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Journal Cover F1000Research
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  This is an Open Access Journal Open Access journal
   ISSN (Online) 2046-1402
   Published by Faculty of 1000 Homepage  [1 journal]
  • Bibliometric analysis of Oropouche research: impact on the surveillance of
           emerging arboviruses in Latin America [version 2; referees: 2 approved]

    • Authors: Carlos Culquichicón, Jaime A. Cardona-Ospina, Andrés M. Patiño-Barbosa, Alfonso J. Rodriguez-Morales
      Abstract: Given the emergence and reemergence of viral diseases, particularly in Latin America, we would like to provide an analysis of the patterns of research and publication on Oropouche virus (OROV). We also discuss the implications of recent epidemics in certain areas of South America, and how more clinical and epidemiological information regarding OROV is urgently needed.
      PubDate: 2017-03-17T17:06:46Z
      DOI: 10.12688/f1000research.10936.2
      Issue No: Vol. 6 (2017)
  • Insight into skin cell-based osteogenesis: a review [version 1; referees:
           2 approved]

    • Authors: Tingliang Wang, Lian Zhu, Ming Pei
      Abstract: For decades, researchers have been fascinated by the strategy of using cell therapy for bone defects; some progress in the field has been made. Owing to its ample supply and easy access, skin, the largest organ in the body, has gained attention as a potential source of stem cells. Despite extensive applications in skin and nerve regeneration, an increasing number of reports indicate its potential use in bone tissue engineering and regeneration. Unfortunately, few review articles are available to outline current research efforts in skin-based osteogenesis. This review first summarizes the latest findings on stem cells or progenitors in skin and their niches and then discusses the strategies of skin cell-based osteogenesis. We hope this article elucidates this topic and generates new ideas for future studies.
      PubDate: 2017-03-17T15:34:07Z
      DOI: 10.12688/f1000research.10280.1
      Issue No: Vol. 6 (2017)
  • Recent advances in managing and understanding uveitis [version 1;
           referees: 3 approved]

    • Authors: Shih-Chou Chen, Shwu-Jiuan Sheu
      Abstract: Uveitis is a sight-threatening disease entity with intraocular inflammation that arises from various causes. It mainly affects working-age individuals and may lead to irreversible visual loss if not treated properly in a timely manner. This article reviews recent advances in the management and understanding of uveitis since 2014, including treatment with new immunosuppressive therapies that use biological agents, local therapy with steroid implants, and imaging studies for the evaluation of uveitis.
      PubDate: 2017-03-16T11:36:46Z
      DOI: 10.12688/f1000research.10587.1
      Issue No: Vol. 6 (2017)
  • How are base excision DNA repair pathways deployed in vivo? [version
           1; referees: 4 approved]

    • Authors: Upasna Thapar, Bruce Demple
      Abstract: Since the discovery of the base excision repair (BER) system for DNA more than 40 years ago, new branches of the pathway have been revealed at the biochemical level by in vitro studies. Largely for technical reasons, however, the confirmation of these subpathways in vivo has been elusive. We review methods that have been used to explore BER in mammalian cells, indicate where there are important knowledge gaps to fill, and suggest a way to address them.
      PubDate: 2017-03-16T10:02:41Z
      DOI: 10.12688/f1000research.10538.1
      Issue No: Vol. 6 (2017)
  • Heat remains unaccounted for in thermal physiology and climate change
           research [version 2; referees: 2 approved]

    • Authors: Andreas D. Flouris, Glen P. Kenny
      Abstract: In the aftermath of the Paris Agreement, there is a crucial need for scientists in both thermal physiology and climate change research to develop the integrated approaches necessary to evaluate the health, economic, technological, social, and cultural impacts of 1.5°C warming. Our aim was to explore the fidelity of remote temperature measurements for quantitatively identifying the continuous redistribution of heat within both the Earth and the human body. Not accounting for the regional distribution of warming and heat storage patterns can undermine the results of thermal physiology and climate change research. These concepts are discussed herein using two parallel examples: the so-called slowdown of the Earth’s surface temperature warming in the period 1998-2013; and the controversial results in thermal physiology, arising from relying heavily on core temperature measurements. In total, the concept of heat is of major importance for the integrity of systems, such as the Earth and human body. At present, our understanding about the interplay of key factors modulating the heat distribution on the surface of the Earth and in the human body remains incomplete. Identifying and accounting for the interconnections among these factors will be instrumental in improving the accuracy of both climate models and health guidelines.
      PubDate: 2017-03-15T15:12:41Z
      DOI: 10.12688/f1000research.10554.2
      Issue No: Vol. 6 (2017)
  • Cell-cell adhesion interface: rise of the lateral membrane [version 1;
           referees: 2 approved]

    • Authors: Vivian Tang
      Abstract: The lateral membrane plays an important role in the mechanical stability of epithelial cell sheet in steady state. In addition, the lateral membrane is continuously remodeled during dynamic processes such as cell extrusion, cytokinesis, and intercellular cell movement. In wound healing, the lateral membrane must be built from flat and spread cells that had crawled into the area of the wound. Thus, forming the lateral membrane is a phenomenon that occurs not only in development but also during homeostatic maintenance and regeneration of differentiated epithelial tissues.
      PubDate: 2017-03-15T13:40:17Z
      DOI: 10.12688/f1000research.10680.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding and preventing human
           papillomavirus-related disease [version 1; referees: 3 approved]

    • Authors: Karin Hellner, Lucy Dorrell
      Abstract: High-risk human papillomaviruses (hrHPV) are responsible for anogenital and oropharyngeal cancers, which together account for at least 5% of cancers worldwide. Industrialised nations have benefitted from highly effective screening for the prevention of cervical cancer in recent decades, yet this vital intervention remains inaccessible to millions of women in low- and middle-income countries (LMICs), who bear the greatest burden of HPV disease. While there is an urgent need to increase investment in basic health infrastructure and rollout of prophylactic vaccination, there are now unprecedented opportunities to exploit recent scientific and technological advances in screening and treatment of pre-invasive hrHPV lesions and to adapt them for delivery at scale in resource-limited settings. In addition, non-surgical approaches to the treatment of cervical intraepithelial neoplasia and other hrHPV lesions are showing encouraging results in clinical trials of therapeutic vaccines and antiviral agents. Finally, the use of next-generation sequencing to characterise the vaginal microbial environment is beginning to shed light on host factors that may influence the natural history of HPV infections. In this article, we focus on recent advances in these areas and discuss their potential for impact on HPV disease.
      PubDate: 2017-03-14T16:38:27Z
      DOI: 10.12688/f1000research.9701.1
      Issue No: Vol. 6 (2017)
  • What serial homologs can tell us about the origin of insect wings [version
           1; referees: 2 approved]

