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Abstract Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Diagnosing MM presents considerable challenges, involving the identification of plasma cells in cytology examinations on hematological slides. At present, this is still a time-consuming manual task and has high labor costs. These challenges have adverse implications, which rely heavily on medical professionals’ expertise and experience. To tackle these challenges, we present an investigation using Artificial Intelligence, specifically a Machine Learning analysis of hematological slides with a Deep Neural Network (DNN), to support specialists during the process of diagnosing MM. In this sense, the contribution of this study is twofold: in addition to the trained model to diagnose MM, we also make available to the community a fully-curated hematological slide dataset with thousands of images of plasma cells. Taken together, the setup we established here is a framework that researchers and hospitals with limited resources can promptly use. Our contributions provide practical results that have been directly applied in the public health system in Brazil. Given the open-source nature of the project, we anticipate it will be used and extended to diagnose other malignancies.

Abstract The ‘landscape of fear’ concept offers valuable insights into wildlife behaviour, yet its practical integration into habitat management for conservation remains underexplored. In this study, conducted in the subtropical monsoon grasslands of Bardia National Park, Nepal, we aimed to bridge this gap through a multi‐year, landscape‐scale experimental investigation in Bardia National Park, Nepal. The park has the highest density of tigers (with an estimated density of ~7 individuals per 100 km2) in Nepal, allowing us to understand the effect of habitat management on predation risk and resource availability especially for three cervid species: chital (Axis axis), swamp deer (Rucervus duvaucelii) and hog deer (Axis porcinus). We used plots with varying mowing frequency (0–4 times per year), size (ranging from small: 49 m2 to large: 3600 m2) and artificial fertilisation type (none, phosphorus, nitrogen) to assess the trade‐offs between probable predation risk and resources for these cervid species, which constitute primary prey for tigers in Nepal. Our results showed distinct responses of these deer to perceived predation risk within grassland habitats. Notably, these deer exhibited heightened use of larger plots, indicative of a perceived sense of safety, as evidenced by the higher occurrence of pellet groups in the larger plots (mean = 0.1 pellet groups m−2 in 3600 m2 plots vs. 0.07 in 400 m2 and 0.05 in 49 m2 plots). Furthermore, the level of use by the deer was significantly higher in larger plots that received mowing and fertilisation treatments compared to smaller plots subjected to similar treatments. Of particular interest is the observation that chital and swamp deer exhibited greater utilisation of the centre (core) areas within the larger plots (mean = 0.21 pellet groups m−2 at the centre vs. 0.13 at the edge) despite the edge (periphery) also provided attractive resources to these deer. In contrast, hog deer did not display any discernible reaction to the experimental treatments, suggesting potential species‐specific variations in response to perceived predation risk arising from management interventions. Our findings emphasise the importance of a sense of security as a primary determinant of habitat selection for medium‐sized deer within managed grassland environments. These insights carry practical implications for park managers, providing a nuanced understanding of integrating the ‘landscape of fear’ into habitat management strategies. This study emphasises that the ‘landscape of fear’ concept can and should be integrated into habitat management to maintain delicate predator–prey dynamics within ecosystems.

Background: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. Methods: Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. Results: Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Pervasive inbreeding is a major genetic threat of population fragmentation and can undermine the efficacy of population connectivity measures. Nevertheless, few studies have evaluated whether wildlife crossings can alleviate the frequency and length of genomic autozygous segments. Here, we provided a genomic inbreeding perspective on the potential effectiveness of mammal population defragmentation measures. We applied a SNP-genotyping case study on the ~2500 wild boar Sus scrofa population of Veluwe, The Netherlands, a 1000-km2 Natura 2000 protected area with many fences and roads but also, increasingly, fence openings and wildlife crossings. We combined a 20K genotyping assessment of genetic status and migration rate with a simulation that examined the potential for alleviation of isolation and inbreeding. We found that Veluwe wild boar subpopulations are significantly differentiated (FST-values of 0.02-0.13) and have low levels of gene flow. One noteworthy exception was the Central and Southeastern subpopulation, which were nearly panmictic and appeared to be effectively connected through a highway wildlife overpass. Estimated effective population sizes were at least 85 for the meta-population and ranged from 31 to 52 for the subpopulations. All subpopulations, including the two connected subpopulations, experienced substantial inbreeding, as evidenced through the occurrence of many long homozygous segments. Simulation output indicated that whereas one or few migrants per generation could undo genetic differentiation and boost effective population sizes rapidly, genomic inbreeding was only marginally reduced. The implication is that ostensibly successful connectivity restoration projects may fail to alleviate genomic inbreeding of fragmented mammal populations. We put forward that defragmentation projects should allow for (i) monitoring of levels of differentiation, migration and genomic inbreeding, (ii) anticipation of the inbreeding status of the meta-population, and, if inbreeding levels are high and/or haplotypes have become fixed, (iii) consideration of enhancing migration and gene flow among meta-populations, possibly through translocation.

The proposal of improving reproducibility by lowering the significance threshold to 0.005 has been discussed, but the impact on conducting clinical trials has yet to be examined from a study design perspective. The impact on sample size and study duration was investigated using design setups from 125 phase II studies published between 2015 and 2022. The impact was assessed using percent increase in sample size and additional years of accrual with the medians being 110.97% higher and 2.65 years longer respectively. The results indicated that this proposal causes additional financial burdens that reduce the efficiency of conducting clinical trials.

