Pollinator-assisted plant phenotyping, selection, and breeding for crop resilience to abiotic stresses.

Food security is threatened by climate change, with heat and drought being the main stresses affecting crop physiology and ecosystem services, such as plant-pollinator interactions. We hypothesize that tracking and ranking pollinators' preferences for flowers under environmental pressure could be used as a marker of plant quality for agricultural breeding to increase crop stress tolerance. Despite increasing relevance of flowers as the most stress sensitive organs, phenotyping platforms aim at identifying traits of resilience by assessing the plant physiological status through remote sensing-assisted vegetative indexes, but find strong bottlenecks in quantifying flower traits and in accurate genotype-to-phenotype prediction. However, as the transport of photoassimilates from leaves (sources) to flowers (sinks) is reduced in low-resilient plants, flowers are better indicators than leaves of plant well-being. Indeed, the chemical composition and amount of pollen and nectar that flowers produce, which ultimately serve as food resources for pollinators, change in response to environmental cues. Therefore, pollinators' preferences could be used as a measure of functional source-to-sink relationships for breeding decisions. To achieve this challenging goal, we propose to develop a pollinator-assisted phenotyping and selection platform for automated quantification of Genotype × Environment × Pollinator interactions through an insect geo-positioning system. Pollinator-assisted selection can be validated by metabolic, transcriptomic, and ionomic traits, and mapping of candidate genes, linking floral and leaf traits, pollinator preferences, plant resilience, and crop productivity. This radical new approach can change the current paradigm of plant phenotyping and find new paths for crop redomestication and breeding assisted by ecological decisions.

[Cu(NN1)2]ClO4, a Copper (I) Complex as an Antimicrobial Agent for the Treatment of Piscirickettsiosis in Atlantic Salmon.

Piscirickettsia salmonis is the pathogen that most affects the salmon industry in Chile. Large quantities of antibiotics have been used to control it. In search of alternatives, we have developed [Cu(NN1)2]ClO4 where NN1 = 6-((quinolin-2-ylmethylene)amino)-2H-chromen-2-one. The antibacterial capacity of [Cu(NN1)2]ClO4 was determined. Subsequently, the effect of the administration of [Cu(NN1)2]ClO4 on the growth of S. salar, modulation of the immune system and the intestinal microbiota was studied. Finally, the ability to protect against a challenge with P. salmonis was evaluated. The results obtained showed that the compound has an MIC between 15 and 33.9 µg/mL in four isolates. On the other hand, the compound did not affect the growth of the fish; however, an increase in the transcript levels of IFN-γ, IL-12, IL-1ß, CD4, lysozyme and perforin was observed in fish treated with 40 µg/g of fish. Furthermore, modulation of the intestinal microbiota was observed, increasing the genera of beneficial bacteria such as Lactobacillus and Bacillus as well as potential pathogens such as Vibrio and Piscirickettsia. Finally, the treatment increased survival in fish challenged with P. salmonis by more than 60%. These results demonstrate that the compound is capable of protecting fish against P. salmonis, probably by modulating the immune system and the composition of the intestinal microbiota.

Symptomatic subgemmal neurogenous plaque in patients with COVID-19: Is there an association?

BACKGROUND: Subgemmal neurogenous plaques (SNP) are composed of neural structures found in the posterolateral portion of the tongue, rarely biopsied as most of them are asymptomatic or eventually only clinically managed. We aimed to investigate a case series of possible correlation of symptomatic subgemmal neurogenous plaque (SNP) with coronavirus disease 2019 (COVID-19). METHODS: Eleven formalin-fixed paraffin-embedded cases from patients with previous confirmed COVID-19 (by RT-PCR) were retrieved from two pathology files. Histological sections were morphologically studied, and then submitted to immunohistochemical reactions against S-100 and neurofilament proteins, neuron-specific enolase, Glial fibrillary acidic protein (GFAP), synaptophysin, CD56, Ki67, cytokeratins (7, 8-18, 19, 20), nucleocapsid and spike proteins (SARS-CoV-1; and -2) and epithelial membrane antigen (EMA) antibodies. Clinical data were retrieved from the patients' medical files, including the symptoms and the complete history of the progression of the disease. RESULTS: The patients who had COVID-19 included in this study experienced painful lesions in the tongue that corresponded to prominent or altered SNP. Microscopically, neural structures were positive for S-100, GFAP and neurofilament protein. And the cellular proliferative index (by Ki-67) was very low. CONCLUSION: Thus, based on the current results, we hypothesize that symptomatic SNP may be a late manifestation of COVID-19 infection.