    • Authors: Yoshinori Tomoyasu, Takahiro Ohde, Courtney Clark-Hachtel
      Abstract: Although the insect wing is a textbook example of morphological novelty, the origin of insect wings remains a mystery and is regarded as a chief conundrum in biology. Centuries of debates have culminated into two prominent hypotheses: the tergal origin hypothesis and the pleural origin hypothesis. However, between these two hypotheses, there is little consensus in regard to the origin tissue of the wing as well as the evolutionary route from the origin tissue to the functional flight device. Recent evolutionary developmental (evo-devo) studies have shed new light on the origin of insect wings. A key concept in these studies is “serial homology”. In this review, we discuss how the wing serial homologs identified in recent evo-devo studies have provided a new angle through which this century-old conundrum can be explored. We also review what we have learned so far from wing serial homologs and discuss what we can do to go beyond simply identifying wing serial homologs and delve further into the developmental and genetic mechanisms that have facilitated the evolution of insect wings.
      PubDate: 2017-03-14T16:18:29Z
      DOI: 10.12688/f1000research.10285.1
      Issue No: Vol. 6 (2017)
  • Recent advances in treating Parkinson’s disease [version 1;
           referees: 2 approved]

    • Authors: Wolfgang H. Oertel
      Abstract: This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson’s disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) —a methodological challenge to be met in the future.
      PubDate: 2017-03-13T16:13:13Z
      DOI: 10.12688/f1000research.10100.1
      Issue No: Vol. 6 (2017)
  • Recent advances in Japanese encephalitis [version 1; referees: 4 approved]

    • Authors: Anirban Basu, Kallol Dutta
      Abstract: Japanese encephalitis is a flaviviral disease that is endemic to the South, Southeast Asia, and Asia Oceania regions. Given that about 60% of the world’s population (about 7.4 billion) resides in this region (about 4.4 billion), this disease poses a significant threat to global health. Active vaccination campaigns conducted in endemic countries have led to a decrease in the number of reported cases over the years. In this article, we strive to briefly highlight recent advances in understanding the role of microRNAs in disease pathology, focus on providing brief summaries of recent clinical trials in the field of Japanese encephalitis therapeutics, and review the current prophylactic strategies.
      PubDate: 2017-03-13T15:44:25Z
      DOI: 10.12688/f1000research.9561.1
      Issue No: Vol. 6 (2017)
  • C3 glomerulopathy [version 1; referees: 4 approved]

    • Authors: H. Terence Cook
      Abstract: C3 glomerulopathy is a recently defined entity that encompasses a group of kidney diseases caused by abnormal control of complement activation with deposition of complement component C3 in glomeruli leading to variable glomerular inflammation. Before the recognition of the unique pathogenesis of these cases, they were variably classified according to their morphological features. C3 glomerulopathy accounts for roughly 1% of all renal biopsies. Clear definition of this entity has allowed a better understanding of its pathogenesis and clinical course and is likely to lead to the design of rational therapies over the next few years.
      PubDate: 2017-03-10T09:58:55Z
      DOI: 10.12688/f1000research.10364.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding and managing gout [version 1; referees: 2

    • Authors: Talia F. Igel, Svetlana Krasnokutsky, Michael H. Pillinger
      Abstract: Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment.
      PubDate: 2017-03-10T09:31:52Z
      DOI: 10.12688/f1000research.9402.1
      Issue No: Vol. 6 (2017)
  • The cyanobacterial nitrogen fixation paradox in natural waters [version 1;
           referees: 2 approved]

    • Authors: Hans Paerl
      Abstract: Nitrogen fixation, the enzymatic conversion of atmospheric N (N2) to ammonia (NH3), is a microbially mediated process by which “new” N is supplied to N-deficient water bodies. Certain bloom-forming cyanobacterial species are capable of conducting N2 fixation; hence, they are able to circumvent N limitation in these waters. However, this anaerobic process is highly sensitive to oxygen, and since cyanobacteria produce oxygen in photosynthesis, they are faced with a paradoxical situation, where one critically important (for supporting growth) biochemical process is inhibited by another. N2-fixing cyanobacterial taxa have developed an array of biochemical, morphological, and ecological adaptations to minimize the “oxygen problem”; however, none of these allows N2 fixation to function at a high enough efficiency so that it can supply N needs at the ecosystem scale, where N losses via denitrification, burial, and advection often exceed the inputs of “new” N by N2 fixation. As a result, most marine and freshwater ecosystems exhibit chronic N limitation of primary production. Under conditions of perpetual N limitation, external inputs of N from human sources (agricultural, urban, and industrial) play a central role in determining ecosystem fertility and, in the case of N overenrichment, excessive primary production or eutrophication. This points to the importance of controlling external N inputs (in addition to traditional phosphorus controls) as a means of ensuring acceptable water quality and safe water supplies. Nitrogen fixation, the enzymatic conversion of atmospheric N2 to ammonia (NH3) is a  microbially-mediated process by which “new” nitrogen is supplied to N-deficient water bodies.  Certain bloom-forming cyanobacterial species are capable of conducting N2 fixation; hence they are able to circumvent nitrogen limitation in these waters. However, this anaerobic process is highly sensitive to oxygen, and since cyanobacteria produce oxygen in photosynthesis, they are faced with a paradoxical situation, where one critically-important (for supporting growth) biochemical process is inhibited by another. Diazotrophic cyanobacterial taxa have developed an array of biochemical, morphological and ecological adaptations to minimize the “oxygen problem”; however, none of these allows N2 fixation to function at a high enough efficiency so that it can supply N needs at the ecosystem scale, where N losses via denitrification, burial and advection often exceed the inputs of “new” N by N2 fixation.  As a result, most marine and freshwater ecosystems exhibit chronic N-limitation of primary production.  Under conditions of perpetual N limitation, external inputs of N from human sources (agricultural, urban, industrial) play a central role in determining ecosystem fertility and in the case of N-overenrichment, excessive primary production, or eutrophication. This points to the importance of controlling external N inputs (in addition to traditional phosphorus controls) as a means of ensuring acceptable water quality and safe water supplies.    
      PubDate: 2017-03-09T12:11:21Z
      DOI: 10.12688/f1000research.10603.1
      Issue No: Vol. 6 (2017)
  • Neuronal substrates for initiation, maintenance, and structural
           organization of sleep/wake states [version 1; referees: 2 approved]

    • Authors: Ada Eban-Rothschild, Luis de Lecea
      Abstract: Animals continuously alternate between sleep and wake states throughout their life. The daily organization of sleep and wakefulness is orchestrated by circadian, homeostatic, and motivational processes. Over the last decades, much progress has been made toward determining the neuronal populations involved in sleep/wake regulation. Here, we will discuss how the application of advanced in vivo tools for cell type–specific manipulations now permits the functional interrogation of different features of sleep/wake state regulation: initiation, maintenance, and structural organization. We will specifically focus on recent studies examining the roles of wake-promoting neuronal populations.
      PubDate: 2017-03-03T12:06:06Z
      DOI: 10.12688/f1000research.9677.1
      Issue No: Vol. 6 (2017)
  • Methodological advances in imaging intravital axonal transport [version 1;
           referees: 3 approved]

    • Authors: James N. Sleigh, Alessio Vagnoni, Alison E. Twelvetrees, Giampietro Schiavo
      Abstract: Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer’s disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions.
      PubDate: 2017-03-01T11:01:26Z
      DOI: 10.12688/f1000research.10433.1
      Issue No: Vol. 6 (2017)
  • Recent advances in the link between physical activity, sedentary behavior,