Hydraulic fracturing is frequently used to increase the permeability of rock formations in energy extraction scenarios such as unconventional oil and gas extraction and enhanced geothermal systems (EGSs). The present study addresses uncertainties in the hydraulic fracturing process pertaining to EGSs in crystalline rock such as granite. Specifically, there is debate in the literature on the mechanisms (i.e. tensile and/or shear) by which these fractures initiate, propagate, and coalesce. We present experiments on Barre granite with pre-cut flaws where the material is loaded to high far-field stresses close to shear failure, and then the fluid pressure in the flaws is increased to move the Mohr's circle to the left and observe the initiation and propagation of fractures using high-speed imaging and acoustic emissions (AEs). We find that the hydraulic fractures initiate as tensile microcracks at the flaw tips, and then propagate as a combination of tensile and shear microcracks. AE focal mechanisms also show elevated levels of tensional microfracturing near the flaw tips during pressurization and final failure. We then consider a numerical model of the experimental setup, where we find that fractures are indeed likely to initiate at flaw tips in tension even at relatively high far-field stresses of 40 MPa where shear failure is generally expected.

Traditional binary combinational logic circuits are generally obtained by cascading multiple basic logic gate circuits, using more components and complicated wiring. In contrast to the binary logic circuit design in this method, ternary combinational logic circuit implementation is more complicated. In this paper, a ternary circuit design method that does not require cascading basic ternary logic gates is proposed based on a tri-valued memristor, which can directly realize specific logic functions through a series connection of memristors. The ternary encoder, ternary decoder, ternary comparator, and ternary data selector are implemented by this method, and the effectiveness of the circuits is verified by LTspice simulations.

Biological vision relies on the intrinsic spatiotemporal structure of a continuously flowing image stream. We review converging psychophysical and physiological evidence about the structure and precision of the perceived spatiotemporal organization of dynamic images. Visual acuity, temporal resolution, and contrast sensitivity have been found to involve (a) motion-produced increases in image contrast, (b) coherent phase relations among temporally varying retinal signals, and (c) physiological preservation of spatiotemporal structure from retina to cortex. Moreover, psychophysical theory and evidence show that the spatiotemporal structure of dynamic retinal images carries precise information for perceiving surfaces and motions—consistent with the corresponding differential structures of spatiotemporal images and environmental surfaces.

Abstract Cannabinoid CB1 receptors (CB1Rs) have been major targets in medication development for the treatment of substance use disorders. However, clinical trials with rimonabant, a CB1R antagonist/inverse agonist, failed due to severe side effects. Here, we evaluated the therapeutic potential of PIMSR, a neutral CB1R antagonist lacking an inverse agonist profile, against cocaine’s behavioral effects in experimental animals. We found that systemic administration of PIMSR dose-dependently inhibited cocaine self-administration under fixed-ratio (FR5), but not FR1, reinforcement, shifted the cocaine self-administration dose-response curve downward, decreased incentive motivation to seek cocaine under progressive-ratio reinforcement, and reduced cue-induced reinstatement of cocaine seeking. PIMSR also inhibited oral sucrose self-administration. Importantly, PIMSR alone is neither rewarding nor aversive as assessed by place conditioning. We then used intracranial self-stimulation (ICSS) to explore the possible involvement of the mesolimbic dopamine system in PIMSR’s action. We found that PIMSR dose-dependently attenuated cocaine-enhanced ICSS maintained by electrical stimulation of the medial forebrain bundle in rats. PIMSR itself failed to alter electrical ICSS, but dose-dependently inhibited ICSS maintained by optical stimulation of midbrain dopamine neurons in transgenic DAT-Cre mice, suggesting the involvement of dopamine-dependent mechanisms. Lastly, we examined the CB1R mechanisms underlying PIMSR’s action. We found that PIMSR pretreatment attenuated Δ9-tetrahydrocannabinol (Δ9-THC)- or ACEA (a selective CB1R agonist)-induced reduction in optical ICSS. Together, our findings suggest that the neutral CB1R antagonist PIMSR deserves further research as a promising pharmacotherapeutic for cocaine use disorder.

Abstract Background Amiodarone is one of the most commonly used anti-arrhythmic agents. Amiodarone pulmonary toxicity is a potentially fatal adverse effect associated with amiodarone use. Previous studies on the epidemiology and risk factors for amiodarone pulmonary toxicity showed diverse results. Methods A multicenter retrospective cohort study was conducted to identify clinic-epidemiologic markers associated with amiodarone pulmonary toxicity for development of a prediction rule. Patients taking amiodarone who were managed in 3 centres in Hong Kong from 2005 to 2015 were included in this study. Penalized logistic regression was used to model the outcome as it is rare. Results A total of 34 cases with amiodarone pulmonary toxicity were identified among 1786 patients taking amiodarone for at least 90 days from 2005 to 2015. The incidence of amiodarone pulmonary toxicity was estimated to be 1.9%. The risk factors for amiodarone pulmonary toxicity included advanced age (OR 1.047, 95% CI 1.010–1.085, p = 0.013), ventricular arrhythmia (OR 2.703, 95% CI 1.053–6.935, p = 0.039), underlying lung disease (OR 2.511, 95% CI 1.146–5.501, p = 0.021) and cumulative dose of amiodarone (OR 4.762, 95% CI 1.310–17.309 p = 0.018). Conclusions The incidence of amiodarone pulmonary toxicity in Chinese patients in Hong Kong is estimated to be 1.9% in this study. Age, underlying lung disease, ventricular arrhythmia and cumulative dose of amiodarone are associated with the development of amiodarone pulmonary toxicity. A prediction rule was developed to inform the risk of developing amiodarone pulmonary toxicity.

