A PubMed query run in June 2018 using the keyword ‘blockchain’ retrieved 40 indexed papers, a reflection of the growing interest in blockchain among the medical and healthcare research and practice communities. Blockchain’s foundations of decentralisation, cryptographic security and immutability make it a strong contender in reshaping the healthcare landscape worldwide. Blockchain solutions are currently being explored for: (1) securing patient and provider identities; (2) managing pharmaceutical and medical device supply chains; (3) clinical research and data monetisation; (4) medical fraud detection; (5) public health surveillance; (6) enabling truly public and open geo-tagged data; (7) powering many Internet of Things-connected autonomous devices, wearables, drones and vehicles, via the distributed peer-to-peer apps they run, to deliver the full vision of smart healthy cities and regions; and (8) blockchain-enabled augmented reality in crisis mapping and recovery scenarios, including mechanisms for validating, crediting and rewarding crowdsourced geo-tagged data, among other emerging use cases. Geospatially-enabled blockchain solutions exist today that use a crypto-spatial coordinate system to add an immutable spatial context that regular blockchains lack. These geospatial blockchains do not just record an entry’s specific time, but also require and validate its associated proof of location, allowing accurate spatiotemporal mapping of physical world events. Blockchain and distributed ledger technology face similar challenges as any other technology threatening to disintermediate legacy processes and commercial interests, namely the challenges of blockchain interoperability, security and privacy, as well as the need to find suitable and sustainable business models of implementation. Nevertheless, we expect blockchain technologies to get increasingly powerful and robust, as they become coupled with artificial intelligence (AI) in various real-word healthcare solutions involving AI-mediated data exchange on blockchains. In order to understand the utility and disruptive potential that blockchain technology offers, one must first review the fundamentals of the technology itself. Blockchain is a decentralised, immutable, and cryptographically secure distributed ledger technology (DLT), broadly used to eliminate the need for trust in data transfer, and well known for powering the Bitcoin cryptocurrency . Our goaThe distribution element of blockchain as a distributed ledger refers to the design of the system on which the blockchain is running  and the number of individuals or organisations that control or own said computers. DLTs are built on consensus utilising algorithms to find agreement among participants , data replication, and peer-to-peer P2P) networking. Decentralisation is a subset of distribution concerning ownership and control of the data on the system and decisions about the system itself  for up to $200 billion per year” . EnsurinSubstandard, falsified, and counterfeit medications are often seen in developing countries, or those with low-income markets. The amount of medication importation also plays a role in the verifiable authenticity of the product, especially with a weak or nonexistent supply chain management system. However, the United States has also been on the receiving end of fraudulent medications. In response to the threat of obtaining more fake medications, the US has started to implement the Drug Supply Chain Security Act (DSCSA). Key requirements for supply chain management technologies compliant to DSCSA are product identification, product tracing, product verification, detection and response to non-standard medications, notification upon identifying a non-standard medication, and the ability to store relevant information including licensures, verification, and product information . BlockchWhile pharmaceutical supply chain management and integrity are incredibly important, safety and security of medical devices and supplies can also be improved through blockchain implementation. Devices including implanted cardiac pacemakers and medication pumps can be compromised and controlled. Blockchain technology can be implemented in this field by holding unique device identifiers for each medical device (a requirement by the US FDA (Food and Drug Administration) and the EU) and by keeping track and issuing firmware updates by utilising smart contracts. A partnership between Edinburgh Napier University, NHS  Scotland, and Spiritus Development is leading an effort to use blockchain technology to track medical devices through their lifecycle , 25. ThiBlockchain technology can improve supply chain management in a number of ways including: “… reducing or eliminating fraud and errors, reducing delays from paperwork, improving inventory management, identifying issues more rapidly, minimising courier costs, and increasing consumer and partner trust” , 26.A major benefit of blockchain technology is moving data ownership from institutions and corporations into the hands of the people who generated said data. This gives them control over who can see or interact with their data in any way. Not only does blockchain protect their data ownership, it also makes it easier to share data in a secure way while receiving benefits or payouts . Health Professor Andrew Lippman, associate director of the MIT Media Lab, recently spoke about MedRec at MIT Technology Review Conference. As he explained, full nodes act as the MedRec data server and maintain the blockchain. These nodes are themselves maintained by the entities generating data . Smart contracts define access and rights to data and is the “language” upon which the blockchain is defined. Patient wallets are how individuals interface with the blockchain. The wallets contain keys that provide access to the appropriate data , 14, 25.The MedRec blockchain sits somewhere in between the Bitcoin blockchain and a tradition database. In the Bitcoin blockchain, anyone can join and take part, which greatly increases complexity and expense to keep the chain running. MedRec restricts who can join the blockchain to medical providers and organisations. They run the full nodes, they maintain the data, and they keep the blockchain secure in a more efficient way than the Bitcoin blockchain could. The MedRec blockchain used to be maintained by medical researchers. As payment for maintaining the blockchain, they would gain access to random, anonymised health data for epidemiological research purposes. At the time of writing, MedRec has moved further to a proof of stake model. There are no transaction fees to move data around or use contracts. There is no coin that needs to be mined for transactions. It is maintained by the group of stakeholders made up by the healthcare organisations that take part in the MedRec blockchain.Claims processing has been identified as a target for blockchain disruption or enhancement, inclusive of streamlining preauthorisation submissions, health insurance claims adjudication, and eligibility management , 31. OneIn addition to the above-mentioned four major categories of blockchain use cases for healthcare, new categories are coalescing and individual use cases continue to emerge . These include, but are not limited to, public health surveillance , enhanciThe Internet of Things (IoT) is the foundation of the smart healthy cities and regions of today and tomorrow , 41. To Ellehauge  also expThe market for IoT devices and apps that negotiate with, and pay, each other for secure, safe operation and services, e.g., mobile and wearable devices that pay for public transportation , and autCitizen engagement in the crowdsourcing of geo-tagged data can be combined with augmented reality (AR) and blockchain technology (blockchain-enabled AR) in powerful new crisis mapping and recovery scenarios, e.g., in the production and real-time updating of an augmented crisis map for navigating a disaster-stricken area, in which geo-tagged AR objects providing critical contextual information and advice are superimposed onto the real world scene on user’s smartphone . The crowdsourced data objects can be blockchain-validated, credited and rewarded .Implementation-wise, FOAM  is a gooAmong the challenges facing geospatial blockchain implementations today, there are three particularly pressing ones (besides the above-mentioned need for sustainable business models) upon which the future success and mainstream adoption of the technology will be hinging. These three challenges require careful consideration and innovative solutions  to address them. The first issue is interoperability, to have blockchains from different providers and services seamlessly talk to each other as appropriate . The secAt the time of writing, a PubMed query using the keyword ‘blockchain’ retrieved 40 indexed papers , a reflesecuring patient and provider identities;managing pharmaceutical and medical device supply chains;clinical research and data monetisation, e.g., –58;medical fraud detection;public health surveillance, e.g., by the US CDC (Centers for Disease Control and Prevention) for sharing public health data to help public health workers respond faster to a crisis ;enabling truly public and open geo-tagged data;powering many IoT-connected autonomous devices, wearables, drones and vehicles, via the distributed peer-to-peer apps they run, to deliver the full vision of smart healthy cities and regions; andblockchain-enabled augmented reality in crisis mapping and recovery scenarios, including mechanisms for validating, crediting and rewarding crowdsourced geo-tagged data, among other emerging blockchain use cases.Blockchain solutions are currently being explored for:Geospatially-enabled blockchain solutions exist today that use a crypto-spatial coordinate system to add an immutable spatial context that regular blockchains lack. These geospatial blockchains do not just record an entry’s specific time, but also require and validate its associated proof of location, thus facilitating the accurate spatiotemporal mapping of physical world events.Blockchain and DLT have the potential to benefit all the above application areas and many more, but also face similar challenges as those faced by any other technology threatening to disintermediate legacy processes and commercial interests, namely the challenges of blockchain interoperability, security and privacy, as well as the need to find suitable and sustainable business models of implementation. Nevertheless, we expect blockchain technologies to get increasingly powerful and robust, as they become coupled with artificial intelligence (AI)  in vario