    • Authors: Vikneswaran Namasivayam, Sam Lim
      Abstract: Physical inactivity is a well-established risk factor for colorectal cancer (CRC). Recent studies have characterized physical activity (PA), sedentary behavior, and cardiorespiratory fitness as distinct, interrelated constructs that influence the risk of CRC and related outcomes. PA levels required to confer protection against CRC may be higher than previously thought. Sedentary behavior, defined as time spent sitting, increases CRC risk independent of PA and may require novel interventions distinct from those targeting PA. Finally, cardiorespiratory fitness is inversely associated with CRC risk and mortality and may provide a potential tool for risk stratification and intervention.
      PubDate: 2017-03-01T10:10:04Z
      DOI: 10.12688/f1000research.9795.1
      Issue No: Vol. 6 (2017)
  • The mechanism of translation [version 1; referees: 3 approved]

    • Authors: Joachim Frank
      Abstract: Translation of the genetic code on the ribosome into protein is a process of extraordinary complexity, and understanding its mechanism has remained one of the major challenges even though x-ray structures have been available since 2000. In the past two decades, single-particle cryo-electron microscopy has contributed a major share of information on structure, binding modes, and conformational changes of the ribosome during its work cycle, but the contributions of this technique in the translation field have recently skyrocketed after the introduction of a new recording medium capable of detecting individual electrons. As many examples in the recent literature over the past three years show, the impact of this development on the advancement of knowledge in this field has been transformative and promises to be lasting.
      PubDate: 2017-03-01T10:09:35Z
      DOI: 10.12688/f1000research.9760.1
      Issue No: Vol. 6 (2017)
  • Tertiary lymphoid organs in systemic autoimmune diseases:  pathogenic or
           protective' [version 1; referees: 2 approved]

    • Authors: William D. Shipman, Dragos C. Dasoveanu, Theresa T. Lu
      Abstract: Tertiary lymphoid organs are found at sites of chronic inflammation in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. These organized accumulations of T and B cells resemble secondary lymphoid organs and generate autoreactive effector cells. However, whether they contribute to disease pathogenesis or have protective functions is unclear. Here, we discuss how tertiary lymphoid organs can generate potentially pathogenic cells but may also limit the extent of the response and damage in autoimmune disease.
      PubDate: 2017-02-28T13:27:55Z
      DOI: 10.12688/f1000research.10595.1
      Issue No: Vol. 6 (2017)
  • Escherichia coli ST131: a multidrug-resistant clone primed for global
           domination [version 1; referees: 2 approved]

    • Authors: Johann D.D. Pitout, Rebekah DeVinney
      Abstract: A single extra-intestinal pathogenic Escherichia coli (ExPEC) clone, named sequence type (ST) 131, is responsible for millions of global antimicrobial-resistant (AMR) infections annually. Population genetics indicate that ST131 consists of different clades (i.e. A, B, and C); however, clade C is the most dominant globally. A ST131 subclade, named C1-M27, is emerging in Japan and has been responsible for the recent increase in AMR ExPEC in that country. The sequential acquisition of several virulence and AMR genes associated with mobile genetic elements during the 1960s to 1980s primed clade C (and its subclades C1 and C2) for success in the 1990s to 2000s. IncF plasmids with F1:A2:B20 and F2:A1:B replicons have shaped the evolution of the C1 and C2 subclades. It is possible that ST131 is a host generalist with different accessory gene profiles. Compensatory mutations within the core genome of this clone have counterbalanced the fitness cost associated with IncF plasmids. ST131 clade C had dramatically changed the population structure of ExPEC, but it still remains unclear which features of this clade resulted in one of the most unprecedented AMR successes of the 2000s.
      PubDate: 2017-02-28T11:10:01Z
      DOI: 10.12688/f1000research.10609.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding and managing IgG4-related disease
           [version 1; referees: 4 approved]

    • Authors: Anna R. Wolfson, Daniel L. Hamilos
      Abstract: IgG4-related disease was only recently discovered, so its description, management, and new discoveries related to its etiology are rapidly evolving. Because IgG4 itself is a unique antibody which is intimately related to the diagnosis of the disease, the role of plasmablasts in the pathophysiology remains an active area of discussion. Recent studies have uncovered a possible role for CD4-positive cytotoxic T lymphocytes, T follicular helper cells, and M2 macrophages. The clinical presentation is variable and can be vague, as this disease affects many organs and new presentations are continuing to be described. The diagnosis depends on clinical and histopathological assessment. The mainstay of treatment is with glucocorticoids, but rituximab has recently shown promise. Monitoring disease activity using imaging modalities (including positron emission tomography) and serum markers is imperative, as relapses are common. IgG4-related disease spans many medical disciplines but is a treatable condition with which all clinicians should be familiar.
      PubDate: 2017-02-23T16:26:43Z
      DOI: 10.12688/f1000research.9399.1
      Issue No: Vol. 6 (2017)
  • Lyssaviruses and rabies: current conundrums, concerns, contradictions and
           controversies [version 1; referees: 2 approved]

    • Authors: Charles Rupprecht, Ivan Kuzmin, Francois Meslin
      Abstract: Lyssaviruses are bullet-shaped, single-stranded, negative-sense RNA viruses and the causative agents of the ancient zoonosis rabies. Africa is the likely home to the ancestors of taxa residing within the Genus Lyssavirus, Family Rhabdoviridae. Diverse lyssaviruses are envisioned as co-evolving with bats, as the ultimate reservoirs, over seemingly millions of years. In terms of relative distribution, overt abundance, and resulting progeny, rabies virus is the most successful lyssavirus species today, but for unknown reasons. All mammals are believed to be susceptible to rabies virus infection. Besides reservoirs among the Chiroptera, meso-carnivores also serve as major historical hosts and are represented among the canids, raccoons, skunks, mongooses, and ferret badgers.  Perpetuating as a disease of nature with the mammalian central nervous system as niche, host breadth alone precludes any candidacy for true eradication. Despite having the highest case fatality of any infectious disease and a burden in excess of or comparative to other major zoonoses, rabies remains neglected. Once illness appears, no treatment is proven to prevent death. Paradoxically, vaccines were developed more than a century ago, but the clear majority of human cases are unvaccinated. Tens of millions of people are exposed to suspect rabid animals and tens of thousands succumb annually, primarily children in developing countries, where canine rabies is enzootic. Rather than culling animal populations, one of the most cost-effective strategies to curbing human fatalities is the mass vaccination of dogs. Building on considerable progress to date, several complementary actions are needed in the near future, including a more harmonized approach to viral taxonomy, enhanced de-centralized laboratory-based surveillance, focal pathogen discovery and characterization, applied pathobiological research for therapeutics, improved estimates of canine populations at risk, actual production of required vaccines and related biologics, strategies to maximize prevention but minimize unnecessary human prophylaxis, and a long-term, realistic plan for sustained global program support to achieve success in disease control, prevention, and elimination.
      PubDate: 2017-02-23T16:26:03Z
      DOI: 10.12688/f1000research.10416.1
      Issue No: Vol. 6 (2017)
  • Understanding the role of serotonin in psychiatric diseases [version 1;
           referees: 3 approved]

