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Abstract Young children receiving outpatient cancer care are vulnerable to undermanaged pain. App‐based solutions that provide pain treatment advice to parents in real‐time and in all environments may improve access to quality pain care. We used a parent co‐design approach involving iterative rounds of user testing and software modification to develop a usable Pain Caregiver Resource (PainCaRe) real‐time pediatric cancer pain management app. Parents of children (2–11 years) with cancer completed three standardized modules using a PainCaRe prototype. App usability and acceptability were evaluated using the validated System Usability Scale and a thematic analysis of app testing sessions and interviews. Iterative testing sessions were conducted until data saturation. Interview themes were synthesized into action items that guided revisions to PainCaRe and additional testing rounds were conducted as necessary. Twenty‐two parents participated in three testing cycles. Overall, parents described PainCaRe as an acceptable and potentially clinically useful pain management tool. Mean system usability scores were in the acceptable scale range during each testing cycle. Usability issues identified and resolved included those related to software malfunction, complicated app navigation logic, lack of clarity on pain assessment questions, and the need for pain management advice specifically tailored to child developmental stage. Using co‐design methods, the PainCaRe cancer pain management app was successfully refined for its acceptability and utility to parents. Next steps will include a PainCaRe pilot study before evaluating the impact of the app on younger children's pain outcomes in a randomized controlled trial.

BackgroundA challenge facing researchers conducting mobile health (mHealth) research is the amount of resources required to develop mobile apps. This can be a barrier to generating relevant knowledge in a timely manner. The recent rise of “no-code” software development platforms may overcome this challenge and enable researchers to decrease the cost and time required to develop mHealth research apps. ObjectiveWe aimed to describe the development process and the lessons learned to build Pathverse, a no-code mHealth app design platform. MethodsThe study took place between November 2019 and December 2021. We used a participatory research framework to develop the mHealth app design platform. In phase 1, we worked with researchers to gather key platform feature requirements and conducted an exploratory literature search to determine needs related to this platform. In phase 2, we used an agile software framework (Scrum) to develop the platform. Each development sprint cycle was 4 weeks in length. We created a minimum viable product at the end of 7 sprint cycles. In phase 3, we used a convenience sample of adults (n=5) to gather user feedback through usability and acceptability testing. In phase 4, we further developed the platform based on user feedback, following the V-model software development process. ResultsOur team consulted end users (ie, researchers) and utilized behavior change technique taxonomy and behavior change models (ie, the multi-process action control framework) to guide the development of features. The first version of the Pathverse platform included features that allowed researchers to (1) design customized multimedia app content (eg, interactive lessons), (2) set content delivery logic (eg, only show new lessons when completing the previous lesson), (3) implement customized participant surveys, (4) provide self-monitoring tools, (5) set personalized goals, and (6) customize app notifications. Usability and acceptability testing revealed that researchers found the platform easy to navigate and that the features were intuitive to use. Potential improvements include the ability to deliver adaptive interventions and add features such as community group chat. ConclusionsTo our knowledge, Pathverse is the first no-code mHealth app design platform for developing mHealth interventions for behavior. We successfully used behavior change models and the behavior change technique taxonomy to inform the feature requirements of Pathverse. Overall, the use of a participatory framework, combined with the agile and hybrid-agile software development process, enabled our team to successfully develop the Pathverse platform.

Purpose: Physical activity promotion has mostly focused on theories of intention-formation, with the assumption that positive intentions will lead to behaviour. Though necessary, exercise intentions alone are often not sufficient to improve physical activity behaviour. The Multi-Process Action Control (M-PAC) framework builds on previous intention-based theories by including both determinants of intention formation and its translation into behaviour. The purpose of this study was to describe the process of developing a self-guided web-based intervention to promote physical activity among adults using the M-PAC model. Procedures: The development process consisted of the following three phases: 1) Intervention planning: determine intervention needs and requirements; 2) Intervention development: use an iterative process to design a web-based physical activity intervention based on the M-PAC framework; 3) Pilot testing: conduct usability and acceptability assessment on the web-based intervention to further enhance user experience. Principal results: The intervention planning phase suggested that there is a need for web-based physical activity interventions and there is currently no web-based intervention designed using the M-PAC model. In phase two, we adopted an iterative process to develop a 10-week self-guided web-based intervention to help adults (>18 years of age) to meet 150 min of moderate to vigorous physical activity per week. The pilot testing phase yielded valuable feedback on usability, content, and design of the web-based intervention. Major conclusions: The development of a web-based physical activity intervention using the M-PAC model could further enhance the effectiveness of web-based interventions and have a significant impact on extending the reach of existing physical activity promotion programs. This study has reinforced the importance of an iterative development process that involves a multi-disciplinary team to design a web-based intervention to promote physical activity. The process enabled the team to clarify the needs for an intervention for our target users, and provided valuable feedback on the design and content of the web-based intervention. Future studies are now needed to evaluate the effectiveness of our web-based intervention.

In Canada and throughout the commonwealth countries, access to justice depends upon free legal clinics to fill gaps. While provinces vary in the amount they invest in Legal Aid Services [...]