Blockchain is a distributed, immutable ledger technology introduced as the enabling mechanism to support cryptocurrencies. Blockchain solutions are currently being proposed to address diverse problems in different domains. This paper presents a scoping review of the scientific literature to map the current research area of blockchain applications in the biomedical domain. The goal is to identify biomedical problems treated with blockchain technology, the level of maturity of respective approaches, types of biomedical data considered, blockchain features and functionalities exploited and blockchain technology frameworks used. The study follows the PRISMA-ScR methodology. Literature search was conducted on August 2018 and the systematic selection process identified 47 research articles for detailed study. Our findings show that the field is still in its infancy, with the majority of studies in the conceptual or architectural design phase; only one study reports real world demonstration and evaluation. Research is greatly focused on integration, integrity and access control of health records and related patient data. However, other diverse and interesting applications are emerging, addressing medical research, clinical trials, medicines supply chain, and medical insurance.  It firsThe blockchain is defined as a chain of blocks that are time-stamped and connected using cryptographic hashes. A block may contain transactions of many users and generally is publicly available to all users of the network. Additionally, each block contains the hash of the previous block and the transaction data, thus creating a secure and immutable, append-only chain. This chain continuously increases in length as each new block is being added in its end. The blockchain is organized in a peer-to-peer network  that conBased on the access and managing permissions, there are three types of blockchains: public, private and consortium blockchain. A public (or permissionless) blockchain is highly distributed and anyone can participate implementing a miner; this ensures maximum immutability, although limits efficiency due to consensus achieved collaboratively via the highly extended miner network. On the other end, in a private blockchain blocks are processed by miners of a single organization; immutability can be tampered with, but efficiency is maximized. A consortium (or federated) blockchain can provide the efficiency of a private one, while it combines a partially distributed miner network which includes nodes provided by selected organizations.https://en.bitcoinwiki.org/wiki/Blockchain_Projects_List, accessed on November 19, 2018). Blockchain infrastructures charge for each transaction a fee (known as ‘gas’) proportional to the computational burden that the execution will impose on the blockchain.A large number of blockchain technology frameworks exist ; publications not related to blockchain and publications not related to biomedical domain. When we were not able to discern the above information from the title or abstract, the paper was included for further study. The reviewers discussed their findings and agreed on a consolidated publication list.Subsequently, the two reviewers studied independently and in detail the full text of all the publications in the list retained after the first screening, in order to agree on a final list of papers related to blockchain technologies in biomedical domain. This final list was studied to identify and organize papers into three pools: (1) research papers; (2) reviews of any type; and (3) position papers. Papers in the first pool were included for this scoping review and further analyzed using the data charting approach presented in the following subsection. Papers in the second and third pool were retained for statistical analysis and further general reference.2.6A data charting form was developed jointly by the authors to determine which variables to extract. Subsequently, they independently charted the data and discussed the results. Minor discrepancies were resolved by discussion and a consolidated data chart was constructed (available upon request).-Year of publication: as this is stated in the citation exported by the database.-Source type: publication types considered include (a) journal paper; (b) conference proceedings paper; (c) magazine article; and (d) book chapter.-Article type: (a) research papers reporting novel applications of blockchain technologies in the biomedical domain; (b) reviews of any type ; and (c) position papers discussing general aspects of the field, but not reporting on novel research or systematically reviewing existing research.For each paper included in the list after the first screening, the following data items were extracted:-Application area: the specific biomedical area considered in the publication, e.g. health records, clinical trials, medicines, medical evidence databases, medical education.-Maturity of approach: using the following scale (a) research proposal of a novel blockchain application; (b) architectural design of a system or system component employing blockchain technologies; (c) implementation of a working prototype of the proposed blockchain system component, with details on the technical platforms and tools used; and (d) evaluation in the real setting.-Biomedical data: the type of data considered in the proposed blockchain application, e.g. medical health records, personal health records, consent forms, drug information, environmental data, location, medical evidence data, etc.-Reasons for using blockchain: to what end blockchain technology is exploited in each application, for example, access control, non-repudiation, data auditing, data provenance, data versioning and integrity.-Blockchain technology: the specific blockchain infrastructure (if any) used or proposed for the implementation, e.g. Bitcoin, Ethereum, Hyperledger Fabric, etc.For each research paper included in the scoping review, further data items where extracted in order to categorize the paper. Since we have not managed to identify another systematic or scoping review on the same topic and research questions, we opted for a topic-specific alternative for the classification of papers, as described in guidelines for systematic mapping studies in software engineering . The aut2.7We analyzed the overall results after the first screening to present an overview of existing literature in blockchain applications in the biomedical domain. Subsequently, we focused on literature presenting original research in order to identify the breath  and depth (maturity level) of existing research. The individual characteristics of each included publication are presented in tabular form. We have also computed and graphed summaries of charted data frequencies. Finally, we summarize and discuss scoping review finding for each of the identified application areas.33.1A total of 3647 abstracts were retrieved . After the first screening 3527 papers were excluded: 417 were not in English, 126 had no abstract, 50 were not scientific papers, 2917 were about blockchain technologies but not related to biomedical domain or they were not about blockchain technology at all. Thus, after the initial title and abstract screening, we retained 137 papers for further study. After removing 17 duplicates, 120 unique papers were identified for full paper analysis. During the second screening, 37 papers were further excluded as not relevant to blockchain applications in biomedical domain. From the remaining 83 papers, 5 papers were identified as reviews, 31 papers were identified as position papers, and 47 as research papers. The 47 research papers were included in the scoping review, while the reviews and position papers were retained for further study as papers related to blockchain applications in the biomedical domain. The source selection process is shown in Overall, 3% of the retrieved papers were found relevant to the topic of this study . Further analysis of the 83 papers related to blockchain applications in the biomedical domain shows that more than half (53%) are journal papers and around 41% are full papers in conference proceedings  present novel research; 37% are position papers presenting general discussions on the field and only 6% are reviews of different subdomains  or in conference proceedings. Journal papers were published in 13 different journals; only 4 journal titles have published more than one paper on biomedical applications of blockchain, namely Journal of Medical Systems (9 papers), Computational and Structural Biotechnology Journal (3 papers), IEEE Access (3 papers) and F1000 Research (2 papers). Conference papers were published in 19 different conference proceedings; only one conference proceedings title published more than one paper included in this scoping review, namely Studies in Health Technology and Informatics.https://www.goconqr.com).Based on the iterative identification of data charting keywords  used; a summary of data charted is shown in The most prevalent biomedical data type (81%) refers to medical data related to health records, including medical records (48%), personal biosensor data (22%), and personal health records (6%). The rest of proposed solutions consider diverse biomedical data types: clinical trial data (4%), biomedical database queries (4%), ambient measurements such as location and temperature (4%), and financial data (2%). A graph of frequencies for the different biomedical data types considered in the blockchain applications included in the scoping review is presented in Blockchain is employed to address several information security components . Most pa4Although several publications have presented an overview of blockchain applications in the biomedical domain, to the best of our knowledge this is the first systematic study covering a large part of the published literature in the biomedical domain. In particular, an earlier review of blockchain applications in 2017 identified some applications related to electronic and personal health care records ; the samMain findings of the scoping review show that blockchain technology has so far been proposed to address several security issues in a number of different biomedical applications as summarized in the following paragraphs.As defined by the International Organization for Standardization (ISO), electronic health records include any computer processable repository of information regarding the health status of an individual . AlthougBlockchains have been proposed to achieve integration of distributed personal health record segments in a unified personal health record ,52, ofteCritical appraisal of all health record related studies shows that main reasons for proposing blockchain technology in medical records relate to addressing long lasting medical record integration problems associated either with integrating record segments under a virtually common ledger (the blockchain) or providing a unified mechanism for controlling access to records or their segments. Another important application related to health records considers data integrity and unified logging of medical acts. However, we should note that very often there is a confusion of what data are put in the blockchain. Thus, in many cases, the blockchain is (mistakenly we believe) proposed to store the entire health record data, rather than used as is designed, i.e. to create a rigorous and tamper proof registry of data and of actions.Overall, blockchain applications in health records are at a rather initial stage of maturity. Less than half (42%) show some degree of implementation, which is limited to laboratory or simulation testing. No study presents a real-world demonstration or evaluation of the proposed solution. We anticipate that as technology matures and more industrial applications emerge, real world pilot demonstrations will help shape the field and will reveal the most suitable applications of blockchain in medical records. Indeed, in 2016, the Estonian Health and Welfare Information Systems Centre launched a project to create and secure a log file of all medical data processing activities in the national health record system using blockchain technology; the project, probably the first nationwide deployment, and is currently in pilot stages . The samThe recent trend of quantified self  brought A different, emerging field of blockchain applications in the biomedical domain refers to supporting research. One particular type involves clinical trials, where blockchain technology has been