    • Authors: Donatella Marazziti
      Abstract: Serotonin (5-HT) continues to attract researchers’ interest after almost a century. However, despite these efforts, its role has not yet been fully elucidated. It is now evident that 5-HT does not modulate single functions but rather a multiplicity of activities and behaviors present in both normal and several pathological conditions in a less deterministic way than previously assumed. This article aims to briefly review some of the latest advancements in the general role of 5-HT in psychiatry, particularly in depression, and offer the author’s personal reflections.
      PubDate: 2017-02-23T11:40:03Z
      DOI: 10.12688/f1000research.10094.1
      Issue No: Vol. 6 (2017)
  • Advances in understanding hypopituitarism [version 1; referees: 2

    • Authors: Mareike R. Stieg, Ulrich Renner, Günter K. Stalla, Anna Kopczak
      Abstract: The understanding of hypopituitarism has increased over the last three years. This review provides an overview of the most important recent findings. Most of the recent research in hypopituitarism has focused on genetics. New diagnostic techniques like next-generation sequencing have led to the description of different genetic mutations causative for congenital dysfunction of the pituitary gland while new molecular mechanisms underlying pituitary ontogenesis have also been described. Furthermore, hypopituitarism may occur because of an impairment of the distinctive vascularization of the pituitary gland, especially by disruption of the long vessel connection between the hypothalamus and the pituitary. Controversial findings have been published on post-traumatic hypopituitarism. Moreover, autoimmunity has been discussed in recent years as a possible reason for hypopituitarism. With the use of new drugs such as ipilimumab, hypopituitarism as a side effect of pharmaceuticals has come into focus. Besides new findings on the pathomechanism of hypopituitarism, there are new diagnostic tools in development, such as new growth hormone stimulants that are currently being tested in clinical trials. Moreover, cortisol measurement in scalp hair is a promising tool for monitoring cortisol levels over time.
      PubDate: 2017-02-22T15:30:13Z
      DOI: 10.12688/f1000research.9436.1
      Issue No: Vol. 6 (2017)
  • Non-small cell lung cancer: the new T1 categories [version 1; referees: 2

    • Authors: Paul E. Van Schil
      Abstract: Recently, major changes have occurred in the staging, diagnosis, and treatment of early stage lung cancer. By screening high-risk populations, we are now able to detect lung cancers at an early stage, but the false-positive rate is high. A new pathological classification was published in 2011 and fully incorporated in the 2015 World Health Organisation (WHO) Classification of Tumours of the Lung, Pleura, Thymus, and Heart. The new eighth edition of the tumour–node–metastasis (TNM) staging system has been fully published and will be in use from January 2017. T1 lesions are subdivided into T1a, T1b, and T1c lesions corresponding to lung cancers up to 10 mm, between 11 and 20 mm, and between 21 and 30 mm, respectively. To determine the size, only the solid part on computed tomographic scanning of the chest and the invasive part on pathological examination will be considered. Prognosis is significantly better for the smallest lesions. For some specific subgroups, sublobar resection may be oncologically valid and yield good long-term outcome, but the results of recently performed randomised trials are awaited.
      PubDate: 2017-02-22T10:10:08Z
      DOI: 10.12688/f1000research.10600.1
      Issue No: Vol. 6 (2017)
  • New insights into bacterial type II polyketide biosynthesis [version 1;
           referees: 2 approved]

    • Authors: Zhuan Zhang, Hai-Xue Pan, Gong-Li Tang
      Abstract: Bacterial aromatic polyketides, exemplified by anthracyclines, angucyclines, tetracyclines, and pentangular polyphenols, are a large family of natural products with diverse structures and biological activities and are usually biosynthesized by type II polyketide synthases (PKSs). Since the starting point of biosynthesis and combinatorial biosynthesis in 1984–1985, there has been a continuous effort to investigate the biosynthetic logic of aromatic polyketides owing to the urgent need of developing promising therapeutic candidates from these compounds. Recently, significant advances in the structural and mechanistic identification of enzymes involved in aromatic polyketide biosynthesis have been made on the basis of novel genetic, biochemical, and chemical technologies. This review highlights the progress in bacterial type II PKSs in the past three years (2013–2016). Moreover, novel compounds discovered or created by genome mining and biosynthetic engineering are also included.
      PubDate: 2017-02-21T16:21:06Z
      DOI: 10.12688/f1000research.10466.1
      Issue No: Vol. 6 (2017)
  • Advances in the understanding of mitochondrial DNA as a pathogenic factor
           in inflammatory diseases [version 1; referees: 3 approved]

    • Authors: Ray K. Boyapati, Arina Tamborska, David A. Dorward, Gwo-Tzer Ho
      Abstract: Mitochondrial DNA (mtDNA) has many similarities with bacterial DNA because of their shared common ancestry. Increasing evidence demonstrates mtDNA to be a potent danger signal that is recognised by the innate immune system and can directly modulate the inflammatory response. In humans, elevated circulating mtDNA is found in conditions with significant tissue injury such as trauma and sepsis and increasingly in chronic organ-specific and systemic illnesses such as steatohepatitis and systemic lupus erythematosus. In this review, we examine our current understanding of mtDNA-mediated inflammation and how the mechanisms regulating mitochondrial homeostasis and mtDNA release represent exciting and previously under-recognised important factors in many human inflammatory diseases, offering many new translational opportunities.
      PubDate: 2017-02-20T15:48:24Z
      DOI: 10.12688/f1000research.10397.1
      Issue No: Vol. 6 (2017)
  • Revisiting blood transfusion and predictors of outcome in cardiac surgery
           patients: a concise perspective [version 1; referees: 2 approved]

    • Authors: Carlos E Arias-Morales, Nicoleta Stoicea, Alicia A Gonzalez-Zacarias, Diana Slawski, Sujatha P. Bhandary, Theodosios Saranteas, Eva Kaminiotis, Thomas J Papadimos
      Abstract: In the United States, cardiac surgery-related blood transfusion rates reached new highs in 2010, with 34% of patients receiving blood products. Patients undergoing both complex (coronary artery bypass grafting [CABG] plus valve repair or replacement) and non-complex (isolated CABG) cardiac surgeries are likely to have comorbidities such as anemia. Furthermore, the majority of patients undergoing isolated CABG have a history of myocardial infarction. These characteristics may increase the risk of complications and blood transfusion requirement. It becomes difficult to demonstrate the association between transfusions and mortality because of the fact that most patients undergoing cardiac surgery are also critically ill. Transfusion rates remain high despite the advances in perioperative blood conservation, such as the intraoperative use of cell saver in cardiac surgery. Some recent prospective studies have suggested that the use of blood products, even in low-risk patients, may adversely affect clinical outcomes. In light of this information, we reviewed the literature to assess the clinical outcomes in terms of 30-day and 1-year morbidity and mortality in transfused patients who underwent uncomplicated CABG surgery.
      PubDate: 2017-02-20T14:41:12Z
      DOI: 10.12688/f1000research.10085.1
      Issue No: Vol. 6 (2017)
  • Recent advances in understanding the cellular roles of GSK-3 [version 1;
           referees: 3 approved]