Data Acquisition for Condition Monitoring in Tactical Vehicles: On-Board Computer Development.

This paper outlines the development of an onboard computer prototype for data registration, storage, transformation, and analysis. The system is intended for health and use monitoring systems in military tactical vehicles according to the North Atlantic Treaty Organization Standard Agreement for designing vehicle systems using an open architecture. The processor includes a data processing pipeline with three main modules. The first module captures the data received from sensor sources and vehicle network buses, performs a data fusion, and saves the data in a local database or sends them to a remote system for further analysis and fleet management. The second module provides filtering, translation, and interpretation for fault detection; this module will be completed in the future with a condition analysis module. The third module is a communication module for web serving data and data distribution systems according to the standards for interoperability. This development will allow us to analyze the driving performance for efficiency, which helps us to know the vehicle's condition; the development will also help us deliver information for better tactical decisions in mission systems. This development has been implemented using open software, allowing us to measure the amount of data registered and filter only the relevant data for mission systems, which avoids communication bottlenecks. The on-board pre-analysis will help to conduct condition-based maintenance approaches and fault forecasting using the on-board uploaded fault models, which are trained off-board using the collected data.

A General-Purpose Distributed Analytic Platform Based on Edge Computing and Computational Intelligence Applied on Smart Grids.

Currently, in many data landscapes, the information is distributed across various sources and presented in diverse formats. This fragmentation can pose a significant challenge to the efficient application of analytical methods. In this sense, distributed data mining is mainly based on clustering or classification techniques, which are easier to implement in distributed environments. However, the solution to some problems is based on the usage of mathematical equations or stochastic models, which are more difficult to implement in distributed environments. Usually, these types of problems need to centralize the required information, and then a modelling technique is applied. In some environments, this centralization may cause an overloading of the communication channels due to massive data transmission and may also cause privacy issues when sending sensitive data. To mitigate this problem, this paper describes a general-purpose distributed analytic platform based on edge computing for distributed networks. Through the distributed analytical engine (DAE), the calculation process of the expressions (that requires data from diverse sources) is decomposed and distributed between the existing nodes, and this allows sending partial results without exchanging the original information. In this way, the master node ultimately obtains the result of the expressions. The proposed solution is examined using three different computational intelligence algorithms, i.e., genetic algorithm, genetic algorithm with evolution control, and particle swarm optimization, to decompose the expression to be calculated and to distribute the calculation tasks between the existing nodes. This engine has been successfully applied in a case study focused on the calculation of key performance indicators of a smart grid, achieving a reduction in the number of communication messages by more than 91% compared to the traditional approach.

Design of a Tension Infiltrometer with Automated Data Collection Using a Supervisory Control and Data Acquisition System.

This study highlights the importance of water infiltration in hydrological basin management, emphasizing its role in water services, water quality regulation, and temporal patterns. To measure this crucial function, this study introduces a portable and user-friendly tension infiltrometer designed for easy assembly and data collection. The tension infiltrometer, based on the 2009 design by Spongrová and Kechavarzi, offers a comprehensive characterization of the soil properties related to water flow. It eliminates the influence of preferential flow, providing accurate data. Additionally, it accommodates changes in pore size distribution within the soil, which is crucial for understanding water movement. This study discusses the challenges associated with traditional infiltration measurement tools, like double-ring infiltrometers and single rings, which are not easily transported and can lead to inaccuracies. In response, the proposed infiltrometer simplifies data collection, making it accessible to a broader range of users. This study also explores the use of the VL53L0X distance sensor in the infiltrometer, providing an innovative solution for measuring the water column height. The system's user interface allows real-time data collection and analysis, significantly reducing the processing time compared to that of the manual methods. Overall, this work demonstrates the potential for advancement in hydrological basin management using user-friendly instrumentation and automated data collection, paving the way for improved research and decision making in environmental services, conservation, and restoration efforts within these ecosystems.