Plasma-based next-generation sequencing (NGS) has demonstrated the potential to guide the personalized treatment of non-small cell lung cancer (NSCLC). Inherent differences in mutational genomic profiles of NSCLC exist between Asian and Western populations. However, the published mutational genomic data of NSCLC has largely focused on Western populations. We retrospectively analyzed results from comprehensive NGS of plasma (Guardant360®) from patients with advanced non-squamous NSCLC, as seen in clinical practice. Tests were ordered between January 2016 and December 2020 in Hong Kong, Korea, Taiwan, Japan and Southeast Asia. The assay identified single-nucleotide variants (SNV), insertions and deletions, and fusions and amplifications in 74 genes. In total, 1608 plasma samples from patients with advanced non-squamous NSCLC were tested. The median turnaround time for test results was 7 days. Of the samples with detectable ctDNA (85.6%), 68.3% had alterations in at least one NCCN-recommended NSCLC biomarker. EGFR driver mutations were most frequent (48.6%), followed by alterations of KRAS (7.9%), ERBB2 (4.1%) and ALK (2.5%). Co-mutations of EGFR and KRAS occurred in 4.7% of samples. KRAS G12C was identified in 18.6% of all samples with KRAS mutations. Common mutations, such as exon 19 deletions and L858R, accounted for 88.4% of EGFR driver mutations. Among the samples with any EGFR driver mutation, T790M was present in 36.9%, including 7.7% with additional alterations associated with osimertinib resistance (MET amplification, C797X). Comprehensive plasma-based NGS provided the timely and clinically informative mutational genomic profiling of advanced non-squamous NSCLC in East Asian patients.

Abstract Triangle Island on Canada's Pacific coast is home to a large, globally important seabird breeding colony. The shrub Salmonberry Rubus spectabilis and tussock‐forming Tufted Hairgrass Deschampsia cespitosa together form ~70% of vegetation coverage and contain the vast majority (~90%) of seabird nesting burrows. Salmonberry has in recent decades greatly expanded its coverage, while that of Tufted Hairgrass has receded. Seabirds prefer not to burrow under Salmonberry, making its ongoing expansion a potential conservation issue. We investigated three hypotheses proposed to explain Salmonberry's expansion (climate change, biopedturbation, and nutrient input), using comparisons of stomatal density of Salmonberry leaves sampled from Triangle Island, other seabird colonies, other coastal locations, and from historical specimens in herbaria. Stomatal density helps regulate photosynthetic gain and control water loss, and responds to light, nutrient, carbon dioxide, and water availability. Differing patterns of stomatal density are expected among sample locations depending on which of the hypothesized factors most strongly affects Salmonberry's performance. Our data are most consistent with the nutrient input hypothesis. We discuss possible reasons why Salmonberry has expanded so recently, even though Triangle has been a large seabird colony for at least a century and likely much longer.

Habitat availability determines the distribution of migratory waterfowl along their flyway, which further influences the transmission and spatial spread of avian influenza viruses (AIVs). The extensive habitat loss in the East Asian-Australasian Flyway (EAAF) may have potentially altered the virus spread and transmission, but those consequences are rarely studied. We constructed 6 fall migration networks that differed in their level of habitat loss, wherein an increase in habitat loss resulted in smaller networks with fewer sites and links. We integrated an agent-based model and a susceptible-infected-recovered model to simulate waterfowl migration and AIV transmission. We found that extensive habitat loss in the EAAF can 1) relocate the outbreaks northwards, responding to the distribution changes of wintering waterfowl geese, 2) increase the outbreak risk in remaining sites due to larger goose congregations, and 3) facilitate AIV transmission in the migratory population. In addition, our modeling output was in line with the predictions from the concept of "migratory escape", i.e., the migration allows the geese to "escape" from the location where infection risk is high, affecting the pattern of infection prevalence in the waterfowl population. Our modeling shed light on the potential consequences of habitat loss in spreading and transmitting AIV at the flyway scale and suggested the driving mechanisms behind these effects, indicating the importance of conservation in changing spatial and temporal patterns of AIV outbreaks.

Stopover sites are vital to the state of the population of many migratory bird species. The greater white-fronted goose Anser albifrons is the most numerous Eurasian goose species, and migrates on a broad front over European Russia. Stopover and staging sites have specific habitat requirements. They are located near open water, have nearby (

Abstract Wildlife crime is one of the most profitable illegal industries worldwide. Current actions to reduce it are far from effective and fail to prevent population declines of many endangered species, pressing the need for innovative anti-poaching solutions. Here, we propose and test a poacher early warning system that is based on the movement responses of non-targeted sentinel animals, which naturally respond to threats by fleeing and changing herd topology. We analyzed human-evasive movement patterns of 135 mammalian savanna herbivores of four different species, using an internet-of-things architecture with wearable sensors, wireless data transmission and machine learning algorithms. We show that the presence of human intruders can be accurately detected (86.1% accuracy) and localized (less than 500 m error in 54.2% of the experimentally staged intrusions) by algorithmically identifying characteristic changes in sentinel movement. These behavioral signatures include, among others, an increase in movement speed, energy expenditure, body acceleration, directional persistence and herd coherence, and a decrease in suitability of selected habitat. The key to successful identification of these signatures lies in identifying systematic deviations from normal behavior under similar conditions, such as season, time of day and habitat. We also show that the indirect costs of predation are not limited to vigilance, but also include (1) long, high-speed flights; (2) energetically costly flight paths; and (3) suboptimal habitat selection during flights. The combination of wireless biologging, predictive analytics and sentinel animal behavior can benefit wildlife conservation via early poacher detection, but also solve challenges related to surveillance, safety and health.