Abstract Context Prostate‐specific antigen is non‐specific for prostate cancer. This is improved by multiparametric MRI but a significant amount of indolent prostate cancer is detected by the current MRI pathway and data is emerging that clinically significant cancers maybe missed using a standard PSA threshold. Volatile organic compound (VOC) analysis may offer novel biomarkers for prostate cancer and clinically significant disease. Objective To perform a systematic review of the literature to evaluate the current evidence for the use of VOCs as novel biomarkers for prostate cancer and clinically significant prostate cancer. Evidence Acquisition A systematic search of MEDLINE, Scopus, Web of Science and the Cochrane Library was undertaken by two independent reviewers and papers were assessed for inclusion in the review. Study characteristics, sensitivity and specificity of GC–MS or eNose were extracted. Risk of bias and applicability issues were determined using QUADAS 2 and the quality of reporting using the STARD checklist. Evidence Synthesis Nineteen studies were included, of which 6 utilised eNose and 13 GC–MS. eNose sensitivity and specificity were 0.71–0.95 and 0.79–0.96, respectively, and GC–MS found a sensitivity and specificity of 0.66–1.00 and 0.53–0.97, respectively. There were concerns about bias in patient recruitment due to differences in the timing of the index test relative to the reference standard. Conclusion This review has found promising early results for urinary metabolomics in the detection of prostate cancer. However, there is a need for larger, high‐quality studies to validate this. Future work should focus on the detection of clinically significant prostate cancer.

Abstract Background Implantable vagus nerve stimulation is a promising approach for restoring autonomic cardiovascular functions after heart transplantation. For successful treatment a system should have multiple electrodes to deliver precise stimulation and complex neuromodulation patterns. Methods This paper presents an implantable multi-channel stimulation system for vagal-cardiac neuromodulation studies in swine species. The system comprises an active electrode array implant percutaneously connected to an external wearable controller. The active electrode array implant has an integrated stimulator ASIC mounted on a ceramic substrate connected to an intraneural electrode array via micro-rivet bonding. The implant is silicone encapsulated for biocompatibility and implanted lifetime. The stimulation parameters are remotely transmitted via a Bluetooth telemetry link. Results The size of the encapsulated active electrode array implant is 8 mm × 10 mm × 3 mm. The stimulator ASIC has 10-bit current amplitude resolution and 16 independent output channels, each capable of delivering up to 550 µA stimulus current and a maximum voltage of 20 V. The active electrode array implant was subjected to in vitro accelerated lifetime testing at 70 °C for 7 days with no degradation in performance. After over 2 h continuous stimulation, the surface temperature change of the implant was less than 0.5 °C. In addition, in vivo testing on the sciatic nerve of a male Göttingen minipig demonstrated that the implant could effectively elicit an EMG response that grew progressively stronger on increasing the amplitude of the stimulation. Conclusions The multi-channel stimulator is suitable for long term implantation. It shows potential as a useful tool in vagal-cardiac neuromodulation studies in animal models for restoring autonomic cardiovascular functions after heart transplantation.

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF V600E mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies.

Key Clinical Message Unilateral tongue atrophy can be a rare and crucial early indicator of metastatic prostate cancer, highlighting the need for vigilant monitoring in clinical assessments. This case underscores the importance of considering cranial nerve involvement, especially the twelfth, for timely intervention and comprehensive patient care. Abstract Prostate cancer, ranking among the most prevalent cancers, often manifests with skeletal metastases. Cranial nerve involvement, particularly the twelfth cranial nerve (XII), as an initial presentation is exceptionally rare. This case report outlines a unique instance of unilateral tongue atrophy as the primary clinical manifestation in a patient diagnosed with metastatic prostate cancer. A 54‐year‐old man presented with dysarthria and progressive weakness, later revealing signs of hypoglossal nerve paralysis, unilateral tongue atrophy, and skeletal metastases involving the base of the skull. Imaging studies, including CT and MRI, confirmed diffuse lytic lesions and cranial nerve entrapment. Further investigations identified elevated PSA levels, confirming acinar prostate adenocarcinoma. The patient underwent hormone therapy due to the poor prognosis. Prostate cancer's skeletal metastases are well‐documented, but cranial nerve involvement remains rare, particularly with isolated XII nerve manifestation. The discussion emphasizes the diagnostic challenges, imaging techniques' roles, and the impact on prognosis and quality of life. This case underscores the rarity of unilateral XII nerve involvement as the initial presentation of metastatic prostate cancer. Clinicians should consider this manifestation, especially in men over 40, warranting a thorough diagnostic approach, including PSA measurement and referral for appropriate oncological and urological interventions.

Abstract In proteomics, spectral archives organize the enormous amounts of publicly available peptide tandem mass spectra by similarity, offering opportunities for error correction and novel discoveries. Here we adapt an indexing algorithm developed by Facebook for organizing online multimedia resources to tandem mass spectra and achieve practically instantaneous retrieval and clustering of approximate nearest neighbors in a large spectral archive. An interactive web-based graphical user interface enables the user to view a query spectrum in its clustered neighborhood, which facilitates contextual validation of peptide identifications and exploration of the dark proteome.

