Intravenous Lidocaine for Refractory Pain in Patients With Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis: A Multicenter Prospective Nonrandomized Pilot Study.

INTRODUCTION: Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively. METHODS: Multicenter prospective nonrandomized pilot study included patients with moderate or severe pain (Numeric Rating Scale ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5 mg/kg was followed by continuous infusion at 1.5 mg/kg/hr. The dose was raised every 15 minutes until treatment response (up to a maximum 2 mg/kg/hr) and consecutively administered for 2 hours. Primary outcome was the mean difference in pain severity, preinfusion, and the first day after (Brief Pain Inventory [BPI] scale 1-10). A BPI decrease ≥1.3 points was considered clinically relevant. RESULTS: Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day 1 was 1.1 (SD ± 1.3) points for patients with PDAC and 0.5 (SD ± 1.7) for patients with CP. A clinically relevant decrease in BPI on day 1 was reported in 9 of 29 patients (31%), and this response lasted up to 1 month. No serious complications were reported, and only 3 minor complications (vertigo, nausea, and tingling of mouth). Treatment with lidocaine did not impact quality of life. DISCUSSION: Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.

The focus on life-prolonging anticancer treatment hampers shared decision-making in people with advanced cancer: A qualitative embedded multiple-case study.

BACKGROUND: Implementing shared decision-making in oncology practice is often limited, particularly integrating the patient's context into decision-making. To improve this, we conducted a quality improvement project, CONtext. CONtext attempts to accomplish this by: (1) Integrating the patient's context into shared decision-making during consultation with the medical oncologist; (2) Actively involving the GP and case manager (a specialized oncology nurse), who often have knowledge about the patient's context, and; (3) Giving the person with advanced cancer a time-out period of up to 2 weeks to consider and discuss treatment options with others, including close family and friends. AIM: To explore how persons with advanced cancer and their involved professionals experienced shared decision-making after the introduction of CONtext. DESIGN: A qualitative embedded multiple-case study using in-depth interviews analysed with inductive content analysis. PARTICIPANTS: A purposive sample of 14 cases, each case consisting of a patient with advanced cancer and ideally their medical oncologist, case manager, and GP. RESULTS: Four themes were identified: shared decision-making is a dynamic and continuous process (1), in which the medical oncologist's treatment recommendation is central (2), fuelled by the patients' experience of not having a choice (3), and integrating the patient's context into shared decision-making was considered important but hampered (4), for example, by the association with the terminal phase. CONCLUSIONS: The prevailing tendency among medical oncologists and persons with advanced cancer to prioritize life-prolonging anticancer treatments restricts the potential for shared decision-making. This undermines integrating individual context into decision-making, a critical aspect of the palliative care continuum.

Vacuum-Deposited Bifacial Perovskite Solar Cells.

Bifacial perovskite solar cells (Bi-PSCs) require thick perovskite layers to sufficiently absorb higher wavelength light. Also, it is critical to know which electrode (top or bottom) can more efficiently harvest the direct incident solar irradiance. Here, fully vacuum-deposited Bi-PSCs are reported with perovskite layer thicknesses ranging from ∼720 nm to 1.3 µm. With an optimized ITO top-electrode, the Bi-PSCs generated higher current density under top-illumination by >1 mA/cm2, attaining the highest value of 24.98 mA/cm2. The best Bi-PSC exhibited an efficiency of 19.6% under top-illumination and 18.71% under bottom-illumination, resulting in a high bifaciality factor of ∼0.95. Furthermore, even after employing cover glass encapsulation on the top-electrode, the Bi-PSCs still produced higher current density from top-illumination. Upon bifacial illumination using simulated 1-Sun light as the main illumination and a white LED light albedo of ∼0.21, the champion Bi-PSC demonstrated a current density value of ∼30.00 mA/cm2.

Bacterial killing and the dimensions of bacterial death.

Bacteria can be dead, alive, or exhibit slowed or suspended life forms, making bacterial death difficult to establish. Here, agar-plating, microscopic-counting, SYTO9/propidium-iodide staining, MTT-conversion, and bioluminescence-imaging were used to determine bacterial death upon exposure to different conditions. Rank correlations between pairs of assay outcomes were low, indicating different assays measure different aspects of bacterial death. Principal-component analysis yielded two principal components, named "reproductive-ability" (PC1) and "metabolic-activity" (PC2). Plotting of these principal components in two-dimensional space revealed a dead region, with borders defined by the PC1 and PC2 values. Sensu stricto implies an unpractical reality that all assays determining PC1 and PC2 must be carried out in order to establish bacterial death. Considering this unpracticality, it is suggested that at least one assay determining reproductive activity (PC1) and one assay determining metabolic activity (PC2) should be used to establish bacterial death. Minimally, researchers should specifically describe which dimension of bacterial death is assessed, when addressing bacterial death.

Advancing Ki67 hotspot detection in breast cancer: a comparative analysis of automated digital image analysis algorithms.