Multitraction with rubber bands and surgical silk as a method to facilitate endoscopic submucosal dissection.

We propose this variant of the clip technique as a method that assist traction during endoscopic submucosal dissection (ESD): traction on the mucosa plane using an hemoclip carrying a surgical silk and three rubber bands, before the incision, to allow easier access to the submucosa space. We propose this variant with the intention of facilitating access to ESD quickly and safely for beginners.

Brief Consent Methods Enable Rapid Enrollment in Acute Stroke Trial: Results From the TICH-2 Randomized Controlled Trial.

BACKGROUND: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. METHODS: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. RESULTS: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up. CONCLUSIONS: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

Design and Evaluation of a Heterogeneous Lightweight Blockchain-Based Marketplace.

The proposal of this paper is to introduce a low-level blockchain marketplace, which is a blockchain where participants could share its power generation and demand. To achieve this implementation in a secure way for each actor in the network, we proposed to deploy it over efficient and generic low-performance devices. Thus, they are installed as IoT devices, registering measurements each fifteen minutes, and also acting as blockchain nodes for the marketplace. Nevertheless, it is necessary that blockchain is lightweight, so it is implemented as a specific consensus protocol that allows each node to have enough time and computer requirements to act both as an IoT device and a blockchain node. This marketplace will be ruled by Smart Contracts deployed inside the blockchain. With them, it is possible to make registers for power generation and demand. This low-level marketplace could be connected to other services to execute matching algorithms from the data stored in the blockchain. Finally, a real test-bed implementation of the marketplace was tested, to confirm that it is technically feasible.

Accuracy diagnosis improvement of Fabry disease from dried blood spots: Enzyme activity, lyso-Gb3 accumulation and GLA gene sequencing.

The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the diagnostic role of α-galactosidase A activity (α-Gal A), levels of lyso-Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α-Gal A activity in suspected FD patients in DBS was made followed by lyso-Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α-Gal A was more sensitive than lyso-Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.

Central and peripheral nervous system involvement by COVID-19: a systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings.

BACKGROUND: SARS-CoV-2 can affect the human brain and other neurological structures. An increasing number of publications report neurological manifestations in patients with COVID-19. However, no studies have comprehensively reviewed the clinical and paraclinical characteristics of the central and peripheral nervous system's involvement in these patients. This study aimed to describe the features of the central and peripheral nervous system involvement by COVID-19 in terms of pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings. METHODS: We conducted a comprehensive systematic review of all the original studies reporting patients with neurological involvement by COVID-19, from December 2019 to June 2020, without language restriction. We excluded studies with animal subjects, studies not related to the nervous system, and opinion articles. Data analysis combined descriptive measures, frequency measures, central tendency measures, and dispersion measures for all studies reporting neurological conditions and abnormal ancillary tests in patients with confirmed COVID-19. RESULTS: A total of 143 observational and descriptive studies reported central and peripheral nervous system involvement by COVID-19 in 10,723 patients. Fifty-one studies described pathophysiologic mechanisms of neurological involvement by COVID-19, 119 focused on clinical manifestations, 4 described neuropathology findings, 62 described neuroimaging findings, 28 electrophysiology findings, and 60 studies reported cerebrospinal fluid results. The reviewed studies reflect a significant prevalence of the nervous system's involvement in patients with COVID-19, ranging from 22.5 to 36.4% among different studies, without mortality rates explicitly associated with neurological involvement by SARS-CoV-2. We thoroughly describe the clinical and paraclinical characteristics of neurological involvement in these patients. CONCLUSIONS: Our evidence synthesis led to a categorical analysis of the central and peripheral neurological involvement by COVID-19 and provided a comprehensive explanation of the reported pathophysiological mechanisms by which SARS-CoV-2 infection may cause neurological impairment. International collaborative efforts and exhaustive neurological registries will enhance the translational knowledge of COVID-19's central and peripheral neurological involvement and generate therapeutic decision-making strategies. REGISTRATION: This review was registered in PROSPERO 2020 CRD42020193140 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020193140.