The 2022–2023 mpox outbreak predominantly affected adult men; 1.3% of reported cases were in children and adolescents

This study explores the implementation of the analytic hierarchy process in usability evaluations, specifically focusing on user interface assessment during software development phases. Addressing the challenge of diverse and unstandardized evaluation methodologies, our research develops and applies a tailored algorithm that simplifies heuristic prioritization. This novel method combines the analytic hierarchy process framework with a bespoke algorithm that leverages transitive properties for efficient pairwise comparisons, significantly reducing the evaluative workload. The algorithm is designed to facilitate the estimation of heuristic relevance regardless of the number of items per heuristic or the item scale, thereby streamlining the evaluation process. Rigorous simulation testing of this tailored algorithm is complemented by its empirical application, where seven usability experts evaluate a web interface. This practical implementation demonstrates our method’s ability to decrease the necessary comparisons and simplify the complexity and workload associated with the traditional prioritization process. Additionally, it improves the accuracy and relevance of the user interface usability heuristic testing results. By prioritizing heuristics based on their importance as determined by the Usability Testing Leader—rather than merely depending on the number of items, scale, or heuristics—our approach ensures that evaluations focus on the most critical usability aspects from the start. The findings from this study highlight the importance of expert-driven evaluations for gaining a thorough understanding of heuristic UI assessment, offering a wider perspective than user-perception-based methods like the questionnaire approach. Our research contributes to advancing UI evaluation methodologies, offering an organized and effective framework for future usability testing endeavors.

Abstract Background The high diversity and complexity of the microbial community make it a formidable challenge to identify and quantify the large number of proteins expressed in the community. Conventional metaproteomics approaches largely rely on accurate identification of the MS/MS spectra to their corresponding short peptides in the digested samples, followed by protein inference and subsequent taxonomic and functional analysis of the detected proteins. These approaches are dependent on the availability of protein sequence databases derived either from sample-specific metagenomic data or from public repositories. Due to the incompleteness and imperfections of these protein sequence databases, and the preponderance of homologous proteins expressed by different bacterial species in the community, this computational process of peptide identification and protein inference is challenging and error-prone, which hinders the comparison of metaproteomes across multiple samples. Results We developed metaSpectraST, an unsupervised and database-independent metaproteomics workflow, which quantitatively profiles and compares metaproteomics samples by clustering experimentally observed MS/MS spectra based on their spectral similarity. We applied metaSpectraST to fecal samples collected from littermates of two different mother mice right after weaning. Quantitative proteome profiles of the microbial communities of different mice were obtained without any peptide-spectrum identification and used to evaluate the overall similarity between samples and highlight any differentiating markers. Compared to the conventional database-dependent metaproteomics analysis, metaSpectraST is more successful in classifying the samples and detecting the subtle microbiome changes of mouse gut microbiomes post-weaning. metaSpectraST could also be used as a tool to select the suitable biological replicates from samples with wide inter-individual variation. Conclusions metaSpectraST enables rapid profiling of metaproteomic samples quantitatively, without the need for constructing the protein sequence database or identification of the MS/MS spectra. It maximally preserves information contained in the experimental MS/MS spectra by clustering all of them first and thus is able to better profile the complex microbial communities and highlight their functional changes, as compared with conventional approaches. tag the videobyte in this section as ESM4 Video Abstract

This study provides a general observation of the status of naturally occurring radioactive materials (NORMs) distribution in mining and industrial areas of Ghana in order to establish regional and national data on NORMs. The study includes data on radioactivity concentrations of U-238, Th-232, and K-40 in soils and for water concentrations of Ra-226, Th-228, and K-40 from various mining, oil, and gas communities, as well as water sources used for crop farming and farmlands. The average activity concentrations of U-238, Th-232, and K-40 in the soil samples were found to be 59 ± 16 Bq/kg, 48 ± 15 Bq/kg, and 286 ± 57 Bq/kg, respectively. The average concentration of Ra-226, Th-228, and K-40 in the water samples were found to be 1.62 ± 0.33 Bq/L, 2.08 ± 0.53 Bq/L, and 22.36 ± 3.44 Bq/L, respectively. The estimated average annual effective doses from external and internal exposure pathways in soil and water samples were 0.09 mSv/y and 0.54 mSv/y, respectively. The total annual effective dose resulting from both exposure pathways was calculated to be 0.63 mSv/y, which is below the 1 mSv/y dose limit recommended by the International Commission on Radiological Protection (ICRP) for controlling public radiation exposure. Based on the radiological hazard indices, the majority of the soil samples were found to be suitable as building materials as their respective indices were below the limits except for two sample locations and the sludge and scale samples. The average Excess Lifetime Cancer Risk (ELCR) value of the water samples was 1.6 times greater than the recommended value of 1.16 × 10−3, presenting a relatively higher risk to the public of developing cancer. No significant regional differences in the levels of radioactive elements. The regression models demonstrate strong interrelationships between the studied elements, with high R-squared values suggesting a predictable nature of one element’s concentration based on others.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to 80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