Abstract Fire is rampant throughout subtropical South and Southeast Asian grasslands. However, very little is known about the role of fire and pyric herbivory on the functioning of highly productive subtropical monsoon grasslands lying within the Cwa climatic region. We assessed the temporal effect of fire on postfire regrowth quality and associated pyric‐herbivory in the subtropical monsoon grasslands of Bardia National Park, Nepal. Every year, grasslands are burned as a management intervention in the park, especially between March and May. Within a week after fire, at the end of March 2020, we established 60 m × 60 m plots within patches of burned grassland in the core area of the Park. We collected grass samples from the plots and determined physical and chemical properties of the vegetation at regular 30‐day intervals from April to July 2020, starting from 30 days after fire to assess postfire regrowth forage quality. We counted pellet groups of cervids that are abundant in the area for the same four months from 2 m × 2 m quadrats that were permanently marked with pegs along the diagonal of each 60 m × 60 m plot to estimate intensity of use by deer to the progression of postfire regrowth. We observed strong and significant reductions in crude protein (mean value 9.1 to 4.1 [55% decrease]) and phosphorus (mean value 0.2 to 0.11 [45% decrease]) in forage collected during different time intervals, that is, from 30 days to 120 days after fire. Deer utilized the burned areas extensively for a short period, that is, up to two months after fire when the burned areas contained short grasses with a higher level of crude protein and phosphorus. The level of use of postfire regrowth by chital (Axis axis) differed significantly over time since fire, with higher intensity of use at 30 days after fire. The level of use of postfire regrowth by swamp deer (Rucervus duvaucelii) did not differ significantly until 90 days after fire, however, decreased significantly after 90 days since fire. Large‐scale single event fires, thus, may not fulfil nutritional requirements of all species in the deer assemblage in these subtropical monsoon grasslands. This is likely because the nutritional requirements of herbivores differ due to differences in body size and physiological needs—maintenance, reproduction, and lactation. We recommend a spatiotemporal manipulation of fire to reinforce grazing feedback and to yield forage of high quality for the longest possible period for a sustainable high number of deer to maintain a viable tiger population within the park.

Introduction: Upfront next-generation sequencing (NGS) in patients with metastatic NSCLC has been associated with cost savings and shorter time-to-test results in the United States. Nevertheless, this may not apply in jurisdictions where the prevalence of patients with actionable mutations, cost of health care, and reimbursement models differ. Methods: A decision analytical model was built to compare sequential, panel, exclusionary, and upfront NGS testing in patients with metastatic NSCLC in Hong Kong. In sequential and panel testing, patients were tested for genomic alterations (GAs) with treatment followed by sequential or NGS. In exclusionary testing, EGFR and ALK were tested first, followed by NGS. For each modality, the mutation identified, time to receive testing results, and costs (2020 U.S. dollars) were estimated. Results: Exclusionary testing required the shortest time-to-results (1.6 wk) and was most cost saving. In the scenario where all patients used exclusionary testing, a cost saving of $4.6 million was expected relative to current practice, with 90.7% of actionable and 46.5% of nonactionable GAs detected; when all patients used NGS, it would be $2.9 million more expensive with a 100% GA detection rate. Results were sensitive to testing costs and the proportion of patients that continued testing. Conclusions: Exclusionary testing is the best option in terms of cost and time-to-results in Hong Kong. This finding may be applicable for other Asian countries; however, exclusionary testing does not capture all possible GAs. As more GAs become actionable and the cost of NGS declines, NGS may become a cost-saving option.

Abstract Introduction Lower-dose ceritinib (450 mg) once-daily with food was approved in 2018 in Hong Kong (HK) for first-line treatment of patients with anaplastic lymphoma kinase-positive (ALK +) advanced non-small cell lung cancer (NSCLC). This study examined the cost-effectiveness of ceritinib vs. crizotinib in the first-line treatment of ALK + NSCLC from a HK healthcare service provider's or government's perspective. Methods Costs and effectiveness of first-line ceritinib vs. crizotinib over a 20-year time horizon was evaluated using a partitioned survival model with three health states (stable disease, progressed disease, and death). The efficacy data for ceritinib were obtained from a phase 3 trial comparing ceritinib with chemotherapy for advanced non-small cell lung cancer (ASCEND-4) and extrapolated using parametric survival models. Long-term survival associated with crizotinib were estimated using hazard ratio of crizotinib vs. ceritinib obtained from matching-adjusted indirect comparison based on ASCEND-4 and PROFILE 1014 trials. Drug acquisition, administration, adverse events costs, and medical costs associated with each health state were obtained from public sources and converted to 2018 US Dollars. Incremental costs per quality-adjusted-life-year (QALY) and life-year (LY) gained were estimated for ceritinib vs. crizotinib. Results The base case results showed that ceritinib was associated with 3.22 QALYs, 4.51 LYs, and total costs of $157,581 over 20 years. Patients receiving crizotinib had 2.68 QALYs, 3.85 LYs, and $150,424 total costs over the same time horizon. The incremental cost per QALY gained for ceritinib vs crizotinib was $13,343. Results were robust to deterministic sensitivity analyses in most scenarios. Conclusion Ceritinib offers a cost-effective option compared to crizotinib for previously untreated ALK + advanced NCSLC in HK.

