integration approach was adopted for combining the prediction probabilities of each modality and producing an integrated decision. Results: Integrating different diagnostic data demonstrated a modest increase in predictive performance. The highest area under the curve (AUC) was achieved by CT and laboratory data integration (AUC of 0.83, 95% confidence interval 0.81-0.85, P < 0.001), whereas the performance of individual models trained on laboratory and CT data independently yielded AUCs of 0.81 and 0.73, respectively. Conclusions: In our retrospective cohort, integrating different noninvasive data modalities improved performance.

Frequency selectivity in monkey auditory nerve studied with suprathreshold multicomponent stimuli.

Data from non-human primates can help extend observations from non-primate species to humans. Here we report measurements on the auditory nerve of macaque monkeys in the context of a controversial topic important to human hearing. A range of techniques have been used to examine the claim, which is not generally accepted, that human frequency tuning is sharper than traditionally thought, and sharper than in commonly used animal models. Data from single auditory-nerve fibers occupy a pivotal position to examine this claim, but are not available for humans. A previous study reported sharper tuning in auditory-nerve fibers of macaque relative to the cat. A limitation of these and other single-fiber data is that frequency selectivity was measured with tonal threshold-tuning curves, which do not directly assess spectral filtering and whose shape is sharpened by cochlear nonlinearity. Our aim was to measure spectral filtering with wideband suprathreshold stimuli in the macaque auditory nerve. We obtained responses of single nerve fibers of anesthetized macaque monkeys and cats to a suprathreshold, wideband, multicomponent stimulus designed to allow characterization of spectral filtering at any cochlear locus. Quantitatively the differences between the two species are smaller than in previous studies, but consistent with these studies the filters obtained show a trend of sharper tuning in macaque, relative to the cat, for fibers in the basal half of the cochlea. We also examined differences in group delay measured on the phase data near the characteristic frequency versus in the low-frequency tail. The phase data are consistent with the interpretation of sharper frequency tuning in monkey in the basal half of the cochlea. We conclude that use of suprathreshold, wide-band stimuli supports the interpretation of sharper frequency selectivity in macaque nerve fibers relative to the cat, although the difference is less marked than apparent from the assessment with tonal threshold-based data.

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Introduction: Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. Methods: The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. Discussion: This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. Clinical Trial Registration: The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Data analysis supports monitoring and surveillance of goat health and welfare in the Netherlands.

Monitoring and surveillance systems have an increasingly important role in contemporary society ensuring high levels of animal health and welfare, securing export positions, and protecting public health by ensuring animal health and product safety. In the Netherlands, a voluntary monitoring and surveillance system is in place since 2003 to provide a broad overview of livestock trends in addition to disease-specific surveillance systems, including insight into the occurrence and prevalence of new and emerging non-notifiable diseases and disorders. Being a major surveillance component of this monitoring and surveillance system for small ruminant health in the Netherlands, an annual data analysis on routine census data is performed to retrospectively monitor trends and developments regarding goat health and welfare. This paper aims to describe the process of the data analysis on goat farms in the Netherlands in 2020 and subsequent results are discussed. The data analysis provides key monitoring indicators such as animal and farm density, mortality, animal movements, and numbers and origin of imported small ruminants. Trends were analysed over a five-year, period and associations between herd characteristics and herd health are evaluated. Results showed that in 2020 the Dutch goat population consisted of 670,842 goats, distributed over 14,730 unique herds and increased by 2.3 % compared to 2019. Between 2016 and 2020, although probably underestimated, recorded mortality rates showed a decline on both small-scale and professional farms, with a strongest decrease on farms with herd sizes over more than 200 animals. Seventy-five percent of all professional farms registered animal introductions, in addition to 63 % of small-scale farms, including 2439 imported goats. Performing risks analyses requires demographic knowledge of the goat industry. During and after several disease outbreaks, such as bluetongue and Schmallenberg virus disease, the data analysis proved to function as a valuable tool, however, appeared just as important for recording outbreak-free data. Since its start in 2006, the concept of the data-analysis has continuously been improved, and will in the future be further developed, especially if more complete data sets become available. Subsequently, data analysis will increasingly support monitoring and surveillance of goat health and welfare.

The state of the art in beyond 5G distributed massive multiple-input multiple-output communication system solutions.

Beyond fifth generation (5G) communication systems aim towards data rates in the tera bits per second range, with improved and flexible coverage options, introducing many new technological challenges in the fields of network architecture, signal pro- cessing, and radio frequency front-ends. One option is to move towards cell-free, or distributed massive Multiple-Input Multiple-Output (MIMO) network architectures and highly integrated front-end solutions. This paper presents an outlook on be- yond 5G distributed massive MIMO communication systems, the signal processing, characterisation and simulation challenges, and an overview of the state of the art in millimetre wave antennas and electronics.

Epigenetic profiling demarcates molecular subtypes of muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer.

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease.

Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer.

Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.

FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy.

PURPOSE: We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). METHODS: Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR, 

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Psychometric properties of the Exercise Self-efficacy Scale in Dutch Primary care patients with type 2 diabetes mellitus.