Structural basis for gene regulation by a B12-dependent photoreceptor.

Photoreceptor proteins enable organisms to sense and respond to light. The newly discovered CarH-type photoreceptors use a vitamin B12 derivative, adenosylcobalamin, as the light-sensing chromophore to mediate light-dependent gene regulation. Here we present crystal structures of Thermus thermophilus CarH in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure. These structures provide visualizations of how adenosylcobalamin mediates CarH tetramer formation in the dark, how this tetramer binds to the promoter -35 element to repress transcription, and how light exposure leads to a large-scale conformational change that activates transcription. In addition to the remarkable functional repurposing of adenosylcobalamin from an enzyme cofactor to a light sensor, we find that nature also repurposed two independent protein modules in assembling CarH. These results expand the biological role of vitamin B12 and provide fundamental insight into a new mode of light-dependent gene regulation.

Development and validation of a laboratory-based risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19.

BACKGROUND: Early identification of patients with COVID-19 who may develop critical illness is of great importance. METHODS: In this study a retrospective cohort of 264 COVID-19 cases admitted at Macarena University was used for development and internal validation of a risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. Backward stepwise logistic regression was used to derive the model, including clinical and laboratory variables predictive of critical illness. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in a cohort of 154 cases admitted at Valme and Virgen del Rocio University Hospital. RESULTS: A total of 62 (23.5%) patients developed a critical illness during their hospitalization stay, 21 (8.0%) patients needed invasive ventilation, 34 (12.9%) were admitted at the ICU and the overall mortality was of 14.8% (39 cases). 5 variables were included in the final model: age >59.5 years (OR: 3.11;95%CI 1.39-6.97), abnormal CRP results (OR: 5.76;95%CI 2.32-14.30), abnormal lymphocytes count (OR: 3.252;95%CI 1.56-6.77), abnormal CK results (OR: 3.38;95%CI 1.59-7.20) and abnormal creatinine (OR: 3.30;95%CI 1.42-7.68). The AUC of this model was 0.850 with sensitivity of 65% and specificity of 87% and the IDI and NRI were 0.1744 and 0.2785, respectively. The validation indicated a good discrimination for the external population. CONCLUSIONS: Biomarkers add prognostic information in COVID-19 patients. Our risk-score provides an easy to use tool to identify patients who are likely to develop critical illness during their hospital stay.

A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases.

BACKGROUND: Our aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature. METHODS: We performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature. RESULTS: Our patient is a six-year-old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non-classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat-soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0-54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity. CONCLUSION: The first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.

OpenADR and Agreement Audit Architecture for a Complete Cycle of a Flexibility Solution.

Nowadays, the presence of renewable generation systems and mobile loads (i.e., electric vehicle) spread throughout the distribution network is increasing. The problem is that this type of system introduces an added difficulty since they present a strong dependence on the meteorology and the mobility needs of the users. This problem forces the distribution system operators to seek tools that make it possible to balance the relationship between consumption and generation. In this sense, automated demand response systems are an appropriate solution that allow the operator to request specific reductions in customers' consumption, offering a discount to the customer and avoiding network congestion. This paper analyzes the implementation and architecture of a demand response solution based on OpenADR standard and its possible integration with a building management system through a use case. As will be analyzed, a key part of the architecture is the measurement system based on smart meters acting as sensors. This is the base of the auditing system which makes it possible to verify compliance with the consumption reduction agreements. Additionally, this study is completed with a parallel auditing system which makes it possible to verify compliance with the consumption reduction agreements. All of the proposed demand response cycle is implemented as a proof of concept in a classroom in the Escuela Politécnica Superior at the University of Seville, which makes it possible to identify the advantages of this architecture in the ambit of connection between distribution network and buildings.

Evaluation of the Antiviral Activity against Infectious Pancreatic Necrosis Virus (IPNV) of a Copper (I) Homoleptic Complex with a Coumarin as Ligand.