Abstract Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18‐ to 65‐year‐old AML patients refractory to first‐line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high‐dose cytarabine consolidation, with clofarabine (30 mg/m2/d, Days 1‐5), cytarabine (750 mg/m2/d, Days 1‐5), and mitoxantrone (12 mg/m2/d, Days 3‐5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The mutational profile of a 69‐gene panel was evaluated. Twenty‐six men and 26 women at a median age of 46 (22‐65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty‐two CR/CRi patients underwent allo‐HSCT. The 2‐year overall survival (OS), relapse‐free survival (RFS), and event‐free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo‐HSCT (P = .005), and superior RFS and EFS were associated with allo‐HSCT (P

Abstract Background Pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-naïve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. Methods A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30 years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer’s perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. Results In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab, the estimated ICER was USD8,904. Conclusions Pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong.

The nanoscale size and controllable memristance of Memristor (MR) have shown evident superiorities for structuring new integrated circuits with different functions. With regards to the reported MR based filters, their cut-off frequencies could be hardly hot-line controlled on purposes. In this paper, by using the boundary values of memristance, a method for hot-line adjusting cut-off frequencies is newly proposed by inputting a preset DC voltage together with the to-be-filtered signal, without the requirement of extra memristance write circuits, which is hence beneficial for integrated implementation. The floating MR emulator is firstly presented and the saturation operation of its memristance is interpreted. A family of MR based low-pass filters with controllable cut-off frequency are proposed by combining the connection nodes of a memristive circuit network Z with the op amp. Two circuits of the low-pass filter family are chosen for demonstration, and the cut-off frequency and passband gain are calculated. Square and sinusoidal voltage signals are used to test the performance of the proposed low-pass filter family. Both the simulation and experimental results show that the proposed filters can achieve cut-off frequency adjustment with good filtering performance.

A chaotic system with a hyperbolic function flux-controlled memristor is designed, which exhibits conditional symmetry and attractor growing. The newly introduced cosine function keeps the polarity balance when some of the variables get polarity inversed and correspondingly conditional symmetric coexisting chaotic attractors are coined. Due to the periodicity of the cosine function, the memristive system with infinitely many coexisting attractors shows attractor growing in some special circumstances. Analog circuit experiment proves the theoretical and numerical analysis.

Abstract We assessed the hypothesized negative correlation between the influence of multiple predators and body condition and fecundity of the European hare, from 13 areas in the Netherlands. Year‐round abundance of predators was estimated by hunters. We quantified predator influence as the sum of their field metabolic rates, as this sum reflects the daily food requirements of multiple individuals. We determined the ratio between body mass and hindfoot length of hares as an index of body condition and the weight of their adrenal gland as a measure of chronic exposure to stress, and we counted the number of placental scars to estimate fecundity of hares. As hypothesized, we found that the sum of field metabolic rate of predators was negatively correlated with body condition and the number of placental scars, whereas it was positively related to the weight of the adrenal glands. In contrast to the sum of the field metabolic rate, the total number of predators did not or weakly affect the investigated risk responses. The sum of the field metabolic rate can be a useful proxy for the influence of multiple predators and takes into account predator abundance, type, body weight, and food requirements of multiple predators. With our findings, our paper contributes to a better understanding of the risk effects of multiple predators on prey fitness. Additionally, we identify a potential contributor to the decline of European hare populations.

Visual perception involves spatially and temporally coordinated variations in diverse physical systems: environmental surfaces and symbols, optical images, electro-chemical activity in neural networks, muscles, and bodily movements—each with a distinctly different material structure and energy. The fundamental problem in the theory of perception is to characterize the information that enables both perceptual awareness and real-time dynamic coordination of these diverse physical systems. Gibson's psychophysical and ecological conception of this problem differed from that of mainstream science both then and now. The present article aims to incorporate Gibson's ideas within a general conception of information for visual perception. We emphasize the essential role of spatiotemporal form, in contrast with symbolic information. We consider contemporary understanding of surface structure, optical images, and optic flow. Finally, we consider recent evidence about capacity limitations on the rate of visual perception and implications for the ecology of vision.

Small soft robotic systems are being explored for myriad applications in medicine. Specifically, magnetically actuated microrobots capable of remote manipulation hold significant potential for the targeted delivery of therapeutics and biologicals. Much of previous efforts on microrobotics have been dedicated to locomotion in aqueous environments and hard surfaces. However, our human bodies are made of dense biological tissues, requiring researchers to develop new microrobotics that can locomote atop tissue surfaces. Tumbling microrobots are a sub-category of these devices capable of walking on surfaces guided by rotating magnetic fields. Using microrobots to deliver payloads to specific regions of sensitive tissues is a primary goal of medical microrobots. Central nervous system (CNS) tissues are a prime candidate given their delicate structure and highly region-specific function. Here we demonstrate surface walking of soft alginate capsules capable of moving on top of a rat cortex and mouse spinal cord ex vivo, demonstrating multi-location small molecule delivery to up to six different locations on each type of tissue with high spatial specificity. The softness of alginate gel prevents injuries that may arise from friction with CNS tissues during millirobot locomotion. Development of this technology may be useful in clinical and preclinical applications such as drug delivery, neural stimulation, and diagnostic imaging.