exploited in three different paradigms. A first application  involvesMedicines supply chain can potentially benefit from blockchain technology to store drug transaction data to immutably trace and track products from the producer to the consumer and thus combat counterfeit drugs ,55. AnotLimitations of this scoping review are linked to the literature databases included for publication retrieval. Our search considered some  of the most popular scientific literature indexing systems for information technology and biomedical research. Additionally, search was limited scientific literature, so applications described in grey literature might have been missed. Since the field is still in its infancy, our broad search based only on the term “blockchain” returned a manageable number of records for study. Considering the increasing popularity trends we have seen in this study, future repetitions of a similar scoping review would have to devise smarted search queries to narrow the retrieved records to blockchain applications in the biomedical domain.5In this paper we present the results of a scoping literature review into the current state of research in the application of blockchain technology in the biomedical domain. Our findings show that the field is still in its infancy. Research maturity of the papers included in this scoping review suggests that blockchain applications in the biomedical domain is still an emerging field. Yearly distribution of related publications supports this finding, showing that research activity in the field starts only in 2016 and is doubled during the first 8 months of 2018, increasing at much higher rates than general position and concept papers in the same field.In this first 3 years, research is greatly focused on integration, integrity and access control of health records and related patient data. However, other diverse and interesting applications are emerging, addressing medical research, clinical trials, medicines supply chain, and medical insurance. As yet, blockchain has still to find its proper application paradigms, moving away from approaches that discuss storing actual health data chunks in the blockchain, to solutions that use the blockchain as a ledger storing mainly references to data or data hashes.Apart from identifying new, promising application areas, research should focus on real world evaluation based on large scale deployments that would highlight technology limitations and most likely indicate most suitable applications. Also, special attention should be drawn to privacy, which is not preserved by default in the common blockchain. One issue that is not fully addressed in current literature is the type of blockchain used, namely public, private or consortium. Only a few publications mention the specific type of blockchain used; even then, a proper justification is lacking. We believe that each different blockchain type has its own niche in biomedical applications and we expect that consortium blockchain (with carefully selected miner node owners) might prove the best solution to both guarantee high enough immutability and ensure required efficiency at a tolerable cost.It is evident that the field still has to find its own forum in the scientific publication realm. So far published literature is greatly scattered in different journals and conferences; the field could benefit from special issues in established scientific journals and dedicated workshops in biomedical conferences, and regular repetitions of similar scoping reviews.To conclude, this study can become a starting point for future research, demonstration and evaluation of blockchain applications in the biomedical domain, and also a guide for regular, systematic reviews of related research progress.European Commission FP7-ICT project CARRE (Grant No. 611140) and the corresponding Greek National Matching funds of the General Secretariat of Research and Technology (GSRT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was partly supported by the


A blockchain is a system for storing and sharing information that is secure because of its transparency. Each block in the chain is both its own independent unit containing its own information, and a dependent link in the collective chain, and this duality creates a network regulated by participants who store and share the information, rather than a third party. Blockchain has many applications in healthcare, and can improve mobile health applications, monitoring devices, sharing and storing of electronic medical records, clinical trial data, and insurance information storage. Research about blockchain and healthcare is currently limited, but blockchain is on the brink of transforming the healthcare system; through its decentralized principles, blockchain can improve accessibility and security of patient information, and can therefore overturn the healthcare hierarchy and build a new system in which patients manage their own care. In the world of healthcare today, there are two major focuses that must be addressed: data security and data ownership. Sensitive medical records currently lack a secure structure, leading to data breaches with severe consequences. In 2018, the Department of Health and Human Services’ Office for Civil Rights (OCR) received notifications of many data breaches that resulted in the exposure of 13 million total healthcare records [Blockchain technology may provide the answer.Invented in 2008 by Satoshi Nakomoto for the cryptocurrency Bitcoin, the technology offers a verifiable, permanent, and attack-resistant system for recording data . Next, tThis process involves using computation power to test random input strings until one produces an output string that meets the requirements. The first miner to succeed gets to add his block to the blockchain, thus completing the transaction, and the next round begins . BlockchMobile applications and remote monitoring machines are essential for patient care in today’s technological age. Blockchain can be applied to these technologies and improve security and quality of machinery. For example, a group of researchers created and tested an mHealth  smart phone application for cognitive behavioral therapy for insomnia . The appFurthermore, another mobile application, called Healthcare Data Gateway (HGD), has been presented for organization of patient data . The appSecurity concerns are associated with mobile monitoring of healthcare, as patient health information is private and sensitive. Mobile malware has destroyed blockchain in the past, and the blockchain that controls mobile applications must be completely secure before it can be used to store health information. One study investigated root exploit, the most vicious type of mobile malware, and its interactions with blockchain . Root exMoreover, Logitboost was also found to predict root exploit in the Root Exploit Detection System (RODS) curated in the study. More studies need to investigate mobile health and remote monitoring security concerns to ensure that the blockchain can store patient information successfully within these types of devices.Blockchain technology can also be applied to the accessing and sharing of patient medical records. Medical records can be difficult to access because they are generally spread out across many different healthcare facilities, and blockchain can enable patients to have full and secure access to all of their records and medical history. A few systems based on blockchain have been proposed for organization of and access to patient medical records. MedBlock, a blockchain based information management system, enables efficient EMR access and retrieval through distributed blockchain principles . The impSimilarly, a blockchain based Data Preservation System (DPS) for medical data has been engineered . DPS useThis new cryptographic framework based on multiple levels of encryption maximizes security. Sharing of healthcare data in a secure way is also an integral part of healthcare. Zhang and Lin curated a patient information sharing plan, called a BSPP  scheme, that may improve diagnosis of patients in virtual health systems . Their sLikewise, Dubovitskaya et al.  created Blockchain technology has also been applied to clinical trials and, very recently, to medical insurance storage. Blockchains can easily detect fake information because of their transparency, and smart contracts in the blockchain can serve as security promoters for clinical trial data . These sWe propose a medical data management system using blockchain technology that is secure and allows patients to retain ownership over their own records while allowing hospitals to have easy access  contracts. Multisig requires multiple users, in this case the patient and the hospital, to both use their private keys to sign a transaction for authentication. This way, the patient cannot alter the record without permission of the hospital, but he still has control over who can access his record. A new swarm hash must be generated each time after the data has been accessed (since the old swarm hash is now known), so we add a “last accessed” timestamp. The change in the data will automatically change the swarm hash, which can then be secured once again until it receives the required permissions for access. This model not only provides the security and immutability provided by blockchain, but also offers a multisig solution to data ownership and accessibility.Although blockchains are extremely secure, they are by nature susceptible to a type of attack known as the 51% attack  . This occurs when a miner, or group of miners, controls over 50% of the total mining hash rate (computing power) in the network and becomes able to prevent new transactions or reverse completed transactions. By controlling over 50% of the computing power, the malicious user is able to form blocks at a faster rate than the rest of the network, and by the longest chain rule , the network is forced to switch to the attacker’s desired chain. However, although 51% attacks are possible, the probability of a successful attack is extremely low, so blockchain remains one of the most secure forms of technology.EthereumPrice.org, 2019). The vast amount of transactions needed to be processed in hospital settings would amount to a sizable cost. However, the use of a blockchain system would replace current storage systems , personal medical records, disease registries, and other databases ) and eliminate costly data breaches and other errors, ultimately rendering the system cost-efficient.Another potential concern is the cost of implementing a blockchain system. When a transaction is requested, the user must pay for the computation. In the Ethereum network, the payment is calculated in “gas” and the gas is paid in “ETH,” valued around $120 USD as of January 2019 (Because blockchain maximizes security and accessibility, the technology can be used in many different areas of the healthcare system, such as for storing and sharing medical records and insurance information both in healthcare venues and in mobile applications and remote monitoring systems, and for clinical trials. Research about blockchain’s applications to healthcare is currently limited, but more research becomes available every day. Blockchain is one of the most active areas of software research currently, and it can change the hierarchy of healthcare by returning authority over medical records and health data to the patient. This transfer of authority may lead to an overall shift toward patient-centered care; the blockchain movement for patients is just beginning.