    • Authors: Kevin W. Cormier, James R. Woodgett
      Abstract: Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed protein kinase that sits at the nexus of multiple signaling pathways. Its deep integration into cellular control circuits is consummate to its implication in diseases ranging from mood disorders to diabetes to neurodegenerative diseases and cancers. The selectivity and insulation of such a promiscuous kinase from unwanted crosstalk between pathways, while orchestrating a multifaceted response to cellular stimuli, offer key insights into more general mechanisms of cell regulation. Here, we review recent advances that have contributed to the understanding of GSK-3 and its role in driving appreciation of intracellular signal coordination.
      PubDate: 2017-02-20T14:39:43Z
      DOI: 10.12688/f1000research.10557.1
      Issue No: Vol. 6 (2017)
  • The challenges with the validation of research antibodies [version 1;
           referees: 3 approved]

    • Authors: Jan L.A. Voskuil
      Abstract: This article further discusses the reproducibility crisis in biomedical science and how poor conduct of commercial antibodies contribute to this. In addition, the way quality data are presented on product sheets by antibody vendors is scrutinized. The article proposes that there is a distinction between testing data and validation data, and special attention is asked for consistency between batches and aliquots. Moreover, the article separates the specifics, such as formulation, antigen and price, from the specifics on performance. Finally, a two-tier approach is discussed, enabling scientists to anticipate how an antibody is likely to perform when repeated purchases are required.
      PubDate: 2017-02-17T16:24:05Z
      DOI: 10.12688/f1000research.10851.1
      Issue No: Vol. 6 (2017)
  • Surgical education and adult learning: Integrating theory into practice
           [version 1; referees: 2 approved]

    • Authors: Prem Rashid
      Abstract: Surgical education continues to evolve from the master-apprentice model. Newer methods of the process need to be used to manage the dual challenges of educating while providing safe surgical care. This requires integrating adult learning concepts into delivery of practical training and education in busy clinical environments. A narrative review aimed at outlining and integrating adult learning and surgical education theory was undertaken. Additionally, this information was used to relate the practical delivery of surgical training and education in day-to-day surgical practice. Concepts were sourced from reference material. Additional material was found using a PubMed search of the words: ‘surgical education theory’ and ‘adult learning theory medical’. This yielded 1351 abstracts, of which 43 articles with a focus on key concepts in adult education theory were used. Key papers were used to formulate structure and additional cross-referenced papers were included where appropriate. Current concepts within adult learning have a lot to offer when considering how to better deliver surgical education and training. Better integration of adult learning theory can be fruitful. Individual teaching surgical units need to rethink their paradigms and consider how each individual can contribute to the education experience. Up skilling courses for trainers can do much to improve the delivery of surgical education. Understanding adult learning concepts and integrating these into day-to-day teaching can be valuable.
      PubDate: 2017-02-14T14:19:19Z
      DOI: 10.12688/f1000research.10870.1
      Issue No: Vol. 6 (2017)
  • Growth performance and feed utilization of keureling fish Tor tambra
           (Cyprinidae) fed formulated diet supplemented with enhanced probiotic.
           [version 1; referees: 2 approved]

    • Authors: Zainal A. Muchlisin, Tanzil Murda, Cut Yulvizar, Irma Dewiyanti, Nur Fadli, Fardin Afrido, Mohd Nor Siti-Azizah, Abdullah A. Muhammadar
      Abstract: Background The objective of the present study was to determine the optimum dosage of probiotic in the diet of keureling fish (Tor tambra) fry. Methods Lactobacillus casei from Yakult® was used as a starter, and enhanced with Curcuma xanthorrhiza, Kaempferia galanga and molasses. The mixture was fermented for 7 days prior to use as probiotic in a formulated diet containing 30% crude protein. Four levels of probiotic dosage; 0 ml kg-1 (control), 5 ml kg-1, 10 ml kg-1 and 15 ml kg-1 were tested in this study. The fish was fed twice a day at 08.00 AM and 06.00 PM at the ration of 5% body weight for 80 days. Results The results showed that growth performance and feed efficiency increased with increasing probiotic dosage in the diet from control (no probiotic) to 10 ml kg-1 of probiotic dosage and then decreased when the dosage was increased up to 15 ml kg-1. Conclusions The best values for all measured parameters were recorded at the dosage of 10 ml kg-1. Therefore, it was concluded that the optimum dosage of enhanced probiotic for T. tambra fry was 10 ml kg-1 of feed.
      PubDate: 2017-02-14T10:53:18Z
      DOI: 10.12688/f1000research.10693.1
      Issue No: Vol. 6 (2017)
  • The Dockstore: enabling modular, community-focused sharing of Docker-based
           genomics tools and workflows [version 1; referees: 2 approved]

    • Authors: Brian D. O'Connor, Denis Yuen, Vincent Chung, Andrew G. Duncan, Xiang Kun Liu, Janice Patricia, Benedict Paten, Lincoln Stein, Vincent Ferretti
      Abstract: As genomic datasets continue to grow, the feasibility of downloading data to a local organization and running analysis on a traditional compute environment is becoming increasingly problematic. Current large-scale projects, such as the ICGC PanCancer Analysis of Whole Genomes (PCAWG), the Data Platform for the U.S. Precision Medicine Initiative, and the NIH Big Data to Knowledge Center for Translational Genomics, are using cloud-based infrastructure to both host and perform analysis across large data sets. In PCAWG, over 5,800 whole human genomes were aligned and variant called across 14 cloud and HPC environments; the processed data was then made available on the cloud for further analysis and sharing. If run locally, an operation at this scale would have monopolized a typical academic data centre for many months, and would have presented major challenges for data storage and distribution. However, this scale is increasingly typical for genomics projects and necessitates a rethink of how analytical tools are packaged and moved to the data. For PCAWG, we embraced the use of highly portable Docker images for encapsulating and sharing complex alignment and variant calling workflows across highly variable environments. While successful, this endeavor revealed a limitation in Docker containers, namely the lack of a standardized way to describe and execute the tools encapsulated inside the container. As a result, we created the Dockstore (, a project that brings together Docker images with standardized, machine-readable ways of describing and running the tools contained within. This service greatly improves the sharing and reuse of genomics tools and promotes interoperability with similar projects through emerging web service standards developed by the Global Alliance for Genomics and Health (GA4GH).
      PubDate: 2017-01-18T12:35:43Z
      DOI: 10.12688/f1000research.10137.1
      Issue No: Vol. 6 (2017)
  • Genome-wide measurement of spatial expression in patterning mutants of
           Drosophila melanogaster [version 1; referees: 2 approved]

    • Authors: Peter A. Combs, Michael B. Eisen
      Abstract: Patterning in the Drosophila melanogaster embryo is affected by multiple maternal factors, but the effect of these factors on spatial gene expression has not been systematically analyzed. Here we characterize the effect of the maternal factors Zelda, Hunchback and Bicoid by cryosectioning wildtype and mutant blastoderm stage embryos and sequencing mRNA from each slice. The resulting atlas of spatial gene expression highlights the intersecting roles of these factors in regulating spatial patterns, and serves as a resource for researchers studying spatial patterning in the early embryo. We identify a large number of genes with both expected and unexpected patterning changes, and through integrated analysis of transcription factor binding data identify common themes in genes with complex dependence on these transcription factors.
      PubDate: 2017-01-12T16:15:22Z
      DOI: 10.12688/f1000research.9720.1
      Issue No: Vol. 6 (2017)
  • Characterization of BRCA1/2 mutations in patients with family history of
           breast cancer in Armenia [version 1; referees: 2 approved]