Abstract Background Cancer outcomes vary widely among different countries. However, comparisons of cost-effectiveness and cost-efficiency of different systems are complex because the incidences of different cancers vary across countries and their chances of cure also differ substantially. We aim to propose a new standardized method for global comparison and to explore its relationship with economic indicators. Methods Cancer statistics from all 184 countries and 27 cancers listed in GLOBOCAN 2012 were analyzed. The complement of age-standardized mortality/incidence ratio [1 – (ASM/ASI)] was taken as the proxy relative survival (RS). Accounting for various country-specific cancer patterns, the cancer site-standardized proxy RS (proxy SS-RS) of individual countries were calculated by weighting the proportion of specific cancer sites as compared with the global pattern of incidence. Economic indicators of different countries listed by the World Bank were correlated with corresponding proxy SS-RS. Results Substantial variation in site-specific survival and new case distribution supported the use of proxy SS-RS, which ranged from 0.124 to 0.622 (median 0.359). The median total health expenditure per capita (HEpc) increased from US$44 for countries with proxy SS-RS

Abstract Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.

Abstract Spatial variation in habitat riskiness has a major influence on the predator–prey space race. However, the outcome of this race can be modulated if prey shares enemies with fellow prey (i.e., another prey species). Sharing of natural enemies may result in apparent competition, and its implications for prey space use remain poorly studied. Our objective was to test how prey species spend time among habitats that differ in riskiness, and how shared predation modulates the space use by prey species. We studied a one‐predator, two‐prey system in a coastal dune landscape in the Netherlands with the European hare (Lepus europaeus) and European rabbit (Oryctolagus cuniculus) as sympatric prey species and red fox (Vulpes vulpes) as their main predator. The fine‐scale space use by each species was quantified using camera traps. We quantified residence time as an index of space use. Hares and rabbits spent time differently among habitats that differ in riskiness. Space use by predators and habitat riskiness affected space use by hares more strongly than space use by rabbits. Residence time of hare was shorter in habitats in which the predator was efficient in searching or capturing prey species. However, hares spent more time in edge habitat when foxes were present, even though foxes are considered ambush predators. Shared predation affected the predator–prey space race for hares positively, and more strongly than the predator–prey space race for rabbits, which were not affected. Shared predation reversed the predator–prey space race between foxes and hares, whereas shared predation possibly also released a negative association and promoted a positive association between our two sympatric prey species. Habitat riskiness, species presence, and prey species’ escape mode and foraging mode (i.e., central‐place vs. noncentral‐place forager) affected the prey space race under shared predation.

Temozolomide (TMZ), an oral alkylating agent, is a cornerstone of standard-of-care multimodality therapy for glioblastoma. In spite of significant efforts to treat this disease, the tumor carries a poor prognosis and is considered incurable largely due to the development of chemoresistance. One of the main mechanisms for this phenomenon is the activation of tumor DNA repair systems, such as O-6-methylguanine-DNA methyltransferase, that removes TMZ-induced DNA adducts and restores genomic integrity. Recent advances in the understanding of TMZ resistance oncobiology have introduced several novel independent molecular mechanisms involving epigenetic, transcriptomic, proteomic aberrations as well as alterations in apoptosis-autophagy processes, receptor tyrosine kinase activity, the tumor microenvironment, and the emergence of glioma stem cells. This article describes a multifaceted summary of the latest proposed causes for TMZ resistance and their complex interactions. It is believed that only by comprehending this growing network of interdependent mechanisms can effective combinatorial oncologic therapeutic strategies be developed to improve patient overall survival.

While firefighters currently have low smoking rates, rates of smokeless tobacco (SLT) use among this population are remarkably high and substantially greater than similar occupational groups, and the general population. This study explored determinants associated with SLT use, barriers to cessation, and motivators for SLT cessation in the fire service. Key informant interviews were conducted in 23 career firefighters who were current (n = 14) and former (n = 9) SLT users from across the U.S. Discussions were recorded and independently coded according to questions and themes. Major themes that developed among firefighters regarding SLT use determinants included positive perceptions of SLT products, social influences from their peers and family members, acceptability of SLT use in the fire service, and a coping resource for job stress. Firefighters discussed several barriers to SLT cessation, including intrapersonal barriers such as SLT use habits and its dependency, concerns about withdrawal symptoms; and social-environmental barriers including lack of support from health and other services providers, and lack of enforcement of existing tobacco policies regarding SLT use. Firefighters also mentioned both internal and external motivators for cessation. Internal motivators included self-motivation and their health concerns while external motivators included friends and family support, incentives or rewards, and price of SLT products. Findings provide unique perspectives from firefighters on factors that influence SLT use and barriers and motivators to SLT cessation. These are insufficiently assessed and considered by the fire service organizations and their health care providers. Thus, the organizations must understand these issues in order to mitigate barriers and motivate the personnel to quit using SLT. Information gained from firefighters who were current and former SLT users can be used to develop an effective, culturally-tailored intervention that is acceptable to fire service personnel.

The molecular assembly of cells depends not only on the balance between anabolism and catabolism but to a large degree on the building blocks available in the environment. For cultured mammalian cells, this is largely determined by the composition of the applied growth medium. Here, we study the impact of lipids in the medium on mitochondrial membrane architecture and function by combining LC-MS/MS lipidomics and functional tests with lipid supplementation experiments in an otherwise serum-free and lipid-free cell culture model. We demonstrate that the composition of mitochondrial cardiolipins strongly depends on the lipid environment in cultured cells and favors the incorporation of essential linoleic acid over other fatty acids. Simultaneously, the mitochondrial respiratory complex I activity was altered, whereas the matrix-localized enzyme citrate synthase was unaffected. This raises the question on a link between membrane composition and respiratory control. In summary, we found a strong dependency of central mitochondrial features on the type of lipids contained in the growth medium. This underlines the importance of considering these factors when using and establishing cell culture models in biomedical research. In summary, we found a strong dependency of central mitochondrial features on the type of lipids contained in the growth medium.