In their article entitled, "Are high flow arteriovenous accesses associated with worsehaemodialysis"-p value of 0.056.The authors are to be commended for conducting such a study and initiate a dialogue aboutthe impact of high flow fistulas on important dialysis parameters. Several investigatorshave provided the rationale for volume overload in patients with high flow fistulasversus 4 patients). Second, the confidence intervalis very large representing a small sample size. Third, the p value isslightly above significance (i.e. > 0.05). The evaluation of volume overload wasperformed by employing bioimpedance spectroscopy. From a clinical standpoint, volumeoverload is corrected by ultrafiltration. The authors do not provide information on theultrafiltration rate. In support of the study, it is worth pointing out that both normaland high flow fistulas received the same duration of dialysis therapy . Additionally, no informationis available on the weight gain for the high flow fistulas. It is conceivable that thehigh flow fistulas had a higher weight gain due to a higher fluid intake.While the study was a bold attempt, a few elements raise concerns regarding the findingsfrom both statistical and clinical standpoint. First of all, the sample size isextremely small (6 The study, however, raised important concerns about high flow fistulas including theircardiovascular impact. A large sample size should explore the volume overload in highflow fistulas to conclusively establish their adverse impact on volume status. In themeantime, in an effort to avoid high flow fistulas, we suggest an opinion-basedalgorithm as shown in


The laying performance of hens plays a major role in the production of laying hens because it determines the economic benefits of farmers. Indole-3-acetate sodium is a derivative of indole-3-acetate (a major plant growth hormone). This study shows that indole-3-acetate sodium inclusion in diets improved the serum reproductive hormone levels and egg production performance of Danzhou chickens. We found that indole-3-acetate sodium could be considered as an effective feed additive to improve the laying performance of hens, but more comprehensive studies need to be performed in the future.p < 0.05) and egg yolk ratio (0.05 < p < 0.1), but also significantly reduced the feed:egg ratio (p < 0.05). In addition, the dietary supplementation of IAA-Na significantly increased the serum estradiol levels (p < 0.05) and decreased serum alkaline phosphatase activity (p < 0.05). Compared with the control group, the addition of IAA-Na to the diet had no significant effect on the intestinal tissue morphology or serum antioxidant capacity of Danzhou chickens. This study preliminarily provides evidence that dietary IAA-Na can improve laying performance, indicating that IAA-Na is a potentially effective feed additive for laying hens, but further studies are required before arriving at definite conclusions.This study was conducted to investigate the effects of indole-3-acetate sodium (IAA-Na) inclusion in diets on the egg production performance, egg quality, intestinal tissue morphology, serum hormone levels and biochemical parameters of Danzhou chickens to preliminarily explore the efficacy of IAA-Na as a feed additive. A total of 192 Danzhou chickens (50 weeks old) were randomly assigned to 2 groups of 96. The diets for the treatment group consisted of the basal diets, supplemented with IAA-Na (200 mg/kg). The formal feeding trial lasted for four weeks. The results showed that the feed supplemented with IAA-Na not only increased the laying rate ( Eggs are an important source of nutrients for humans. Although egg production is one of the most efficient industries in animal production nowadays, there remains great potential for further advancement. Therefore, improving the health status of poultry, improving laying performance and prolonging the peak production period have become a research field of great concern. A large number of antibiotic growth promoters are being used on laying hens to reduce the occurrence of diseases and improve the performance of laying hens . HoweverThe effects of plant hormones on various aspects of plant growth and development have been widely studied and commercialized. Previous studies have shown that plant hormones, such as gibberellin  and daidThe aim of this study was to test the effects of dietary IAA-Na supplementation on the laying performance, egg quality, ovary tissue morphology, intestinal tissue morphology, serum biochemical parameters and hormone levels of Danzhou chickens, as well as provide a theoretical basis for developing IAA-Na as a potential feed additive.All procedures and the use of animals in this experiment were carried out in accordance with the Hunan Normal University Animal Ethics Committee guidelines (AEC number 2019/230).A total of 192 Danzhou hens (50 weeks old) housed in wire cages were randomly allotted to 2 groups of 96. Each group was further divided into six replicate blocks of 8 cages with 2 hens per cages. The diets for the treatment group consisted of basal diets  supplemeThe health condition and laying performance were assessed daily. At the end of the trial, a single healthy laying hen was randomly selected from each group replicate, with 6 in each group, for a total of 12 hens, which were then sacrificed. Blood samples were collected from the axillary vein into vacuum tubes containing coagulant. After centrifugation, serum was collected and stored at −80 °C. The intestinal samples were fixed with a 4% formaldehyde-phosphate buffer and stored at room temperature for histological examination. Specimens of cross-sections of the intestinal segments were embedded in paraffin wax. The samples were then sectioned to a thickness of 5 mm and stained with hematoxylin and eosin. All tissue sections were determined under a microscope, using an image processing and analysis system . The villus height (VH), crypt depth (CD) and villus width (VW) of each intestine were measured by Program Image-pro Plus 6.0.Egg production as well as the egg mass and feed intake were recorded to calculate the average total egg weight, average laying rate, average daily feed intake (ADFI) and feed:egg ratio (grams of feed consumed per gram of egg) during the first two weeks after the formal experiment. At the end of the second week of the trial period, two eggs were randomly selected from each repetition to evaluate the egg quality and cholesterol content. The cholesterol content of the egg yolk was determined using a kit from the Nanjing Jiancheng Institute of Biological Engineering.An automatic biochemical analyzer was used to detect the serum biochemical indicators of the laying hens, including the total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total protein (TP), albumin (ALB), alanine aminotransferase (ALT), as well as the aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activity and the triglyceride (TG), glucose (Glu), calcium (Ca) and urea nitrogen (BUN) contents. The total antioxidant capacity (T-AOC), catalase activity (CAT), superoxide dismutase activity (SOD) and malondialdehyde (MDA) contents in the serum were assayed by using commercial kits . The concentrations of the serum hormone parameters, including estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), were also assayed using Nanjing Jiancheng Bioengineering Institute assay kits .p ≤ 0.05 and highly significant at p ≤ 0.01, unless otherwise stated.Data analyses were performed by an independent-sample T-test using SPSS 20.0. Data were presented as means with a standard error (means ± SEM). Differences were considered as statically significant at p < 0.05), but also significantly reduced the feed:egg ratio (p < 0.05).The laying performance of hens plays a major role in the economic benefits of farmers. As shown in p < 0.1). The ratio of the egg yolk is known as an important indicator to measure the nutrition of eggs, and increasing the ratio of egg yolk is equivalent to increasing the overall nutritional level of eggs [Eggs are an important source of nutrients for humans, and it is well known that their composition can be modified through the manipulation of laying hen diets . As show of eggs .Antioxidative stress is one of the important factors affecting the performance and egg quality of laying hens. As shown in p < 0.05) and trended to significantly increased LH levels (0.05 < p < 0.1). However, there was no significant difference in the serum FSH concentrations. The variation of laying rates was mainly determined by the hypothalamic–pituitary–gonadal axis [The serum hormone level has been considered a sensitive indicator of laying performance . As showdal axis ,22. Prevdal axis . The impdal axis . It was p > 0.05) in the p < 0.05). The relationship between serum ALP and egg production remains obscure. The opposite relationship between dietary Ca and serum ALP has been revealed [Biochemical indicators in the blood can be used to display the health status of hens. No significant differences in ALB, AST, TP, BUN, TG, CHOL, HDL, LDL, GLU, ALB or Ca were found among the treatment group and the control group (revealed . The serrevealed . The valThe dietary IAA-Na had no significant effect on the intestinal tissue morphology and structure of Danzhou chickens .This study was conducted to investigate the effects of IAA-Na inclusion in diets on the egg production performance, egg quality, intestinal tissue morphology, serum hormone levels and biochemical parameters of Danzhou chickens. The results showed that the feed supplemented with IAA-Na had significant beneficial effects on the laying rate and the secretion of reproductive hormones. According to our findings, IAA-Na may be considered as a potential feed additive to improve the laying performance of hens. However, since this experiment is preliminary an exploration experiment with a relatively short experimental period, a longer experiment period and larger scale experiments need to be performed in the future.