BackgroundThe prevalence of diabetes in West Africa is increasing, posing a major public health threat. An estimated 24 million Africans have diabetes, with rates in West Africa around 2-6% and projected to rise 129% by 2045 according to the WHO. Over 90% of cases are Type 2 diabetes (IDF, World Bank). As diabetes is ambulatory care sensitive, good primary care is crucial to reduce complications and mortality. However, research on factors influencing diabetes primary care access, utilisation and quality in West Africa remains limited despite growing disease burden. While research has emphasised diabetes prevalence and risk factors in West Africa, there remains limited evidence on contextual influences on primary care. This scoping review aims to address these evidence gaps.Methods and analysisUsing the established methodology by Arksey and O'Malley, this scoping review will undergo six stages. The review will adopt the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Review (PRISMA-ScR) guidelines to ensure methodological rigour. We will search four electronic databases and search through grey literature sources to thoroughly explore the topic. The identified articles will undergo thorough screening. We will collect data using a standardised data extraction form that covers study characteristics, population demographics, and study methods. The study will identify key themes and sub-themes related to primary healthcare access, utilisation, and quality. We will then analyse and summarise the data using a narrative synthesis approach.ResultsThe findings and conclusive report will be finished and sent to a peer-reviewed publication within six months.ConclusionThis review protocol aims to systematically examine and assess the factors that impact the access, utilisation, and standard of primary healthcare services for diabetes in West Africa.

Abstract Introduction The efficacy of abatacept is enhanced in anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF)-positive versus -negative patients with rheumatoid arthritis (RA). Four early RA abatacept trials were analyzed to understand the differential impact of abatacept among patients with SeroPositive Early and Active RA (SPEAR) compared to non-SPEAR patients. Methods Pooled patient-level data from AGREE, AMPLE, AVERT, and AVERT-2 were analyzed. Patients were classified as SPEAR if they were ACPA +, RF +, disease duration

Abstract In January 2020, SARS-CoV-2 virus was identified as a cause of an outbreak in China. The disease quickly spread worldwide, and the World Health Organization (WHO) declared the pandemic in March 2020. From the first notifications of spread of the disease, the WHO’s Emergency Programme implemented a global COVID-19 surveillance system in coordination with all WHO regional offices. The system aimed to monitor the spread of the epidemic over countries and across population groups, severity of the disease and risk factors, and the impact of control measures. COVID-19 surveillance data reported to WHO is a combination of case-based data and weekly aggregated data, focusing on a minimum global dataset for cases and deaths including disaggregation by age, sex, occupation as a Health Care Worker, as well as number of cases tested, and number of cases newly admitted for hospitalization. These disaggregations aim to monitor inequities in COVID-19 distribution and risk factors among population groups. SARS-CoV-2 epidemic waves continue to sweep the world; as of March 2022, over 445 million cases and 6 million deaths have been reported worldwide. Of these, over 327 million cases (74%) have been reported in the WHO surveillance database, of which 255 million cases (57%) are disaggregated by age and sex. A public dashboard has been made available to visualize trends, age distributions, sex ratios, along with testing and hospitalization rates. It includes a feature to download the underlying dataset. This paper will describe the data flows, database, and frontend public dashboard, as well as the challenges experienced in data acquisition, curation and compilation and the lessons learnt in overcoming these. Two years after the pandemic was declared, COVID-19 continues to spread and is still considered a Public Health Emergency of International Concern (PHEIC). While WHO regional and country offices have demonstrated tremendous adaptability and commitment to process COVID-19 surveillance data, lessons learnt from this major event will serve to enhance capacity and preparedness at every level, as well as institutional empowerment that may lead to greater sharing of public health evidence during a PHEIC, with a focus on equity.

Background Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched.Methods The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of ‘High’ or above were added to an operational watchlist and assistance was deployed as needed.Results Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%–67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available.Conclusions The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators.

Net-zero emission targets are crucial, given the environmental impact of the food and beverage industries. Our study proposes an environmentally focused Sustainable Business Model (SBM) using data from 252 food, beverage, and tobacco companies that reported to the Carbon Disclosure Project (CDP). We investigated the risks, opportunities, business strategies, emission reduction initiatives, and supply chain interactions associated with climate change by analyzing their qualitative answers using the NVivo software. Following the grounded theory approach, we identified the Environmental Sustainability Factors (ESFs) that support businesses in meeting pollution reduction targets. The ESFs were integrated with Osterwalder's business model canvas to create an archetype focused on delivering “net-zero” or “carbon neutral” value to customers. The model's efficacy is enhanced by the advantages and motivations of environmental collaborations. The paper provides critical support for sustainability theories and assists Small and Medium Enterprises (SMEs) to develop strategic business models for net-zero emission targets.