    • Authors: Sofi Atshemyan, Andranik Chavushyan, Nerses Berberian, Arthur Sahakyan, Roksana Zakharyan, Arsen Arakelyan
      Abstract: Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives. Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool. Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations. Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers.
      PubDate: 2017-01-10T10:48:11Z
      DOI: 10.12688/f1000research.10434.1
      Issue No: Vol. 6 (2017)
  • Low-cost, rapidly-developed, 3D printed in vitro corpus callosum model for
           mucopolysaccharidosis type I [version 2; referees: 2 approved]

    • Authors: Anthony Tabet, Matthew Gardner, Sebastian Swanson, Sydney Crump, Austin McMeekin, Diana Gong, Rebecca Tabet, Benjamin Hacker, Igor Nestrasil
      Abstract: The rising prevalence of high throughput screening and the general inability of (1) two dimensional (2D) cell culture and (2) in vitro release studies to predict in vivo neurobiological and pharmacokinetic responses in humans has led to greater interest in more realistic three dimensional (3D) benchtop platforms. Advantages of 3D human cell culture over its 2D analogue, or even animal models, include taking the effects of microgeometry and long-range topological features into consideration. In the era of personalized medicine, it has become increasingly valuable to screen candidate molecules and synergistic therapeutics at a patient-specific level, in particular for diseases that manifest in highly variable ways. The lack of established standards and the relatively arbitrary choice of probing conditions has limited in vitro drug release to a largely qualitative assessment as opposed to a predictive, quantitative measure of pharmacokinetics and pharmacodynamics in tissue. Here we report the methods used in the rapid, low-cost development of a 3D model of a mucopolysaccharidosis type I patient’s corpus callosum, which may be used for cell culture and drug release. The CAD model is developed from in vivo brain MRI tracing of the corpus callosum using open-source software, printed with poly (lactic-acid) on a Makerbot Replicator 5X, UV-sterilized, and coated with poly (lysine) for cellular adhesion. Adaptations of material and 3D printer for expanded applications are also discussed.
      PubDate: 2017-03-16T12:13:59Z
      DOI: 10.12688/f1000research.9861.2
      Issue No: Vol. 5 (2017)
  • Evidence synthesis and decision modelling to support complex decisions:
           stockpiling neuraminidase inhibitors for pandemic influenza usage [version
           2; referees: 2 approved]

    • Authors: Samuel I. Watson, Yen-Fu Chen, Jonathan S. Nguyen-Van-Tam, Puja R. Myles, Sudhir Venkatesan, Maria Zambon, Olalekan Uthman, Peter J. Chilton, Richard J. Lilford
      Abstract: Objectives: The stockpiling of neuraminidase inhibitor (NAI) antivirals as a defence against pandemic influenza is a significant public health policy decision that must be made despite a lack of conclusive evidence from randomised controlled trials regarding the effectiveness of NAIs on important clinical end points such as mortality. The objective of this study was to determine whether NAIs should be stockpiled for treatment of pandemic influenza on the basis of current evidence. Methods: A decision model for stockpiling was designed. Data on previous pandemic influenza epidemiology was combined with data on the effectiveness of NAIs in reducing mortality obtained from a recent individual participant meta-analysis using observational data. Evidence synthesis techniques and a bias modelling method for observational data were used to incorporate the evidence into the model. The stockpiling decision was modelled for adults (≥16 years old) and the United Kingdom was used as an example. The main outcome was the expected net benefits of stockpiling in monetary terms. Health benefits were estimated from deaths averted through stockpiling. Results: After adjusting for biases in the estimated effectiveness of NAIs, the expected net benefit of stockpiling in the baseline analysis was £444 million, assuming a willingness to pay of £20,000/QALY ($31,000/QALY). The decision would therefore be to stockpile NAIs. There was a greater probability that the stockpile would not be utilised than utilised. However, the rare but catastrophic losses from a severe pandemic justified the decision to stockpile. Conclusions: Taking into account the available epidemiological data and evidence of effectiveness of NAIs in reducing mortality, including potential biases, a decision maker should stockpile anti-influenza medication in keeping with the postulated decision rule.
      PubDate: 2017-03-16T11:51:39Z
      DOI: 10.12688/f1000research.9414.2
      Issue No: Vol. 5 (2017)
  • whoishRisk – an R package to calculate WHO/ISH cardiovascular risk
           scores for all epidemiological subregions of the world [version 2;
           referees: 2 approved, 1 approved with reservations]

    • Authors: Dylan Collins, Joseph Lee, Niklas Bobrovitz, Constantinos Koshiaris, Alison Ward, Carl Heneghan
      Abstract: The World Health Organisation and International Society of Hypertension (WHO/ISH) cardiovascular disease (CVD) risk assessment charts have been implemented in many low- and middle-income countries as part of the WHO Package of Essential Non-Communicable Disease (PEN) Interventions for Primary Health Care in Low-Resource settings. Evaluation of the WHO/ISH cardiovascular risk charts and their use is a key priority and since they only existed in paper or PDF formats, we developed an R implementation of the charts for all epidemiological subregions of the world. The main strengths of this implementation are that it is built in a free, open-source, coding language with simple syntax, can be downloaded from github as a package (“whoishRisk”), and can be used with a standard computer.
      PubDate: 2017-03-08T16:49:18Z
      DOI: 10.12688/f1000research.9742.2
      Issue No: Vol. 5 (2017)
  • Finger stick blood collection for gene expression profiling and storage of
           tempus blood RNA tubes [version 2; referees: 1 approved, 2 approved with

    • Authors: Darawan Rinchai, Esperanza Anguiano, Phuong Nguyen, Damien Chaussabel
      Abstract: With this report we aim to make available a standard operating procedure (SOP) developed for RNA stabilization of small blood volumes collected via a finger stick. The anticipation that this procedure may be improved through peer-review and/or readers public comments is another element motivating the publication of this SOP. Procuring blood samples from human subjects can, among other uses, enable assessment of the immune status of an individual subject via the profiling of RNA abundance using technologies such as real time PCR, NanoString, microarrays or RNA-sequencing. It is often desirable to minimize blood volumes and employ methods that are the least invasive and can be practically implemented outside of clinical settings. Finger stick blood samples are increasingly used for measurement of levels of pharmacological drugs and biological analytes. It is a simple and convenient procedure amenable for instance to field use or self-collection at home using a blood sample collection kit. Such methodologies should also enable the procurement of blood samples at high frequency for health or disease monitoring applications.
      PubDate: 2017-03-03T14:06:53Z
      DOI: 10.12688/f1000research.8841.2
      Issue No: Vol. 5 (2017)
  • dbVar structural variant cluster set for data analysis and variant
           comparison [version 2; referees: 2 approved]