We aimed to investigate if the effectiveness of Gla‐300 is reproducible in real‐world settings.Randomized controlled trials have shown that insulin glargine 300 U/mL (Gla‐300) has a more stable and prolonged glucose lowering effect among patients with type 2 diabetes (T2DM) compared to insulin glargine 100 U/mL (Gla‐100), resulting in a reduced risk of hypoglycaemia while maintaining a similar efficacy of lowering HbA1c levels, body weight and insulin dose were calculated from baseline period and over a follow‐up period of 180 days. Documented hypoglycaemia events were also explored.In this retrospective cohort study, data from a large state‐mandated health organization were used to identify adult T2DM patients who were previously on insulin and initiated Gla‐300 therapy between 6/ 2016 and 12/2017. Changes in HbA1c was 8.7 ± 1.6% and 42.5% were females. Among all patients with HbA1c measurement during follow‐up (n = 1508), HbA1c was significantly reduced by −0.6%  from baseline, with a significant reduction in body weight .A total of 1797 patients were included in this study with a mean age of 64.2 (SD = ±11.0y), baseline HbAP = .04) reduction of 40.5% in patients with hypoglycaemia events was recorded during follow‐up period, from 2.1% (n = 37) at the baseline period to 1.2% (n = 22).Additionally, a significant (This real‐world study supports evidence from RCTs regarding the effectiveness of Gla‐300 among T2DM patients by improving glycaemic control. In this real‐world study, the effectiveness and safety among 1797 type 2 diabetes patients were investigated. The article provides evidence that insulin glargine 300 is effective in reducing blood glucose levels without increasing body weight or hypoglycaemic events. This insulin is a new formulation of insulin glargine with a more stable and prolonged glucose lowering effect compared to insulin glargine 100 U/mL .In June 2016, insulin glargine 300 U/mL  decreasing the risk of hypoglycaemia for nocturnal hypoglycaemia events in patients with T2DM between 6 and 12‐month post‐treatment period in patients previously on basal insulin In the EDITION randomized clinical trial programme, glycaemic control and hypoglycaemia were evaluated by comparing the efficacy and safety of Gla‐300 versus Gla‐100 insulin in patients with T2DM. Gla‐300 was demonstrated its efficiency by lowering HbAFurthermore, in the head‐to‐head BRIGHT RCT, a 24 weeks treatment of Gla‐300 was compared to insulin degludec (IDeg) and demonstrated similar glycaemic control improvement, where Gla‐300 showed lower hypoglycaemic events during titration period.1c following 6 months of treatment with Gla‐300 insulin.Recently published real‐world retrospective and prospective evidence studies showed a significant reduction in HbAThe aims of this study are therefore to investigate the effectiveness and safety of a longer basal insulin, Gla‐300, in a real‐world setting to assist patients, clinicians and health care systems in making informed decisions on effective care and treatment for T2DM patients.22.1The study utilized de‐identified data from the Maccabi Healthcare Services (MHS) central computerized database, the second largest state‐mandated health provider in Israel, serving more than 2.2 million (25% of the population) members and is a representative sample of the Israeli population. This fully computerized database captures all information on patient interaction . Based on this information, MHS had developed daily updated registries for major chronic diseases, such as hypertension, cardiovascular diseases and diabetes in order to improve disease management and quality of care for MHS members. More than 180 000 patients were accounted for based on medication dispenses, laboratory measurements and diagnoses and defined as having diabetes. Specific inclusion criteria for the diabetes registry are available and are described elsewhere.2.21c measurement (last measurement within 180 days prior to index date). Patients who were not on insulin during baseline period were excluded from main analysis and were briefly described in the results. Baseline period was defined as 180 days prior to the index date and follow‐up period was defined as 180 days afterwards. Patients with continuality of less than year in MHS defined as having T1DM or with indication of pregnancy between 9 months prior to index date and 9 months after to end of study were excluded. Discontinuation was defined as the first time having a gap larger than 90 days between two dispenses dates, taking into account cover days.In this noninterventional retrospective cohort study, we identified adult MHS members (ages > 18 years) who initiated treatment with Gla‐300 from 1 June 2016 until 31 December 2017 (was defined as the index date), included in diabetes registry prior to index date and treated with Gla‐300 for at least 180 days. Additional inclusion criterion was having a baseline HbAReported hypoglycaemic events were based on any diagnoses documented through the MHS database and recorded per outpatient visitation or per hospitalization when necessary.Approval was obtained from the Institutional Review Board (IRB) and Ethics Committee of MHS for the purposes of accessing and analysing the data. Individual patient informed consent was not required because of the anonymized nature of the patient records.2.31c levels, blood lipids, antihyperglycaemic regimen and comorbidities (based on including in MHS registries prior to index date). Anthropometric measurements and laboratory measurements were defined as last measurement during baseline period, while antihyperglycaemic regimen was defined as having at least 1 medication containing the specific ingredient. Cardiovascular disease, hypertension CKD stage and cancer comorbidities were based on our highly validated chronic registries, while revascularization procedure (coronary artery bypass graft and percutaneous coronary intervention) was based on procedures conducted during baseline period.Study population was characterized at baseline and presented by patients' demographics, anthropometric measurements, HbAInternational Classification of Diseases version 9 (ICD‐9) codes: 251.0, 251.2, 962.3) during baseline and follow‐up periods were evaluated. Changes in HbA1c, weight and BMI were evaluated from baseline (last measurement during baseline period) and follow‐up measurement (closest measurement within 180 ± 90 days after index date). Changes in insulin dosage  were evaluated from baseline period and follow‐up period and during follow‐up period (0‐90 and 91‐180 days after the index date) among patients who were on insulin for at least 180 days prior to index date. The daily insulin dosage was evaluated by using information on actual dispenses, which included data on the amount of insulin dispensed in specific time frames.Differences in documented hypoglycaemia (based on recorded 2.4d) was calculated to assess the magnitude of change between baseline and follow‐up period as follows:Descriptive statistics for all baseline characteristics were presented as mean and standard deviation (SD) for continuous variables and as counts and percentages for categorical variables. For continuous variables, statistical analyses were performed by using the t test, or Wilcoxon‐signed rank test, as appropriate. Same procedures were used to compute means and percentages in the various subgroups of patients, as defined in the protocol. Standardized mean difference effect size  from 8.7 ± 1.6 to 8.1 ± 1.4. Higher reduction was observed among patients aged less than 65, patients with higher levels of baseline HbA1c and among patients who were on insulin for less than 5 years  and −0.1 , respectively).There were 1206 patients with valid body weight measurement during baseline and during follow‐up. Among them, statistical significance changes in body weight and in BMI were observed . When stratifying population by time on insulin, trends were similar; however, results were not statistically different. Among patients on insulin for <5 years prior to index date, six patients (7.8 per 1000) were reported with hypoglycaemic events during follow‐up compared to the 11 patients (14.3 per 1000) at baseline (P = .225). For those who were on insulin for over 5 years prior, 16 patients (15.6 per 1000) reported hypoglycaemic events at follow‐up in comparison with 26 (25.3 per 1000) at baseline (P = .096).During the study follow‐up period, a total of 22 patients reported hypoglycaemic events (12.2 per 1000) compared to 37 patients (20.6 per 1000) during the baseline period, representing a 40.5% reduction . Among these patients, the insulin daily dosage was increased during baseline and follow‐up periods by 7.8  and 0.3  units for basal and other insulin (mainly fast acting insulin), respectively. During the follow‐up period, both basal and other insulin (mainly fast acting insulin) dosage were decreased by −3.8  and −1.0  units per day for basal and other insulin, respectively, starting from the first 90 days of treatment initiation and then following 90 days after  in HbA1C and an increase of 1.1 kg  in body weight were observed. No reported hypoglycaemia events were reported during baseline and follow‐up periods.An additional 607 patients were excluded from the main analysis as they were insulin naïve and therefore were evaluated separately. Their mean (SD) age at index date was 63.3 ± 12.4 years, 42.7% were female, and 57.0% were included in the diabetes registry for more than 10 years. At baseline, HbA41c levels and in reported hypoglycaemia events, with no increase in patients' body weight.The results of this real‐world data analysis indicate that treatment with Gla‐300 is associated with a significant reduction in both HbAAdherence to insulin therapy is critical to manage T2DM and to reduce the risk of complications. In an international cross‐sectional web survey of people with T2DM, those who discontinued treatment with basal insulin reported weight gain (48.4%) and hypoglycaemia 25.8%) as the main reason for discontinuation..8% as thOur study results are in accordance with a recent US study where severe hypoglycaemic events were up to 30% lower for a group patients who switched to Gla‐300 in comparison with first generation basal insulin analogues (Gla‐100 and detemir), where rates were similar with IDeg and Gla‐300 patient groups.1c levels, it was associated with a lower risk of glycaemic events, and it demonstrated no weight gain (participants in the Gla‐100 group had an average of 0.66 kg gain). 1c levels from the baseline period compared to the follow‐up period.A continued issue of the previously mentioned study was also published where researchers identified both daytime and nocturnal hypoglycaemic episodes with two comparison groups. The results indicated that Gla‐300 was just as effective at Gla‐100 in lowering HbA1c levels.In comparison with these results, a similar retrospective observational study suggested that patients switching to Gla‐300 from different basal insulin had significant lower daily doses of basal insulin, fewer hypoglycaemic events and significantly lowered HbA1c, body weight and reported hypoglycaemia events observed during follow‐up period were solely due to the larger Gla‐300 dosages or other concurrent factors. Another limitation in our study is lower amounts of hypoglycaemic events were observed compared to other research. This occurrence may be related to the fact that MHS data may not have a complete representation of all hypoglycaemic events that occurred; some events may not have been accounted for by patient reports.The study enjoys several strengths including a relatively large study population, no loss to follow‐up, cohort study design and a systematic data collection including data on repeated lab results, clinical history and purchased medications. Some limitations should be also discussed. In the current analysis, we did not have a comparison group; therefore, we are unable to assess if the changes in HbAA third limitation is therefore a potential surveillance bias where patients put on new insulin are more likely to attend clinician offices and report hypoglycaemic episodes. However, such bias would have resulted in an increase in hypoglycaemia rate during follow‐up period. Furthermore, our last limitation is the calculated dosage form of insulin based on purchases; we do not know the exact amount of insulin injected to the patients, but there was access to the amount dispensed at baseline and at follow‐up periods. From this information, the daily dosage of insulin was calculated.In conclusion, this real‐world study corroborates the findings of previous RCTs demonstrating the effectiveness and safety of Gla‐300 insulin among patients with T2DM.This work was funded by Sanofi. Cheli Melzer Cohen, Tamar Banon, Varda Shalev and Gabriel Chodick have nothing to declare.CMC, TB, VS and GC contributed to the development of the study concept, study design and interpretation of the data. CMC contributed to data collection and analysis. CMC, TB and GC contributed to writing the manuscript. VS contributed to the critical review and revision of the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work.