ABSTRACT Bacteria are important mediators of the larval transition from pelagic to benthic environments for marine organisms. Bacteria can therefore dictate species distribution and success of an individual. Despite the importance of marine bacteria to animal ecology, the identity of inductive microbes for many invertebrates are unknown. Here, we report the first successful isolation of bacteria from natural substrates capable of inducing settlement and metamorphosis of the planula larvae stage of a true jellyfish, the upside-down jellyfish Cassiopea xamachana. Inductive bacteria belonged to multiple phyla, with various capacity to induce settlement and metamorphosis. The most inductive isolates belonged to the genus Pseudoalteromonas, a marine bacterium known to induce the pelago-benthic transition in other marine invertebrates. In sequencing the genome of the isolated Pseudoalteromonas and a semiinductive Vibrio, we found biosynthetic pathways previously implicated in larval settlement were absent in Cassiopea inducing taxa. We instead identified other candidate biosynthetic gene clusters involved in larval metamorphosis. These findings could provide hints to the ecological success of C. xamachana compared to sympatric congeneric species within mangrove environments and provide avenues to investigate the evolution of animal-microbe interactions. IMPORTANCE The pelagic to benthic transition for the larvae of many marine invertebrate species are thought to be triggered by microbial cues. The microbial species and exact cue that initiates this transition remains unknown for many animals. Here, we identify two bacterial species, a Pseudoalteromonas and a Vibrio, isolated from natural substrate that induce settlement and metamorphosis of the upside-down jellyfish Cassiopea xamachana. Genomic sequencing revealed both isolates lacked genes known to induce the life history transition in other marine invertebrates. Instead, we identified other gene clusters that may be important for jellyfish settlement and metamorphosis. This study is the first step to identifying the bacterial cue for C. xamachana, an ecologically important species to coastal ecosystems and an emerging model system. Understanding the bacterial cues provides insight into marine invertebrate ecology and evolution of animal-microbe interactions.

El objetivo de la presente investigación, fue comparar el desempeño de las redes neurales artificiales con la regresión lineal múltiple en la predicción de la actividad biológica de los análogos de la cocaína a partir de descriptores moleculares. Para esto, se seleccionó un conjunto de 14 descriptores moleculares agrupados en descriptores químicos cuánticos y descriptores de la estructura tridimensional de la molécula y se calcularon sus valores de forma teórica, para 65 estructuras análogas de la cocaína, realizándose luego la construcción del modelo de redes neurales artificiales y regresión lineal múltiple, para la predicción de la actividad biológica expresada como afinidad (IC50). Se encontró que las redes neurales artificiales presentaron un R2 de 0,8651, mientras que la regresión múltiple lineal presentó un valor de R2 de 0,039, lo que indica que las redes neurales artificiales tienen un mejor desempeño que la regresión múltiple lineal en la predicción de la actividad biológica de los análogos de la cocaína a partir de los descriptores moleculares seleccionados, y que el efecto de los descriptores sobre la actividad biológica es de naturaleza no lineal.

Mechanic systems are lubricated with oil and their analysis is one of the best practices among industrial routines. It allows for measuring the number of elements and particles in the lubricant. Furthermore, it improves the equipment health monitoring. In mining, the dumpers are a piece of critical equipment that affects production. The continuous monitoring assures systematic reliability. This work can serve as a good reference for engineers who intend to understand oil data and promote the development of lifetime models of components. This paper studies the lifetime expectation of the main components of T6, T16, TH315, and JOY dumpers considering oil data. These lifetimes were analyzed by using both, the Cox proportional hazard model and a new robust version of the same model that is the main contribution of this work. The results show that robust version introduced has better performance than Cox classical model. The correlation analysis from oil variables, and operational context information are also included. It allowed us to identify the components and dumpers with a major risk of failure and their relationship with the work site.

Early detection of marine invasive species is key for mitigating and managing their impacts to marine ecosystems and industries. Human divers are considered the gold standard tool for detecting marine invasive species, especially when dive teams are familiar with the local biodiversity. However, diver operations can be expensive and dangerous, and are not always practical. Remote operated vehicles (ROVs) can potentially overcome these limitations, but it is unclear how sensitive they are compared to trained divers for detecting pests. We assessed the sensitivity and efficiency of ROVs and divers for detecting marine non-indigenous species (NIS), including the potential for automated detection algorithms to reduce post-processing costs of ROV methods. We show that ROVs can detect comparable assemblages of invasive species as divers, but with lower detection rates (0.2 NIS min-1) than divers (0.5 NIS min-1) and covered less seafloor than divers per unit time. While small invertebrates (e.g., skeleton shrimp Caprella mutica) were more easily detected by divers, the invasive goby Acentrogobius pflaumii was only detected by the ROV. We show that implementation of computer vision algorithms can provide accurate identification of larger biofouling organisms and reduce overall survey costs, yet the relative costs of ROV surveys remain almost twice that of diver surveys. We expect that as ROV technologies improve and investment in autonomous and semi-autonomous underwater vehicles increases, much of the current inefficiencies of ROVs will be mitigated, yet practitioners should be aware of limitations in taxonomic resolution and the strengths of specialist diver teams.