    • Authors: Lon Phan, Jeffrey Hsu, Le Quang Minh Tri, Michaela Willi, Tamer Mansour, Yan Kai, John Garner, John Lopez, Ben Busby
      Abstract: dbVar houses over 3 million submitted structural variants (SSV) from 120 human studies including copy number variations (CNV), insertions, deletions, inversions, translocations, and complex chromosomal rearrangements. Users can submit multiple SSVs to dbVAR  that are presumably identical, but were ascertained by different platforms and samples,  to calculate whether the variant is rare or common in the population and allow for cross validation. However, because SSV genomic location reporting can vary – including fuzzy locations where the start and/or end points are not precisely known – analysis, comparison, annotation, and reporting of SSVs across studies can be difficult. This project was initiated by the Structural Variant Comparison Group for the purpose of generating a non-redundant set of genomic regions defined by counts of concordance for all human SSVs placed on RefSeq assembly GRCh38 (RefSeq accession GCF_000001405.26). We intend that the availability of these regions, called structural variant clusters (SVCs), will facilitate the analysis, annotation, and exchange of SV data and allow for simplified display in genomic sequence viewers for improved variant interpretation. Sets of SVCs were generated by variant type for each of the 120 studies as well as for a combined set across all studies. Starting from 3.64 million SSVs, 2.5 million and 3.4 million non-redundant SVCs with count >=1 were generated by variant type for each study and across all studies, respectively. In addition, we have developed utilities for annotating, searching, and filtering SVC data in GVF format for computing summary statistics, exporting data for genomic viewers, and annotating the SVC using external data sources.
      PubDate: 2017-02-28T16:40:17Z
      DOI: 10.12688/f1000research.8290.2
      Issue No: Vol. 5 (2017)
  • Predictors and brain connectivity changes associated with arm motor
           function improvement from intensive practice in chronic stroke [version 2;
           referees: 1 approved, 2 approved with reservations]

    • Authors: George F. Wittenberg, Lorie G. Richards, Lauren M. Jones-Lush, Steven R. Roys, Rao P. Gullapalli, Suzy Yang, Peter D. Guarino, Albert C. Lo
      Abstract: Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke-related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic and intensive conventional therapy arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: Unique identifiers: NCT00372411 \& NCT00333983.
      PubDate: 2017-02-28T10:58:17Z
      DOI: 10.12688/f1000research.8603.2
      Issue No: Vol. 5 (2017)
  • Electronic medical records in humanitarian emergencies – the development
           of an Ebola clinical information and patient management system [version 3;
           referees: 2 approved]

    • Authors: Kiran Jobanputra, Jane Greig, Ganesh Shankar, Eric Perakslis, Ronald Kremer, Jay Achar, Ivan Gayton
      Abstract: By November 2015, the West Africa Ebola epidemic had caused 28598 infections and 11299 deaths in the three countries most affected. The outbreak required rapid innovation and adaptation. Médecins sans Frontières (MSF) scaled up its usual 20-30 bed Ebola management centres (EMCs) to 100-300 beds with over 300 workers in some settings. This brought challenges in patient and clinical data management resulting from the difficulties of working safely with high numbers of Ebola patients. We describe a project MSF established with software developers and the Google Social Impact Team to develop context-adapted tools to address the challenges of recording Ebola clinical information. We share the outcomes and key lessons learned in innovating rapidly under pressure in difficult environmental conditions. Information on adoption, maintenance, and data quality was gathered through review of project documentation, discussions with field staff and key project stakeholders, and analysis of tablet data. In March 2015, a full prototype was deployed in Magburaka EMC, Sierra Leone. Inpatient data were captured on 204 clinical interactions with 34 patients from 5 March until 10 April 2015. Data continued to also be recorded on paper charts, creating theoretically identical record “pairs” on paper and tablet. 83 record pairs for 33 patients with 22 data items (temperature and symptoms) per pair were analysed. The overall Kappa coefficient for agreement between sources was 0.62, but reduced to 0.59 when rare bleeding symptoms were excluded, indicating moderate to good agreement. The time taken to deliver the product was more than that anticipated by MSF (7 months versus 6 weeks). Deployment of the tablet coincided with a dramatic drop in patient numbers and thus had little impact on patient care. We have identified lessons specific to humanitarian-technology collaborative projects and propose a framework for emergency humanitarian innovation. Time and effort is required to bridge differences in organisational culture between the technology and humanitarian worlds. This investment is essential for establishing a shared vision on deliverables, urgency, and ownership of product.
      PubDate: 2017-02-23T15:16:10Z
      DOI: 10.12688/f1000research.8287.3
      Issue No: Vol. 5 (2017)
  • Validation of syngeneic mouse models of melanoma and non-small cell lung
           cancer for investigating the anticancer effects of the soy-derived peptide
           Lunasin [version 2; referees: 1 approved, 2 approved with reservations]

    • Authors: Bharat Devapatla, Chris Shidal, Kavitha Yaddanapudi, Keith R. Davis
      Abstract: Background: Lunasin is a naturally occurring peptide present in soybean that has both chemopreventive and therapeutic activities that can prevent cellular transformation and inhibit the growth of several human cancer types. Recent studies indicate that Lunasin has several distinct potential modes of action including suppressing integrin signaling and epigenetic effects driven by modulation of histone acetylation. In addition to direct effects on cancer cells, Lunasin also has effects on innate immunity that may contribute to its ability to inhibit tumor growth in vivo. Methods: Standard assays for cell proliferation and colony formation were used to assess Lunasin’s in vitro activity against murine Lewis lung carcinoma (LLC) and B16-F0 melanoma cells.  Lunasin’s in vivo activity was assessed by comparing the growth of tumors initiated by subcutaneous implantation of LLC or B16-F0 cells in Lunasin-treated and untreated C57BL/6 mice. Results: Lunasin was found to inhibit growth of murine LLC cells and murine B16-F0 melanoma cells in vitro and in wild-type C57BL/6 mice.  The effects of Lunasin in these two mouse models were very similar to those previously observed in studies of human non-small cell lung cancer and melanoma cell lines. Conclusions: We have now validated two established syngeneic mouse models as being responsive to Lunasin treatment.  The validation of these two in vivo syngeneic models will allow detailed studies on the combined therapeutic and immune effects of Lunasin in a fully immunocompetent mouse model.
      PubDate: 2017-02-22T09:40:59Z
      DOI: 10.12688/f1000research.9661.2
      Issue No: Vol. 5 (2017)
  • Inhibition of CD34+ cell migration by matrix metalloproteinase-2 during
           acute myocardial ischemia, counteracted by ischemic preconditioning
           [version 3; referees: 2 approved]

    • Authors: Dominika Lukovic, Katrin Zlabinger, Alfred Gugerell, Andreas Spannbauer, Noemi Pavo, Ljubica Mandic, Denise T. Weidenauer, Stefan Kastl, Christoph Kaun, Aniko Posa, Inna Sabdyusheva Litschauer, Johannes Winkler, Mariann Gyöngyösi
      Abstract: Background. Mobilization of bone marrow-origin CD34+ cells was investigated 3 days (3d) after acute myocardial infarction (AMI) with/without ischemic preconditioning (IP) in relation to stromal-derived factor-1 (SDF-1α)/ chemokine receptor type 4 (CXCR4) axis, to search for possible mechanisms behind insufficient cardiac repair in the first days post-AMI. Methods. Closed-chest reperfused AMI was performed by percutaneous balloon occlusion of the mid-left anterior descending (LAD) coronary artery for 90min, followed by reperfusion in pigs. Animals were randomized to receive either IP initiated by 3x5min cycles of re-occlusion/re-flow prior to AMI (n=6) or control AMI (n=12). Blood samples were collected at baseline, 3d post-AMI, and at 1-month follow-up to analyse chemokines and mobilized CD34+ cells. To investigate the effect of acute hypoxia, SDF-1α and matrix metalloproteinase (MMP)-2 in vitro were assessed, and a migration assay of CD34+ cells toward cardiomyocytes was performed. Results. Reperfused AMI induced significant mobilisation of CD34+ cells (baseline: 260±75 vs. 3d: 668±180; P
      PubDate: 2017-02-06T11:18:00Z
      DOI: 10.12688/f1000research.9957.3
      Issue No: Vol. 5 (2017)
  • An adaptable toolkit to assess commercial fishery costs and benefits
           related to marine protected area network design [version 2; referees: 2