Nature Communications 10.1038/s41467-019-11181-1, published online 19 July 2019.Correction to: The original version of this Article contained an error in Fig. 5 and Supplementary Fig. 12, in which the colours of the bar plots at the top of the heatmaps were incorrectly given, leading to incorrect mapping of the plots to the corresponding dataset based on the dataset legend. which replaces the previous incorrect version:This has been corrected in both the PDF and HTML versions of the Article.The correct version of Fig. 5 is: which replaces the previous incorrect version:. The HTML has been updated to include a corrected version of the Supplementary Information.The correct version of Supplementary Fig. 12 is:


Nature Communications 10.1038/s41467-020-17051-5, published online 3 July 2020.Correction to: ZCCHC12, +Y: EIF1AY, −X: GABRA3, +21: PCP4, -22q11: MAPK1, -11p13: TRIM44.” The correct version states “For example, the most extreme ranking CNV region gene relative to anatomical change in each CNV was: +X: ZCCHC12, +Y: EIF1AY, −X: GABRA3, +21: PCP4, -22q11: SLC7A4, -11p13: TRIM44.”The original version of this Article contained an error in the “Results” section, which incorrectly read “For example, the most-extreme ranking CNV region gene relative to anatomical change in each CNV was; +X: The original version of this Article contained an error in the “Results” section, which incorrectly read “MS increases in VCFS syndrome (-22q11) and MAPK1 expressing inhibitory neurons.” The correct version removes this sentence.The original version of this Article contained an error in Figs. 1b and 2d.y-axis range was 0e+00 to 3e−04, the x-axis range was −3000 to 3000, and the values for the PRAND-Trans and PRAND-Cis were 0.0094 and 0.0018, respectively.In the original version of Fig. 1b, the graph next to the Chr22 schematic reported the following: the The correct version of Fig. 1 is:which replaces the previous incorrect version:y-axis reported the following class of cells: OPC, Oligo, Neuro-In, Endo, Astro. Among the reported genes in the plot, MAPK1 is included.In the original version of Fig. 2d, the The correct version of Fig. 2 is:which replaces the previous incorrect version:All the errors above have been corrected in both the PDF and HTML versions of the Article.The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which the CVN genes tab, column A (del22q11.2) reported 20 genes in total: DGCR6, PRODH, STK22B, ES2EL, GSCL, SLC25A1, ZDHHC8, RANBP1, HTF9C, DGCR8, T10, ARVCF, COMT, TBX1, GP1BB, UFD1L, HIRA, SNAP29, TMEM191A, MAPK1.The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction.Supplementary Data 1


Nature Communications 10.1038/s41467-020-15560-x, published online 20 April 2020.Correction to: The original version of this article contained several errors, listed below, resulting from an update to the Y chromosomal haplogroup assignments during the final revisions. These do not affect the results or conclusions of the work. which replaces the previous incorrect version: This has been corrected in both the PDF and HTML versions of the article.The original version of this article contained an error in Fig. 4, several labels of ‘Y na’ have now been replaced by ‘Y’ in the corrected figure, the colour of ‘mt’ has also been changed in the corrected figure. The correct version of Fig. 4 is below: The original version of the Supplementary Information associated with this article contained an error in Supplementary Note The original version of the Supplementary Table 5 in the Supplementary Information had several errors in column 16, as well as an error in column 9 (line 15). A line has also been added on line 31. The HTML has been updated to include a corrected version of the Supplementary Information; the original incorrect version can be found as Supplementary Information associated with this Correction.The original version of the Supplementary Data 1 file contained several errors in columns G, H and X. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found associated with this Correction.Supplementary Information


Researchers have begun delivering mindfulness and aerobic exercise training concurrently on the premise that a combination intervention will yield salutary outcomes over and above each intervention alone. An estimate of the effect of combination training on chronic psychosocial stress in a nonclinical population has not been established. The objective of this study was to establish protocol feasibility in preparation of a definitive RCT targeting healthy individuals, and to explore the preliminary effect of combination training on reducing chronic psychosocial stress in this population.Twenty-four participants were allocated to a single-arm pre-post study and subjected to 16 weeks of concurrent mindfulness psychoeducation and aerobic exercise training. Feasibility criteria were collected and evaluated. Within-group changes in chronic psychosocial stress, mindfulness, emotion regulation, and cardiorespiratory fitness were also assessed. Primary analyses were based on 17 participants.dpretest = −0.56, 95% CI ). With regard to secondary measures, there was an increase in the use of cognitive reappraisal, and a reduction in use of maladaptive emotion regulation strategies. We are insufficiently confident to comment on changes in mindfulness and aerobic capacity Retention rate, response rate, recruitment rate, and sample size analyses indicate a definitive trial is feasible for detecting most effects with precision. There was also a decline in our primary dependent measure of chronic psychosocial stress . Retrospectively registered December 9, 2019.ANZCTR . A growing body of research has implicated psychosocial stress with a range of deleterious health outcomes. At an individual level, this includes a greater incidence of depressive symptoms, anxiety, and a decline in wellbeing , 2, as wFew studies have examined the effect of combining aerobic exercise and mindfulness-based training on mental health outcomes. To our knowledge, an estimate of the range and direction of the effect of a combination intervention on chronic psychosocial stress in a nonclinical population, specifically, is also absent from the literature. This pilot and feasibility study was conducted to guide future research on combination training with respect to its effect on chronic psychosocial stress, as well as its potential mechanisms. To this end, we conducted a single-arm pre-post study in preparation for a future randomized controlled trial (RCT). This study comprised an aerobic exercise and mindfulness-based intervention delivered concurrently over 16 weeks, and was designed as a prevention-focused intervention to be used by healthy individuals rather than those presenting with specific mental health risk factors. In the following sections, we discuss the evidence and theorized mechanisms that link mindfulness, aerobic exercise, and combination training to salutary mental health outcomes. We conclude with our study rationale.Mindfulness is a mental practice that draws on contemplative traditions and evidence-based research, and which has been adopted as a therapeutic approach to promote mental and physical health . In a cld, reported in each publication). This includes a reduction in psychosocial stress , anxiety , and depressive symptoms  ) ) ) . There i −0.76]) .Aerobic exercise can be implicated in improvement in cardiorespiratory fitness, which in turn is associated with widespread physiological effects that enhance cardiovascular health. For example, this includes improved glucose tolerance, reduced low-grade chronic inflammation, and a lower prevalence of hypertension . With reSelf-reports of physical activity are a subjective construct that measure behaviors that may be associated with cardiorespiratory fitness. These constructs are often implicated in a reduction in psychosocial stress and the prevalence of stress-related disorders , 25. HowIn the exercise physiology literature, two objective measures include maximal aerobic capacity  economy , 27. \dol health , 29, whil stress . MeanwhiImprovements in mental health outcomes are often observed in interventions that make use of mindfulness in combination with physical activity . One recUnfortunately, such studies tend to examine physical activity broadly, rather than through structured aerobic exercise conducted at a frequency and intensity sufficient to maintain or improve cardiorespiratory fitness. For example, in the above study, physical activity comprised a combination of (unspecified) aerobic and strength exercises. The authors also relied on a subjective measure of intensity  rather than objective assessments via One exception is mental and physical (MAP) training: an intervention involving focused-attention meditation in combination with aerobic exercise   and wave 2 . Recruitment was conducted across a 1-month time period prior to the intervention period of each wave. Pre-test (T0) and post-test (T1) measures were obtained 1 to 4 weeks prior to and after the intervention period. Participants were predominantly postgraduate and undergraduate students from a variety of disciplines, and these periods were selected to correspond to low-stress periods in the academic calendar . Responses to self-report measures were collected online via Qualtrics , and assessments of cardiorespiratory fitness were collected in an exercise laboratory at Monash University. Descriptions of each assessment are provided in the “This study was conducted across two waves: wave 1  pregnancy or suspected pregnancy. All participants reported no engagement in regular running training or meditation practice within 6 months prior to the first assessment.Participants self-selected into the study by responding to an advertisement posted to online community groups based in Melbourne, Australia. These advertisements described the study as a mental and physical training program for stress management. Young adults between the ages of 18 and 35 years were targeted to reduce age-related variance in assessment responses, and because this age group was considered less likely to experience an adverse exercise-related incident. Exclusion criteria were as follows: (1) age not within 18–35 years, (2) prior completion of an endurance event equivalent to a half-marathon (21.1 km), (3) prior completion of a formal meditation program, (4) current diagnosis of a neurological or mental disorder, (5) current diagnosis/history of chronic pain or musculoskeletal conditions, (6) current diagnosis/history of chronic disease of any kind, (7) current diagnosis of a heat or cold disorder, (8) current use of medication that influences the neuroendocrine or immune system, (9) current injury of any kind , (10) current diagnosis of an infectious disease, (11) BMI ≥ 30 kg/mPilot study methodologists suggest that 15–20 participants per cell of a pilot research design can provide a reasonable estimate for most medium to large standardized effects as defined by Cohen , withoutThe training program involved a mindfulness-based intervention (MBI) and aerobic exercise training program completed concurrently over a period of 16 weeks. Each component of the program is described in detail in Briefly, the MBI comprised eight group psychoeducation and reflection activity sessions (55 min each) and formal focused-attention meditation practice . All group training sessions followed a similar structure  Table 1 The exercise program comprised three runs per week over 16 weeks following a half-marathon training schedule  Table 3,http://connect.garmin.com).Adherence requirements for the MBI were that participants attend at least 50% of the group psychoeducation sessions and complete at least 50% of the formal meditation target . Compliance was monitored through attendance records and self-report of formal practice in an online spreadsheet . Adherence requirements for the exercise program were that participants complete at least 50% of all prescribed running sessions . Additional measures of dosage included total running distance (km), total running time (h), and mean exercise intensity  individuals reported a mean dropout rate of 17.0% . HoweverThis measure was quantified as the percentage of participants providing full pre-test (T0) and post-test (T1) data points across the study. An assessment response rate of 95% for our primary dependent variable  was considered an acceptable criterion to recommend proceeding with a definitive trial.n = 80 per trial). This meant that the total maximum number of participants across 10 trials would be n = 200 per treatment arm .Recruitment rate was quantified as the percentage of all applicants who satisfied the inclusion criteria and agreed to participate. The required sample size was computed for T1–T0 gain scores on the chronic psychosocial stress measure (within-group changes), as well as for hypothetical differences between independent arms of a confirmatory trial (between-group changes) . RecruitαT0 =.93; αT1 =.80).The Perceived Stress Scale (PSS-10)  was the αT0 =.87, αT1 =.79; anxiety αT0 =.64, αT1 =.81; stress αT0 =.64, αT1 =.73; WHO-5: wellbeing αT0 =.86, αT1 =.83).To provide converging evidence that changes in this scale were reliable, we additionally assessed several secondary outcomes that should covary with PSS-10 scores. This included depression, anxiety, and stress symptoms using subscales of the Depression Anxiety Stress Scale (DASS-21) , and subαT0 =.86; αT1 =.85).The Mindful Attention Awareness Scale (MAAS)  was usedαT0 =.91; αT1 =.93).The cognitive reappraisal subscale of the Emotion Regulation Questionnaire (ERQ-CR)  was usedMaladaptive rumination (past-oriented) and worry (future-oriented) were used to assess the disposition to engage in self-focused, repetitive, and perseverative thought processes that maintain negative affect during times of psychosocial stress .αT0 =.88; αT1 =.86). Worry was examined using the 16-item Penn State Worry Questionnaire (PSWQ) , p =.024; see Fig. pR =.020). Twelve participants reported a reduction on the PSS-10, and five participants reported no change or an increase. In common language, there was a 72.7% chance that a participant picked at random would report a lower PSS-10 score following the study compared to before the study. Because seven participants dropped out of the study, we also assessed whether survivorship bias was a threat to the validity of this test result. To this end, we conducted a last observation carried forward analysis which included the last known state of the subject in the analysis under the assumption they would report no change had they completed the study. This analysis yielded a small decline in effect size magnitude, but the test remained statistically significant .There was an overall reduction in our primary dependent measure of chronic psychosocial stress  and depressive symptoms , and an overall improvement in global wellbeing . These effects were also robust. However, we are insufficiently confident to comment on the direction of change in anxiety . A robust test did not change this conclusion.Reductions in PSS-10 were corroborated by improvement in several secondary stress measures. There was an overall reduction in stress symptoms . However, these data are compatible with a 0.17 unit decrease in mindfulness as well as a 0.60 unit increase in mindfulness. Therefore, we are insufficiently confident to comment on the direction of this change. A robust test did not change this conclusion.Participants reported an overall increase in dispositional mindfulness . This effect was robust. There was a mean reduction in the use of maladaptive rumination . However, this effect was not robust (pR =.051). Finally, there was an overall reduction in the disposition to worry . This effect was also robust.There was a mean improvement in the use of cognitive reappraisal . However, we are insufficiently confident to comment on the overall direction of this change. A robust test did not change this conclusion.There was a negligible change in ps <.001; see Summarized results of aerobic economy analyses are given in Table F = 7.57, p =.007) and velocity  = 209.18, p <.001). We are insufficiently confident to comment on the presence of an interaction  = 1.20, p =.316). A pairwise (T1–T0) contrast of the main effect of time indicated that, on average, there was a change in oxygen cost across all velocities of There was a statistically significant main effect of time  = 16.09, p <.001) and velocity  = 381.90, p <.001). We are insufficiently confident to comment on the presence of an interaction at a.05 threshold  = 1.90, p =.135). A pairwise (T1–T0) contrast of the main effect of time indicated that, on average, there was a decrease in M= −4.37, 95% CI ; see Fig. There was a statistically significant main effect of time  = 8.13, p =.005) and velocity  = 238.43, p <.001). We are insufficiently confident to comment on the presence of an interaction  = 0.26, p =.855). A pairwise (T1–T0) contrast of the main effect of time indicated there was, on average, a decrease in heart rate across all velocities  = 13.93, p <.001) and velocity  = 237.52, p <.001). We are insufficiently confident to comment on the presence of an interaction  = 0.53, p =.666). A pairwise (T1–T0) contrast of the main effect of time indicated there was, on average, a decrease in RPE across all velocities following the study  training in healthy individuals . This inper treatment arm of an RCT  may represent a reasonable estimate of recruitment feasibility. Based on our sample size analysis, precise estimation of within-group changes in PSS-10 gain scores requires between 89 (δz = −0.60) and 186 (δz = −0.37) paired observations. A precise estimate of differences in gain scores between each arm of an RCT will require between 84 (large difference: δs = 0.80) and 1098  observations per cell. These calculations reflect a retention rate of 70.8%.The study recruitment rate was 53.3%. Across a 2-month recruitment period  and with a total of 45 applicants, this is indicative of a recruitment potential of 12 participants per month for the combination trial arm of a future RCT. With an expanded research team for recruitment, assessment, and facilitation of the intervention, a recruitment potential of 12 participants per month n = 20 per treatment arm  across 10 trial repetitions over 5 years, the total maximum number of participants is n = 200 per treatment arm . A recruitment rate of n = 12 per treatment arm per month is therefore feasible to fill each trial run following the second month of the protocol (estimated sample at month 2: n = 24 per treatment arm) with a start date at month 3 following assessments. Assuming recruitment continues ongoing each month, each trial start date will satisfactorily attain n = 20 participants per treatment arm. Assuming a retention rate of 70.8%, a total recruitment of n = 200 per treatment arm by the end of the protocol is satisfactory to detect within-group changes in PSS-10 gain scores (with precision) as low as δz = −0.37, and between-group difference in gain scores (with precision) up to δs = 0.50. Differences in gain scores of δs = 0.40 will be detectable with 80% power, but these effects may have lower than desired precision. Estimation of very small differences in gain scores  is infeasible. Based on these criteria, we conclude that there is sufficient assurance of protocol feasibility to conduct a confirmatory RCT under the above assumptions and detect most effects precisely .Under the assumption that an RCT is only feasible with Of course, however, these above assumptions do not take into consideration additional uncertainties that may impact the capacity of a single research group to conduct a confirmatory trial. This includes uncertainty in future economic conditions, finances, and resource availability. Therefore, this confirmatory trial may be more appropriately suited to a large multisite clinical trial that spreads risk of conducting 10 trial repetitions across multiple research groups. This approach has the additional benefit of evaluating the trial treatment effect across large and heterogeneous populations in varied treatment settings, and will therefore mitigate multiple threats to the validity of observed effects.Additional considerations for a future definitive trial may also include ensuring that the effects of the intervention are not driven by differences in baseline stress levels or baseline cardiorespiratory fitness levels that differ across groups. While randomization ensures that these differences, on average, should be equal across treatment arms, one option would be to perform block stratified random assignment on factors that might bias results for each trial repetition. With regard to baseline stress, this could include block randomization based on a simple one-item question about overall stress levels that is embedded in the initial application to the intervention, as recommended by Shadish and colleagues . This isA further consideration for a future definitive trial may be to broaden the trial eligibility criteria to allow findings to be more generalizable. Currently, the eligibility criteria only allowed for young and relatively healthy adults as part of a prevention-focused intervention. While this population was the target of interest, it may not be the population that needs this intervention most. However, any deviation from the methods and protocol of this study may require further pilot testing prior to performing a definitive trial.d = −0.74   . If this7,−0.41] . Based oFurther support for the validity of a reduction in PSS-10 scores comes from changes in our secondary mental health outcome measures. This included a reduction in stress and depressive symptoms, and an improvement in global wellbeing. Indeed, mean improvement in wellbeing was of a magnitude of approximately 10 percentage points on the WHO-5 scale, which is indicative of a clinically relevant improvement with respect to the scale . Howeversomewhat frequently to somewhat infrequently, in response how frequent participants reported an absence of attention to or awareness