My objective is a better comprehension of two theoretically fundamental concepts. One, the concept of a substance in an ordinary (non-Aristotelian) sense, ranging over such things as salt, carbon, copper, iron, water, and methane—kinds of stuff that now count as (chemical) elements and compounds. The other I will call the object-concept in the abstract sense of Russell, Wittgenstein, and Frege in their logico-semantical enquiries. The material object-concept constitutes the heart of our received logico/ontic system, still massively influenced by Aristotle after almost 2.5 millennia. On such an account, the fundamentality of material objects and their attributes are the metaphysical basis of the cosmos, as reflected in our received logic, Quine’s ‘canonical notation’—derived via the empiricism of Russell from Frege’s function-based Begriffschrifft, and consisting of concrete singular terms and variables, quantifiers and predicate-expressions. The inadequacy of Frege’s approach to understanding concepts is reflected in his initial question. Frege enquires of ‘what it is that we are calling an object’, remarking that he regards a regular definition as impossible: “we have here something too simple to admit of logical analysis”. The imagined ultimacy or simplicity of the idea of a single object (arithmetically, just a unit—one as opposed to two, three, four, etc.) as foundational to the calculus is just that—imagined. It is also guaranteed to block the comprehension of the substance-concept.

Aim: To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Methods: Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Results: Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Conclusion: Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.

IntroductionAny type of activity that results in caloric expenditure has the potential to reduce the risk of cardiovascular diseases; nonetheless, most people, especially office workers, are physically inactive. This study sought to evaluate the extent of physical inactivity and its determinants among the staff of selected banks in Accra, Ghana.MethodsThis was a cross-sectional study involving 219 banking staff randomly selected from five commercial banking institutions in Accra, Ghana. Demographic data was collected with a structured questionnaire. Physical inactivity was assessed using the Global Physical Activity Questionnaire. Study associations were determined using univariate analysis, and multivariate logistic regression models with adjusted odds ratio (AOR) and 95% confidence intervals (CI) estimated.ResultsTwo hundred and nineteen (219) participants were recruited, out of which 56.6% were males and 43.4% were females. The mean age (± SD) of the participants was 40.0±7.9 years. Physical inactivity was observed in 179 (81.7%) participants. The following were independently associated with physical inactivity: travel-related activities (AOR, 0.151; 95% CI, 0.059-0.384; pConclusionPhysical inactivity was very high among bankers. Travel-related activities reduced physical inactivity whiles working at the bank for more than six years increased physical inactivity. Thus, promoting regular physical activity, frequent monitoring, and implementation of other appropriate healthy lifestyle intervention strategies are vital to reduce risk of early onset disease conditions associated with physical inactivity in this population.

A review of historical data of the effluent of PDVSA’s WWTP was carried out in its research and development subsidiary in the City of Los Teques, Miranda State, during the period 2003-2014. It was sampled for six weeks to calculate the efficiency in the removal of COD, BOD5 and SST. The efficiency for COD was 86.51% and 72.94% in BOD5. The proportion of biological sludge and sour water treated with advanced oxidation processes (POA), necessary for the reduction of COD and BOD5, was determined. The best result obtained in it was 222 mg /L of COD and BOD5 32.15 mg /L, satisfying the national standard for discharge into natural bodies of water.