Many populations of birds depend on networks of sites to survive. Sufficient connectivity that allows movement between the sites throughout the year is a critical requirement. We found that existing international frameworks and policies for identifying sites important for bird conservation focus more at the level of the individual site than on the site network and its connectivity. Only 21% of site criteria acknowledge the importance of movement networks for birds, and such network criteria were mostly (67%) qualitative. We suggest a three-step quantitative approach for informing conservation about the connectivity of bird movements (especially when migrating) from a network perspective, by reviewing current scientific knowledge. The first step is to construct a bird movement network by identifying sites frequently used by birds as ‘nodes’, and then define ‘edges’ from the probability of non-stop flight between each pair of nodes. The second step is to quantify network connectivity, i.e., the extent to which the site network facilitates bird movements. The last step is to assess the importance of each site from its contribution to network connectivity. This approach can serve as a tool for comprehensive and dynamic monitoring of the robustness of site networks during global change.

Magnetic nanoparticles (MNPs) have potential for enhancing drug delivery in selected cancer patients, including those which have cells that have disseminated within cerebrospinal fluid (CSF) pathways. Here, we present data related to the creation and in vitro use of new two-part MNPs consisting of magnetic gold-iron alloy cores which have streptavidin binding sites, and are coated with biotinylated etoposide. Etoposide was chosen due to its previous use in the CSF and ease of biotinylation. Etoposide magnetic nanoparticles (“Etop-MNPs”) were characterized by several different methods, and moved at a distance by surface-walking of MNP clusters, which occurs in response to a rotating permanent magnet. Human cell lines including D283 (medulloblastoma), U138 (glioblastoma), and H2122 (lung adenocarcinoma) were treated with direct application of Etop-MNPs (and control particles), and after remote particle movement. Cell viability was determined by MTT assay and trypan blue exclusion. Results indicated that the biotinylated etoposide was successfully bound to the base MNPs, with the hybrid particle attaining a maximum velocity of 0.13 ± 0.018 cm/sec. Etop-MNPs killed cancer cells in a dose-dependent fashion, with 50 ± 6.8% cell killing of D283 cells (for example) with 24 h of treatment after remote targeting. U138 and H2122 cells were found to be even more susceptible to the killing effect of Etop-MNPs than D283 cells. These findings indicate that the novel Etop-MNPs have a cytotoxic effect, and can be moved relatively rapidly at physiologic distances, using a rotating magnet. While further testing is needed, intrathecal administration of Etop-MNPs holds promise for magnetically-enhanced eradication of cancer cells distributed within CSF pathways, particularly if given early in the course of the disease.

BackgroundHepatocellular carcinoma (HCC) is a rare hepatic malignancy in children. Hepatitis B virus (HBV) infection is a key predisposing factor in endemic regions but its impact on outcome has not been studied. We aim to evaluate the prognostic implication of HBV seropositivity and role of cancer surveillance in children with HCC from East Asian populations with national HBV vaccination.MethodsReview of population-based databases for patients (< 18 years old) diagnosed with HCC from 1993 to 2017 in two Southeast Asian regions with universal HBV vaccination (instituted since 1988 and 1987 in Hong Kong and Singapore, respectively).ResultsThirty-nine patients were identified (Hong Kong, 28; Singapore, 11). Thirty were male; median age at diagnosis was 10.8 years (range, 0.98–16.6). Abdominal pain was the commonest presentation while five patients were diagnosed through surveillance for underlying condition. Alpha-fetoprotein was raised in 36 patients (mean, 500,598 ng/ml). Nineteen had bilobar involvement, among the patients in whom pretreatment extent of disease (PRETEXT) staging could retrospectively be assigned, 3 had stage I, 13 had stage II, 4 had stage III, and 11 had stage IV disease. Seventeen had distant metastasis. HBsAg was positive in 19 of 38 patients. Two patients had fibrolamellar HCC. Upfront management involved tumor resection in 16 (liver transplantation, 2), systemic chemotherapy in 21, interventional procedures in 6 [transarterial chemoembolization (TACE), 5, radiofrequency ablation (RFA), 1], and radiotherapy in 4 (selective internal radiation, 3, external beam radiation, 1). Five-year event-free survival (EFS) and overall survival (OS) were 15.4 ± 6.0 and 26.1 ± 7.2%, respectively. Patient’s HBsAg positivity, metastatic disease and inability to undergo definitive resection represent poor prognostic factors in univariate and multivariable analyses. Patients diagnosed by surveillance had significantly better outcome.ConclusionPediatric HCC has poor outcome. HBV status remains relevant in the era of universal HBV vaccination. HBV carrier has inferior outcome and use of surveillance may mitigate disease course.

Many ungulate populations have a complex history of isolation and translocation. Consequently, ungulate populations may have experienced substantial reductions in the level of overall gene flow, yet simultaneously have augmented levels of long-distance gene flow. To investigate the effect of this dual anthropogenic effect on the genetic landscape of ungulates, we genotyped 35K SNPs in 47 red deer (Cervus elaphus) of Netherlands, including putative autochthonous relic populations as well as allochthonous populations established in private estates and rewilding areas. We applied FST and ordination analyses to determine the meta-population genetic structure and thereby the occurrence of hybridization. At population level, we investigated levels of inbreeding through individual-based diversity measures, including Runs of Homozygosity. We documented that both spatial genetic structure and within-population genetic variation differed markedly from patterns assumed from present-day abundance and distribution. Notwithstanding the small spatial scale, red deer populations formed distinct genetic clusters, and some had higher genetic similarity to distant than to nearby populations. Moreover, the putative autochthonous relic deer populations had much reduced levels of polymorphism and multi-locus heterozygosity, despite relatively large current population sizes. Accordingly, genomes of these deer contained a high proportion of long (>5 Mb) Runs of Homozygosity. Whereas the observed high levels of inbreeding warrant defragmentation measures, the presence of adjacent autochthonous and allochthonous genetic stocks imply that facilitation of gene flow would cause genetic homogenization. Such distortions of the genetic landscape of ungulates creates management dilemmas that cannot be properly anticipated without baseline genetic monitoring.