BACKGROUND: Excercise self-efficacy is believed to influence physical activity bahavior. PURPOSE: The purpose of this study is to assess the psychometric aspects of the Exercise Self-efficacy Scale (ESS) in a type 2 diabetes Dutch Primary care sample. METHOD: Type 2 diabetes patients (n = 322; <80 years old) filled in the ESS and the short questionnaire to assess health enhancing physical activity (SQUASH). The structural validity of the ESS was assessed by means of principal axis factor analyses and confirmatory factor analysis. In addition, reliability and concurrent validity with the SQUASH outcomes "total" and "leisure time minutes/week of moderate to vigorous intensity physical activity" were evaluated. T tests and ANOVAs were used to examine ESS scores in subgroups. In addition, a 13-item version of the ESS was developed. RESULTS: Analyses were performed on complete cases (n = 255). Exploratory factor analysis suggested one underlying factor (total explained variance 54 %), with good internal consistency (α = 0.95). Confirmatory factor analysis showed a poor fit, as did a three-factor model suggested in an earlier research. Therefore, a 13-item ESS was developed with one underlying factor (total explained variance 59 %) and good internal consistency (α = 0.95). Both the 18-item and 13-item ESS correlated significantly with total and leisure time physical activity. ESS scores differed significantly between categories of education level and physical activity level. CONCLUSION: The 13-item ESS had sound psychometric properties in a large sample of primary care type 2 diabetes patients. The 13-item ESS could be useful in (intervention) research on physical activity in type 2 diabetes patients.

High-coherence electron bunches produced by femtosecond photoionization.

With the development of ultrafast electron and X-ray sources it is becoming possible to study structural dynamics with atomic-level spatial and temporal resolution. Because of their short mean free path, electrons are particularly well suited for investigating surfaces and thin films, such as the challenging and important class of membrane proteins. To perform single-shot diffraction experiments on protein crystals, an ultracold electron source was proposed, based on near-threshold photoionization of laser-cooled atoms, which is capable of producing electron pulses of both high intensity and high coherence. Here we show that high coherence electron pulses can be produced by femtosecond photoionization, opening up a new regime of ultrafast structural dynamics experiments. The transverse coherence turns out to be much better than expected on the basis of the large bandwidth of the femtosecond ionization laser pulses. This surprising result can be explained by analysis of classical electron trajectories.

Effects of exercise training on quality of life, symptoms of depression, symptoms of anxiety and emotional well-being in type 2 diabetes mellitus: a systematic review.

AIMS/HYPOTHESIS: Psychological problems are relatively common in people with type 2 diabetes. It is unclear whether exercise training exerts an effect on quality of life, symptoms of depression, symptoms of anxiety and emotional well-being in people with type 2 diabetes. The aim of this study was to conduct a systematic review to assess the effects of exercise training on these outcomes in people with type 2 diabetes. METHODS: MEDLINE, PsycINFO, Embase and ClinicalTrials.gov databases were searched. The review included randomised controlled trials (RCTs) of at least 4 weeks' duration in people with type 2 diabetes that evaluated the effect of exercise training on quality of life, symptoms of depression, symptoms of anxiety and/or emotional well-being compared with usual care. RESULTS: Of 1,261 retrieved articles, 20 RCTs were included with a total of 1,719 participants. Quality of life was assessed in 16 studies. Between-group comparisons showed no significant results for aerobic training with the exception of one study, and mixed results for resistance and combined training. Symptoms of depression were assessed in four studies. In only one study did the intervention decrease symptoms of depression. Emotional well-being was evaluated in four studies, which also showed conflicting results. Symptoms of anxiety were evaluated in one study, which showed a significant improvement. CONCLUSIONS/INTERPRETATION: The effects of exercise training on psychological outcomes in people with type 2 diabetes are conflicting. Therefore, there is a need for further high-quality RCTs in order to gain greater insight into the role of exercise training in people with type 2 diabetes.

Vagus nerve stimulation has a positive effect on mood in patients with refractory epilepsy.

BACKGROUND: Preliminary research on the efficacy of vagus nerve stimulation (VNS) indicated additional effects on neuropsychological variables like mood and quality of life (QOL). OBJECTIVES: The objectives of this prospective longitudinal observational cohort study were to assess the effects of VNS on mood, QOL and cognition in patients with refractory epilepsy and to determine whether these effects occur dependent of seizure control. METHODS: We included 41 patients with refractory epilepsy; treated with VNS as part of usual patient care. A neuropsychological battery was performed during baseline and repeated after 6 months of VNS in order to compare neuropsychological variables before and after VNS. All patients completed seizure diaries. RESULTS: Significant improvements were observed for both mood and QOL after 6 months of VNS; based on the results in the POMS and QOLIE-89 questionnaires (p<0.05). There was no significant change in cognition. Mean percentage change in seizure frequency was -9.0%, while 20% of the patients achieved a seizure frequency reduction of 50% or more. No significant correlation was found between changes in seizure frequency and improvements in mood or QOL. CONCLUSIONS: VNS is associated with improvements in both mood and QOL in patients with refractory epilepsy. Since these improvements appeared to be independent of seizure control, the results of this study indicate an additional antidepressant effect of VNS, which can be of extra value in view of the high co-morbidity of mood disturbances in patients with epilepsy.

Spinal anesthesia for a parturient with the triad of Currarino.

The triad of Currarino, also known as Currarino syndrome or complex, is a rare hereditary syndrome involving a bony sacral defect, an anorectal malformation and a presacral mass. Thus far, only 250 cases have been reported, but milder cases may not be recognized, and many cases may not be published. In addition to disorders of the gastrointestinal and urogenital tracts, sensory and motor deficits may be present. Currently, there are no reports of women with the triad of Currarino undergoing cesarean delivery with the use of neuraxial anesthesia. Neuraxial anesthesia in patients with congenital malformations of the spine may be complicated or contraindicated, depending on the level and severity of the anatomic abnormality. We present the case of a pregnant woman at 36 weeks of gestation who underwent uncomplicated neuraxial anesthesia for cesarean delivery. When neuraxial anesthesia is contemplated in such patients, they should first receive careful neurologic and radiologic evaluation.