Background: Around 7500 people are diagnosed with non-muscle-invasive bladder cancer in the UK annually. Recurrence following transurethral resection of bladder tumour is common, and the intensive monitoring schedule required after initial treatment has associated costs for patients and the NHS. In photodynamic diagnosis, before transurethral resection of bladder tumour, a photosensitiser that is preferentially absorbed by tumour cells is instilled intravesically. Transurethral resection of bladder tumour is then conducted under blue light, causing the photosensitiser to fluoresce. Photodynamic diagnosis-guided transurethral resection of bladder tumour offers better diagnostic accuracy than standard white-light-guided transurethral resection of bladder tumour, potentially reducing the chance of subsequent recurrence. Objective: The objective was to assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis-guided transurethral resection of bladder tumour. Design: This was a multicentre, pragmatic, open-label, parallel-group, non-masked, superiority randomised controlled trial. Allocation was by remote web-based service, using a 1 : 1 ratio and a minimisation algorithm balanced by centre and sex. Setting: The setting was 22 NHS hospitals. Participants: Patients aged ≥ 16 years with a suspected first diagnosis of high-risk non-muscle-invasive bladder cancer, no contraindications to photodynamic diagnosis and written informed consent were eligible. Interventions: Photodynamic diagnosis-guided transurethral resection of bladder tumour and standard white-light cystoscopy transurethral resection of bladder tumour. Main outcome measures: The primary clinical outcome measure was the time to recurrence from the date of randomisation to the date of pathologically proven first recurrence (or intercurrent bladder cancer death). The primary health economic outcome was the incremental cost per quality-adjusted life-year gained at 3 years. Results: We enrolled 538 participants from 22 UK hospitals between 11 November 2014 and 6 February 2018. Of these, 269 were allocated to photodynamic diagnosis and 269 were allocated to white light. A total of 112 participants were excluded from the analysis because of ineligibility (n = 5), lack of non-muscle-invasive bladder cancer diagnosis following transurethral resection of bladder tumour (n = 89) or early cystectomy (n = 18). In total, 209 photodynamic diagnosis and 217 white-light participants were included in the clinical end-point analysis population. All randomised participants were included in the cost-effectiveness analysis. Over a median follow-up period of 21 months for the photodynamic diagnosis group and 22 months for the white-light group, there were 86 recurrences (3-year recurrence-free survival rate 57.8%, 95% confidence interval 50.7% to 64.2%) in the photodynamic diagnosis group and 84 recurrences (3-year recurrence-free survival rate 61.6%, 95% confidence interval 54.7% to 67.8%) in the white-light group (hazard ratio 0.94, 95% confidence interval 0.69 to 1.28; p = 0.70). Adverse event frequency was low and similar in both groups [12 (5.7%) in the photodynamic diagnosis group vs. 12 (5.5%) in the white-light group]. At 3 years, the total cost was £12,881 for photodynamic diagnosis-guided transurethral resection of bladder tumour and £12,005 for white light. There was no evidence of differences in the use of health services or total cost at 3 years. At 3 years, the quality-adjusted life-years gain was 2.094 in the photodynamic diagnosis transurethral resection of bladder tumour group and 2.087 in the white light group. The probability that photodynamic diagnosis-guided transurethral resection of bladder tumour was cost-effective was never > 30% over the range of society’s cost-effectiveness thresholds. Limitations: Fewer patients than anticipated were correctly diagnosed with intermediate- to high-risk non-muscle-invasive bladder cancer before transurethral resection of bladder tumour and the ratio of intermediate- to high-risk non-muscle-invasive bladder cancer was higher than expected, reducing the number of observed recurrences and the statistical power. Conclusions: Photodynamic diagnosis-guided transurethral resection of bladder tumour did not reduce recurrences, nor was it likely to be cost-effective compared with white light at 3 years. Photodynamic diagnosis-guided transurethral resection of bladder tumour is not supported in the management of primary intermediate- to high-risk non-muscle-invasive bladder cancer. Future work: Further work should include the modelling of appropriate surveillance schedules and exploring predictive and prognostic biomarkers. Trial registration: This trial is registered as ISRCTN84013636. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Los vehículos aéreos no tripulados más conocidos como drones han despertado gran interés en los últimos años, teniendo aplicaciones en operaciones militares y civiles, recientemente se ha investigado acerca de las ventajas de su uso en la distribución de paquetes. En esta investigación se aborda un Problema de Ruteo de Vehículos con Drones (VRPD) enfocado a la distribución de última milla, en el cual los drones y camiones pueden trabajan de manera simultánea, considerando un límite de capacidad para el camión y el dron, así como restricciones asociadas al tiempo de la ruta. Dentro de la formulación matemática se propone una ecuación de velocidad de vuelo del dron y se restringen las rutas a un porcentaje límite de batería disponible para evitar mal funcionamiento en el aire. Para resolver esta formulación se usa el algoritmo Adaptive Large Neighborhood Search (ALNS), que es validado usando instancias propuestas en la literatura. Además, se verifica cómo varía la función objetivo de la solución inicial mediante la utilización de las heurísticas de destrucción y reparación, finalmente se realiza un análisis de sensibilidad para algunos parámetros del algoritmo y características de los drones; realizando conclusiones de los resultados arrojados y efectuando recomendaciones para futuras investigaciones.

El objetivo de este estudio fue realizar una prognosis del impacto ambiental de las aguas agrias que resultan del mejoramiento de crudos pesados y extrapesados.Para lograr el objetivo se determinó la concentración total de hidrocarburos de petróleo (TPH) y los valores de la demanda química de oxígeno (DQO). De igual manera se determinaron los compuestos orgánicos en el agua agria mediante Cromatografía de Masa Acoplado a Masa (GC-MS). También, se determinó el contenido de metales pesados por Espectrometría de Masas con Plasma Acoplado Inductivamente (ICP). La concentración de H2S disuelto se determinó mediante la técnica potenciométrica de estandarización del Na2S. La evaluación de impacto ambiental (EIA) se realizó mediante una matriz causa–efecto (Matriz de Leopold). Como resultado se obtuvo una concentración de TPH de 99 ppm, DQO 18100 ppm y 24000 ppm de H2S.Estas concentraciones son superiores a los niveles máximos permitidos por la normativa venezolana para el vertido en plantas y masas de agua y por la normativa de seguridad y salud laboral. Así, estos residuos son tóxicos y tienen un alto impacto ambiental. Los factores ambientales más agredidos son el suelo, las aguas superficiales y subterráneas; mientras que las actividades más agresivas fueron el proceso de mejoramiento del crudo, en la reactividad por sulfuro, la corrosividad por pH, y la vulnerabilidad en el almacenamiento de estas aguas a cielo abierto, por su alto contenido de materia orgánica e inorgánica potencialmente tóxica