Little is known about the overall trend and prioritisations of past and current antimicrobial resistance (AMR) policies. Here we introduce a quantitative method to analyse AMR policies. The AMR-Policy Analysis Coding Toolkit (AMR-PACT) uses several categorical variables. Thirteen AMR action plans from five countries (China, Japan, Norway, the UK and the USA) were used to develop the tool and identify possible values for each variable. The scope and capability of AMR-PACT is demonstrated through the 2015 WHO’s Global Action Plan and 2017 Hong Kong AMR Action Plan (HKAP). Majority of policies were aimed at either human or animal sector with less attention given to the environment, plant or food sector. Both plans shared the same two strategic focus areas, namely the conservation of antibiotics and the improved surveillance of resistance. There were no policies dedicated to improving access to antibiotics in the HKAP. These empirical results provide useful insights into the priorities and gaps of AMR policies. The method proposed here can help understand countries’ priorities regarding AMR, support the creation of AMR policy database and foster innovative policymaking.

Summary: Cardiolipin (CL) is a phospholipid specific for mitochondrial membranes and crucial for many core tasks of this organelle. Its acyl chain configurations are tissue specific, functionally important, and generated via post-biosynthetic remodeling. However, this process lacks the necessary specificity to explain CL diversity, which is especially evident for highly specific CL compositions in mammalian tissues. To investigate the so far elusive regulatory origin of CL homeostasis in mice, we combine lipidomics, integrative transcriptomics, and data-driven machine learning. We demonstrate that not transcriptional regulation, but cellular phospholipid compositions are closely linked to the tissue specificity of CL patterns allowing artificial neural networks to precisely predict cross-tissue CL compositions in a consistent mechanistic specificity rationale. This is especially relevant for the interpretation of disease-related perturbations of CL homeostasis, by allowing differentiation between specific aberrations in CL metabolism and changes caused by global alterations in cellular (phospho-)lipid metabolism. : The lipid architecture of biomembranes is crucial for their cellular functions. The regulatory origins of the strong tissue specificity of cardiolipins, a vital mitochondrial phospholipid class, were so far largely unresolved. Oemer et al. find that a single mechanism explains cardiolipin diversity across tissues on basis of the phospholipid environment. Keywords: cardiolipin, phospholipids, structural diversity, mouse tissue-specificity, membrane lipids, mitochondria, LC-MS/MS, lipidomics, machine learning, artificial neural network

Abstract During times of high activity by predators and competitors, herbivores may be forced to forage in patches of low‐quality food. However, the relative importance in determining where and what herbivores forage still remains unclear, especially for small‐ and intermediate‐sized herbivores. Our objective was to test the relative importance of predator and competitor activity, and forage quality and quantity on the proportion of time spent in a vegetation type and the proportion of time spent foraging by the intermediate‐sized herbivore European hare (Lepus europaeus). We studied red fox (Vulpes vulpes) as a predator species and European rabbit (Oryctolagus cuniculus) as a competitor. We investigated the time spent at a location and foraging time of hare using GPS with accelerometers. Forage quality and quantity were analyzed based on hand‐plucked samples of a selection of the locally most important plant species in the diet of hare. Predator activity and competitor activity were investigated using a network of camera traps. Hares spent a higher proportion of time in vegetation types that contained a higher percentage of fibers (i.e., NDF). Besides, hares spent a higher proportion of time in vegetation types that contained relatively low food quantity and quality of forage (i.e., high percentage of fibers) during days that foxes (Vulpes vulpes) were more active. Also during days that rabbits (Oryctolagus cuniculus) were more active, hares spent a higher proportion of time foraging in vegetation types that contained a relatively low quality of forage. Although predation risk affected space use and foraging behavior, and competition affected foraging behavior, our study shows that food quality and quantity more strongly affected space use and foraging behavior than predation risk or competition. It seems that we need to reconsider the relative importance of the landscape of food in a world of fear and competition.

Abstract Background To examine whether number of physical therapy (PT) visits or amount of use of an internet-based exercise training (IBET) program is associated with differential improvement in outcomes for participants with knee osteoarthritis (OA). Methods A secondary analysis was performed using data from participants in 2 arms of a randomized control trial for individuals with symptomatic knee OA: PT (N = 135) or IBET (N = 124). We examined associations of number of PT visits attended (up to 8) or number of days the IBET website was accessed during the initial 4-month study period with changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, pain and function subscales, as well as a 2-min Step Test, at 4-month and 12-month follow-up. Results Participants with more PT visits experienced greater improvement in WOMAC total score (estimate per additional visit = − 1.18, CI 95% = − 1.91, 0.46, p

The mechanisms that control ciliogenesis have been extensively explored however the signaling mechanisms that control cilium stability remain unclear. Here the authors show that GPCR signaling regulates cilia resorption via the ubiquitin-proteasome system.