of present moment experiences. However, the confidence intervals on these data are also compatible with a partial unit decrease in mindfulness, as well as a greater than half unit increase in mindfulness. Therefore, we are insufficiently confident to comment on the direction of change of this effect in the present study.Participants reported an overall increase in dispositional mindfulness. This represented a partial unit change from d = 0.60, 95% CI . The small magnitude of change in mindfulness in the present study is therefore unexpected . However, it must be noted that measures of mindfulness are not consistently reported for MBI interventions [Dispositional mindfulness represents the quality of attention and awareness with which one attends to the present moment experience, and is considered a core mechanistic component of how MBIs exert their effects , 60. In ventions .neither agree or disagree to agree, in response to questions evaluating the disposition to use this emotion regulation strategy. Evidence from intervention studies [pR =.051 . Notably, there were no outliers in this variable and no evidence of a strong deviation from normality, meaning that the standard  test may be a more appropriate reflection of the data. This interpretation is strengthened by observation that Alderman and colleagues [Participants reported an overall increase in use cognitive reappraisal. In descriptive terms, this represented a unit change from  studies , 63 demo studies , althoug studies . Beyond  studies . Howeverlleagues  reportedFinally, with respect to cardiorespiratory fitness, there was a negligible overall change in protocol  are mostprotocol . This inHowever, there were improvements in aerobic economy across steady-state  exercise velocities in our subgroup analyses. This included a reduction in absolute oxygen cost, relative oxygen cost, heart rate, and perceived exertion. Improvement in indices of aerobic economy is indicative of a cascade of metabolic and cardiopulmonary effects that result in better use of oxygen  relative to a given exercise intensity. This includes more efficient cardiorespiratory responses , thermoregulation , and substrate metabolism . The relNotable strengths of this study included the following: (1) use of a full mindfulness psychoeducation program in contrast to a single mindfulness component ; (2) use of an aerobic exercise program that prescribed exercise of a duration, frequency, and intensity that has been clinically shown to improve or maintain aerobic fitness; (3) complete individualization of aerobic exercise prescriptions through objective cardiorespiratory fitness assessments; (4) comprehensive monitoring of training compliance through GPS data; (5) provision of a detailed methodological protocol that is presented here in sufficient detail to allow for replication; and (6) extensive quantification of multiple protocol feasibility criteria.However, the clearest limitation is that a single-arm study design presents with difficulty in distinguishing between the effects of the treatment and several threats to validity. For example, the observed reduction in chronic psychosocial stress may be an effect of intervention exposure, but it may also be partly explained through a placebo effect, maturation, test effects, or regression to the mean. However, regression to the mean may be a less plausible explanation as this study was designed to coincide with low-stress periods with respect to our study population. Further limitations include that effects have been estimated with low precision . For these reasons, we must emphasize that all results should be treated as preliminary and for readers to avoid exaggerated generalizations of findings. Within the present study, the single-arm research design was an efficient use of limited resources to examine most uncertainties that may arise in each arm of a definitive trial, and to determine feasibility estimates for such a trial. Finally, it is important to note that the results of this study are mostly generalizable to nonclinical populations of young, healthy, and university educated adults.Retention rate and assessment response rate were acceptable, and a sample size analysis indicated that it is feasible to detect most effects in a definitive trial with precision. We recommend that a definitive randomized controlled trial is feasible and should proceed.Additional file 1 Supplementary Materials.Additional file 2 Supplementary Results.


This study revealed that higher proportions of women than men showed preference for most attributes of cassava flour quality. Kwon was 26% (women) and 15% (men). Ease of peeling and stickiness of Kwon were key processing traits. Heap fermented flour had higher pasting temperatures, but lower viscosities than sun‐dried flour, and had lower amylose content compared to fresh root starch. The results demonstrate the importance of gender sensitive participatory evaluation of breeding materials, in tandem with physicochemical evaluation during selection of best possible candidate breeding lines.Cassava breeding programmes in Uganda do not currently select materials based on flour making quality, explaining in part the low adoption rates of many released varieties. In this study, we describe end user trait preferences, processing qualities and physicochemical properties of cassava flour. We found that higher proportion of women than men showed preference for most attributes of cassava flour quality evaluated in this study. Preference for colour was 66% and 52% among women and men, respectively, while that for stickiness of  Manihot esculenta Crantz) is a major root crop grown and consumed in the tropical and sub‐tropical regions of the world  were used to collect quantitative data from Sixty‐two men and Sixty‐six women engaged in cassava production. Purposive sampling ensured respondents were from a range of ages, as well as balancing the number of women and men consulted.Eight focus group discussions (FGDs) led by a facilitator and guided by preset questions were used to collect qualitative data. Moreover, questionnaires  was formed.Eighteen women from the community were each supplied with cassava roots harvested from four genotypes, to process flour at their homes using the traditional heap fermentation practice with nine women processing roots from one replicate. In each woman’s home, cassava roots were peeled and spread on tarpaulin under the sun. Cassava roots were left under the sun for four to six hours to reduce the moisture content of the roots without complete drying of the roots. Thereafter, whole partially dry roots were heaped in a corner inside the house and covered with polythene sacs. The roots were placed on bare ground in heaps to ferment. Fermentation ended within two to three days, when roots were soft and covered with black moulds. The fermented roots were cleaned with knives to remove black moulds. Clean roots were broken into small pieces by pounding them in a local motor with a local pounding pestle called Kwon (thick paste processed from heap fermented cassava flour). Consequently, a structured questionnaire with questions rated by a scale customised to the Likert scale  and stickiness of cassava et al., et al., et al., Physicochemical analyses were done for heap fermented, sun‐dried and fresh root starch samples. Fresh root starch was prepared following a method described by  indicated that gender and variety processed were independent implying that selection of a variety was largely influenced by its inherent attributes.The study showed that most popular cassava landraces processed by both men and women in Zombo are Nyapamitu, Nyarodota and Nyaronega, all of which are bitter Table . Ferment…fermenting removes bitterness, it gives cassava flour a nice smell and the ability to make sticky food… Cassava roots are commonly processed into flour following a stepwise procedure. In Zombo, the procedure of processing roots into flour was by heap fermentation. Apart from reducing levels of HCN, heap fermentation was purported to improve organoleptic attributes of cassava flour.et al. , respectively. Despite this, heavy flour and high dry matter content were preferred by more men than women, although they did not meet the cut‐off point. These flour quality attributes preferred by women and men are linked to cassava Kwon. This finding highlights both the importance of Kwon to the Zombo community and need for participatory product‐based evaluation and selection.A range of attributes were mentioned by men and women in describing their perception of high quality cassava flour Fig. . ConsideP < 0.05) for ease of peeling and stickiness of Kwon . The ability of cassava flour to form a ‘thick paste’ referred to as ‘stickiness’ is a critical starch pasting property whose differences are reported to be genotype dependant   Table . This fiKwon .5 (TableLactobacillus fermentum) which is a key organism involved in fermentation  than that from Nyacharitas. The relationship between amylose content, pasting properties and stickiness of cassava Kwon, if further investigated, could be key in evaluating genotypes for the important attribute – stickiness of cassava Kwon.Results for amylose content are presented in Table et al.  while Nyacharitas had the lowest swellability of 30.20 g of water/g of starch ; Data curation (lead); Formal analysis (lead); Investigation (lead); Methodology ; Writing‐original draft (lead); Writing‐review & editing (lead). RoberT Sezi Kawuki: Conceptualization ; Formal analysis (supporting); Funding acquisition (supporting); Investigation (supporting); Methodology ; Project administration (lead); Resources (supporting); Supervision (lead); Writing‐review & editing . Florence Birungi Kyazze: Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology ; Supervision ; Writing‐review & editing . Williams Esuma: Data curation (supporting); Formal analysis ; Methodology (supporting); Writing‐original draft (supporting); Writing‐review & editing . Enoch Wembabazi: Data curation ; Formal analysis ; Investigation (supporting); Writing‐review & editing . Dominique Dufour: Conceptualization ; Formal analysis ; Investigation (supporting); Methodology ; Supervision ; Writing‐review & editing . Ephraim Nuwamanya: Conceptualization (supporting); Data curation (supporting); Formal analysis ; Investigation (supporting); Methodology ; Supervision ; Writing‐review & editing . Hale Tufan: Conceptualization (lead); Formal analysis (supporting); Funding acquisition (lead); Investigation (supporting); Methodology (lead); Project administration (supporting); Resources (lead); Writing‐original draft (supporting); Writing‐review & editing .Men and women were asked for their consent to participate and were assured of the anonymity of the information they gave. In addition, introduction of the study and its purpose was made. Indeed, respondents were free to cancel the interview any time if they lost interest to participate.https://publons.com/publon/10.1111/ijfs.14940.The peer review history for this article is available at