Biofilm is made up of microbes and their extracellular matrix, making microorganisms highly tolerant, resistant, and resilient to a wide range of antimicrobials. Biofilm treatment with conventional antimicrobial agents can accelerate the evolution and spread of resistance due to the reduced efficacy and increased gene transfer and differentiation within biofilms. Therefore, effective biofilm-targeting compounds are currently highly sought after. In the present study, we identified elasnin as a potent biofilm-targeting compound against methicillin-resistant Staphylococcus aureus (MRSA). Elasnin effectively inhibited biofilm formation and especially eradicated the pre-formed biofilms of MRSA with low cytotoxicity and low risk of resistance development and retains its activity in a chronic wound biofilms model. A comprehensive mechanistic study using multi-omics and confocal and scanning electron microscopy revealed that elasnin induced the biofilm matrix destruction in a time-dependent manner and interfered with the cell division during the exponential phase, primarily by repressing the expression of virulence factors. Cells released from the elasnin-treated biofilms exhibited a defective appearance and became more sensitive to beta-lactam antibiotic penicillin G. Through gene overexpression and deletion assay, we discovered the key role of sarZ during elasnin-induced biofilm eradication. Overall, the present study identified elasnin as a potent biofilm eradicator against MRSA that harbors potential to be developed for biofilm removal and chronic wound treatment, and provided new insights into the molecular targets for biofilm eradication in MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) is a highly dangerous pathogen, and daptomycin has been increasingly used to treat its infections in clinics. Recently, several groups have shown that tolerance and resistance of microbes can evolve rapidly under cyclic antibiotic exposure. We have previously shown that the same tolerance and resistance development occurs in MRSA treated with daptomycin in an adaptive laboratory evolution (ALE) experiment. In the present study, we performed proteomic analysis to compare six daptomycin-tolerant and resistant MRSA strains that were evolved from the same ancestral strain. The strain with a higher tolerance level than the others had the most different proteome and response to antibiotic treatment, resembling those observed in persister cells, which are small subpopulations of bacteria that survive lethal antibiotics treatment. By comparing the proteome changes across strains with similar phenotypes, we identified the key proteins that play important roles in daptomycin tolerance and resistance in MRSA. We selected two candidates to be confirmed by gene overexpression analysis. Overexpression of EcsA1 and FabG, which were up-regulated in all of the tolerant evolved strains, led to increased daptomycin tolerance in wild-type MRSA. The proteomics data also suggested that cell wall modulations were implicated in both resistance and tolerance, but in different ways. While the resistant strains had peptidoglycan changes and a more positive surface charge to directly repel daptomycin, the tolerant strains possessed different cell wall changes that do not involve the peptidoglycan nor alterations of the surface charge. Overall, our study showed the differential proteome profiles among multiple tolerant and resistant strains, pinpointed the key proteins for the two phenotypes and revealed the differences in cell wall modulations between the daptomycin-tolerant/resistant strains.

ABSTRACT Adaptive laboratory evolution (ALE) is a useful tool to study the evolution of antibiotic tolerance in bacterial populations under diverse environmental conditions. The role of population bottlenecks in the evolution of tolerance has been investigated in Escherichia coli, but not in a more clinically relevant pathogen, methicillin-resistant Staphylococcus aureus (MRSA). In this study, we used ALE to evolve MRSA under repetitive daptomycin treatment and incorporated population bottlenecks following antibiotic exposure. We observed that the populations finally attained a tolerance mutation in the yycH gene after 2 weeks of evolution with population bottlenecks, and additional mutations in yycI and several other genes further increased the tolerance level. The tolerant populations also became resistant to another glycopeptide antibiotic, vancomycin. Through proteomics, we showed that yycH and yycI mutations led to the loss of function of the proteins and downregulated the WalKR two-component system and the downstream players, including the autolysin Atl and amidase Sle1, which are important for cell wall metabolism. Overall, our study offers new insights into the evolution of daptomycin tolerance under population bottlenecking conditions, which are commonly faced by pathogens during infection; the study also identified new mutations conferring daptomycin tolerance and revealed the proteome alterations in the evolved tolerant populations. IMPORTANCE Although population bottlenecks are known to influence the evolutionary dynamics of microbial populations, how such bottlenecks affect the evolution of tolerance to antibiotics in a clinically relevant methicillin-resistant S. aureus (MRSA) pathogen are still unclear. Here, we performed in vitro evolution of MRSA under cyclic daptomycin treatment and applied population bottlenecks following the treatment. We showed that under these experimental conditions, MRSA populations finally attained mutations in yycH, yycI, and several other genes that led to daptomycin tolerance. The discovered yycH and yycI mutations caused early termination of the genes and loss of function of the proteins, and they subsequently downregulated the expression of proteins controlled by the WalKR two-component system, such as Atl and Sle1. In addition, we compared our proteomics data with multiple studies on distinct daptomycin-tolerant MRSA mutants to identify proteins with a consistent expression pattern that could serve as biological markers for daptomycin tolerance in MRSA.