AIM: Manual detection and scoring of Ki67 hotspots is difficult and prone to variability, limiting its clinical utility. Automated hotspot detection and scoring by digital image analysis (DIA) could improve the assessment of the Ki67 hotspot proliferation index (PI). This study compared the clinical performance of Ki67 hotspot detection and scoring DIA algorithms based on virtual dual staining (VDS) and deep learning (DL) with manual Ki67 hotspot PI assessment. METHODS: Tissue sections of 135 consecutive invasive breast carcinomas were immunohistochemically stained for Ki67. Two DIA algorithms, based on VDS and DL, automatically determined the Ki67 hotspot PI. For manual assessment; two independent observers detected hotspots and calculated scores using a validated scoring protocol. RESULTS: Automated hotspot detection and assessment by VDS and DL could be performed in 73% and 100% of the cases, respectively. Automated hotspot detection by VDS and DL led to higher Ki67 hotspot PIs (mean 39.6% and 38.3%, respectively) compared to manual consensus Ki67 PIs (mean 28.8%). Comparing manual consensus Ki67 PIs with VDS Ki67 PIs revealed substantial correlation (r = 0.90), while manual consensus versus DL Ki67 PIs demonstrated high correlation (r = 0.95). CONCLUSION: Automated Ki67 hotspot detection and analysis correlated strongly with manual Ki67 assessment and provided higher PIs compared to manual assessment. The DL-based algorithm outperformed the VDS-based algorithm in clinical applicability, because it did not depend on virtual alignment of slides and correlated stronger with manual scores. Use of a DL-based algorithm may allow clearer Ki67 PI cutoff values, thereby improving the clinical usability of Ki67.

Intravenous lidocaine for refractory pain in patients with pancreatic ductal adenocarcinoma and chronic pancreatitis (LIDOPAN): a multicenter prospective non-randomized pilot study.

INTRODUCTION: Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively. METHODS: Multicentre prospective non-randomized pilot study including patients with moderate or severe pain (NRS ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5mg/kg, was followed by continuous infusion at 1.5 mg/kg/hour. The dose was raised every 15 minutes until treatment response (up to a maximum 2mg/kg/hour) and consecutively administered for two hours. Primary outcome was the mean difference in pain severity, pre-infusion and the first day after (Brief Pain Inventory [BPI] scale 1-10). A BPI decrease ≥ 1.3 points was considered clinically relevant. RESULTS: Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day one was 1.1 (SD±1.3) points for patients with PDAC and 0.5 (SD±1.7) for CP patients. A clinically relevant decrease in BPI on day one was reported in 9/29 patients (31%), this response lasted up to one month. No serious complications were reported, and only three minor complications (vertigo, nausea, tingling of mouth). Treatment with lidocaine did not impact quality of life. CONCLUSION: Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group, and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.

Normalization of gene counts affects principal components-based exploratory analysis of RNA-sequencing data.

Normalization of gene expression count data is an essential step of in the analysis of RNA-sequencing data. Its statistical analysis has been mostly addressed in the context of differential expression analysis, that is in the univariate setting. However, relationships among genes and samples are better explored and quantified using multivariate exploratory data analysis tools like Principal Component Analysis (PCA). In this study we investigate how normalization impacts the PCA model and its interpretation, considering twelve different widely used normalization methods that were applied on simulated and experimental data. Correlation patterns in the normalized data were explored using both summary statistics and Covariance Simultaneous Component Analysis. The impact of normalization on the PCA solution was assessed by exploring the model complexity, the quality of sample clustering in the low-dimensional PCA space and gene ranking in the model fit to normalized data. PCA models upon normalization were interpreted in the context gene enrichment pathway analysis. We found that although PCA score plots are often similar independently form the normalization used, biological interpretation of the models can depend heavily on the normalization method applied.

A catalogue of recombination coldspots in interspecific tomato hybrids.

Increasing natural resistance and resilience in plants is key for ensuring food security within a changing climate. Breeders improve these traits by crossing cultivars with their wild relatives and introgressing specific alleles through meiotic recombination. However, some genomic regions are devoid of recombination especially in crosses between divergent genomes, limiting the combinations of desirable alleles. Here, we used pooled-pollen sequencing to build a map of recombinant and non-recombinant regions between tomato and five wild relatives commonly used for introgressive tomato breeding. We detected hybrid-specific recombination coldspots that underscore the role of structural variations in modifying recombination patterns and maintaining genetic linkage in interspecific crosses. Crossover regions and coldspots show strong association with specific TE superfamilies exhibiting differentially accessible chromatin between somatic and meiotic cells. About two-thirds of the genome are conserved coldspots, located mostly in the pericentromeres and enriched with retrotransposons. The coldspots also harbor genes associated with agronomic traits and stress resistance, revealing undesired consequences of linkage drag and possible barriers to breeding. We presented examples of linkage drag that can potentially be resolved by pairing tomato with other wild species. Overall, this catalogue will help breeders better understand crossover localization and make informed decisions on generating new tomato varieties.

Added Value of Sensor-Based Behavioural Monitoring in an Infectious Disease Study with Sheep Infected with Toxoplasma gondii.

Sensor technologies are increasingly used to monitor laboratory animal behaviour. The aim of this study was to investigate the added value of using accelerometers and video to monitor the activity and drinking behaviour of three rams from 5 days before to 22 days after inoculation with Toxoplasma gondii. We computed the activity from accelerometer data as the vectorial dynamic body acceleration (VDBA). In addition, we assessed individual drinking behaviour from video, using frame differencing above the drinker to identify drinking bouts, and Aruco markers for individual identification. Four days after inoculation, rams developed fever and activity decreased. The daytime VDBA from days 4 to 10 was 60-80% of that before inoculation. Animal caretakers scored rams as lethargic on days 5 and 6 and, for one ram, also on the morning of day 7. Video analysis showed that each ram decreased its number of visits to the drinker, as well as its time spent at the drinker, by up to 50%. The fever and corresponding sickness behaviours lasted until day 10. Overall, while we recognize the limited conclusiveness due to the small number of animals, the sensor technologies provided continuous, individual, detailed, and objective data and offered additional insights as compared to routine observations. We recommend the wider implementation of such technologies in animal disease trials to refine experiments and guarantee the quality of experimental results.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.