The aquatic infectious pancreatic necrosis virus (IPNV) causes a severe disease in farmed salmonid fish that generates great economic losses in the aquaculture industry. In the search for new tools to control the disease, in this paper we show the results obtained from the evaluation of the antiviral effect of [Cu(NN1)2](ClO4) Cu(I) complex, synthesized in our laboratory, where the NN1 ligand is a synthetic derivate of the natural compound coumarin. This complex demonstrated antiviral activity against IPNV at 5.0 and 15.0 µg/mL causing a decrease viral load 99.0% and 99.5%, respectively. The Molecular Docking studies carried out showed that the copper complex would interact with the VP2 protein, specifically in the S domain, altering the process of entry of the virus into the host cell.

Endoscopic removal of an embedded uncovered biliary self-expandable metal stent with a mechanichal lithotriptor.

Biliary fully-covered self-expandable metal stents (FCSEMS) can be used for benign conditions since they can be removed. Uncovered SEMS (uSEMS) are employed for malignant biliary obstruction and are intended to be permanent. Furthermore, they are almost impossible to remove because they become embedded in the bile duct. We present a technique for uSEMS removal in a patient in whom a biliary uSEMS had been inserted for two years. Biliary obstruction due pancreatic cancer was misdiagnosed. Finally an IgG4 related-disease (autoimmune pancreatitis) was identified.

A retrospective analysis of the impact of the COVID-19 restrictions on energy consumption at a disaggregated level.

Since the emergence of the virus that causes COVID-19 (the SARS-CoV-2) in Wuhan in December 2019, societies all around the world have had to change their normal life patterns due to the restrictions and lockdowns imposed by governments. These changes in life patterns have a direct reflection on energy consumption. Thanks to Smart Grid technologies, specifically to the Advance Metering Infrastructure at secondary distribution network, this impact can be evaluated even at the customer level. Thus, this paper analyzes the consumption behavior and the impact that this crisis has had using Smart Meter data. The proposed approach includes the selection and normalization of features, automatic clustering, the obtaining of the estimated consumption without considering the crisis (at short and mid-terms) and the impact evaluation. The proposed approach has been tested on a case with a real Smart Meter infrastructure from Manzanilla (Huelva, Spain). The results of this use case showed that residential customers have increased their consumption around 15% during full lockdown and 7.5% during the reopening period. In contrast, globally, non-residential customers have decreased their consumption 38% during full lockdown and 14.5% during the reopening period. However, referring to non-residential customers, five different consumption profiles were found with different short-term and mid-term behaviors during the COVID crisis. The different behavior found shows customers who have maintained their normal consumption during the lockdown, others who have reduced it (to a greater or lesser extent) and have not recovered it after the removal of the restrictions, and others who have reduced the consumption but then they recovered it when the restrictions were removed. The metadata of the customers in each behavior cluster found are highly correlated to the restrictions imposed to control the spread of the virus. This study shows evidence about the proposed approach usefulness to analyze the behavior and the impact at customer level during the COVID-19 crisis.

Conceptual validation of an innovative remote pulmonary rehabilitation solution for Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the world. Pulmonary rehabilitation (PR) reduces COPD hospitalisations, although its use is low. Telerehabilitation is effective; however, in Chile the development of remote PR technology is incipient. Therefore, the aim of the study was to validate conceptual aspects of an innovative remote PR solution for COPD. METHODS: This mixed study used a nonprobabilistic sample of PR professionals and people with COPD (PwCOPD) from Santiago. The perception of a conceptual solution for PR through a semi-structured interview was determined. Professionals were also asked about willingness to use technology using a questionnaire designed and validated in 75 professionals in this study. The study was approved by the Ethics Committee and data were collected after informed consent. RESULTS: Twenty-two participants were recruited, of which 14 were professionals and eight were PwCOPD. Among professionals and patients, the willingness to use the solution is positive because it would reduce visits and improve self-management, although it should include a remote/in-person combination, training, and user-friendly interface. Most of the professionals were willing to use technology for pulmonary rehabilitation. CONCLUSIONS: The development of telehealth technologies should consider the expectations of patients and professionals and may incorporate elements of persuasive technologies in the design. The results could contribute to the development of digital solutions for remote PR in PwCOPD.