    • Authors: Rémi M. Daigle, Cristián J. Monaco, Ashley K. Elgin
      Abstract: Around the world, governments are establishing Marine Protected Area (MPA) networks to meet their commitments to the United Nations Convention on Biological Diversity. MPAs are often used in an effort to conserve biodiversity and manage fisheries stocks. However, their efficacy and effect on fisheries yields remain unclear. We conducted a case-study on the economic impact of different MPA network design strategies on the Atlantic cod (Gadus morhua) fisheries in Canada. The open-source R package that we developed to analyze this case study can be customized to conduct similar analyses for other systems. We used a spatially-explicit individual-based model of population growth and dispersal coupled with a fisheries management and harvesting component. We found that MPA networks that both protect the target species’ habitat and were spatially optimized to improve population connectivity had the highest net present value (i.e., were most profitable for the fishing industry). These higher profits were achieved primarily by reducing the distance travelled for fishing and reducing the probability of a moratorium event. These findings add to a growing body of knowledge demonstrating the importance of incorporating population connectivity in the MPA planning process, as well as the ability of this R package to explore ecological and economic consequences of alternative MPA network designs.
      PubDate: 2017-02-22T15:50:40Z
      DOI: 10.12688/f1000research.7312.2
      Issue No: Vol. 4 (2017)
  • A double blinded, placebo-controlled pilot study to examine reduction of
           CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission
           induced by neoadjuvant valspodar in dogs with large B-cell lymphoma
           [version 2; referees: 2 approved]

    • Authors: Daisuke Ito, Michael Childress, Nicola Mason, Amber Winter, Timothy O’Brien, Michael Henson, Antonella Borgatti, Mitzi Lewellen, Erika Krick, Jane Stewart, Sarah Lahrman, Bartek Rajwa, Milcah C Scott, Davis Seelig, Joseph Koopmeiners, Stephan Ruetz, Jaime Modiano
      Abstract: We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.
      PubDate: 2017-02-10T15:55:02Z
      DOI: 10.12688/f1000research.6055.2
      Issue No: Vol. 4 (2017)
  • Aspiration in injections: should we continue or abandon the practice'
           [version 3; referees: 2 approved]

    • Authors: Yasir Sepah, Lubna Samad, Arshad Altaf, Muhammad Sohail Halim, Nithya Rajagopalan, Aamir Javed Khan
      Abstract: Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health’s PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well.
      PubDate: 2017-03-01T11:11:57Z
      DOI: 10.12688/f1000research.1113.3
      Issue No: Vol. 3 (2017)
  • Using complex networks for refining survival prognosis in prostate cancer
           patient [version 1; referees: 2 approved]

    • Authors: Massimiliano Zanin
      Abstract: Complex network theory has been used, during the last decade, to understand the structures behind complex biological problems, yielding new knowledge in a large number of situations. Nevertheless, such knowledge has remained mostly qualitative. In this contribution, I show how information extracted from a network representation can be used in a quantitative way, to improve the score of a classification task. As a test bed, I consider a dataset corresponding to patients suffering from prostate cancer, and the task of successfully prognosing their survival. When information from a complex network representation is added on top of a simple classification model, the error is reduced from 27.9% to 23.8%. This confirms that network theory can be used to synthesize information that may not readily be accessible by standard data mining algorithms.
      PubDate: 2016-11-16T11:05:24Z
      DOI: 10.12688/f1000research.8282.1
      Issue No: Vol. 5 (2016)
  • Predicting survival time for metastatic castration resistant prostate
           cancer: An iterative imputation approach [version 1; referees: 2 approved,
           1 approved with reservations]

    • Authors: Detian Deng, Yu Du, Zhicheng Ji, Karthik Rao, Zhenke Wu, Yuxin Zhu, R. Yates Coley
      Abstract: In this paper, we present our winning method for survival time prediction in the 2015 Prostate Cancer DREAM Challenge, a recent crowdsourced competition focused on risk and survival time predictions for patients with metastatic castration-resistant prostate cancer (mCRPC). We are interested in using a patient's covariates to predict his or her time until death after initiating standard therapy. We propose an iterative algorithm to multiply impute right-censored survival times and use ensemble learning methods to characterize the dependence of these imputed survival times on possibly many covariates. We show that by iterating over imputation and ensemble learning steps, we guide imputation with patient covariates and, subsequently, optimize the accuracy of survival time prediction. This method is generally applicable to time-to-event prediction problems in the presence of right-censoring. We demonstrate the proposed method's performance with training and validation results from the DREAM Challenge and compare its accuracy with existing methods.
      PubDate: 2016-11-16T11:00:20Z
      DOI: 10.12688/f1000research.8628.1
      Issue No: Vol. 5 (2016)
  • Improving data transparency in clinical trials using blockchain smart
           contracts [version 1; referees: 3 approved]

    • Authors: Timothy Nugent, David Upton, Mihai Cimpoesu
      Abstract: The scientific credibility of findings from clinical trials can be undermined by a range of problems including missing data, endpoint switching, data dredging, and selective publication. Together, these issues have contributed to systematically distorted perceptions regarding the benefits and risks of treatments. While these issues have been well documented and widely discussed within the profession, legislative intervention has seen limited success. Recently, a method was described for using a blockchain to prove the existence of documents describing pre-specified endpoints in clinical trials. Here, we extend the idea by using smart contracts - code, and data, that resides at a specific address in a blockchain, and whose execution is cryptographically validated by the network - to demonstrate how trust in clinical trials can be enforced and data manipulation eliminated. We show that blockchain smart contracts provide a novel technological solution to the data manipulation problem, by acting as trusted administrators and providing an immutable record of trial history.
      PubDate: 2016-10-20T09:43:16Z
      DOI: 10.12688/f1000research.9756.1
      Issue No: Vol. 5 (2016)
  • Neurosteroids are reduced in diabetic neuropathy and may be associated
           with the development of neuropathic pain [version 1; referees: 1 approved,
           2 approved with reservations]

    • Authors: Stephen R. Humble
      Abstract: Introduction: Peripheral and central sensitisation are implicated in the development of neuropathic pain. Hypersensitivity of pain pathway neurons has been described in animal models of diabetic neuropathy, which is postulated to be related to an imbalance between inhibitory and excitatory signals within the spinal cord. GABAergic neurons within the pain pathway are vital for the transmission of painful stimuli to higher centres. A developmental change in the rate of exponential decay of GABAergic synaptic events has been observed in other types of neurons and this may be associated with fluctuations in endogenous neurosteroid tone.    Methods: The whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from wild type mice between the ages of 6 and 80 days in the spinal cord, the nucleus reticularis of the thalamus and the cerebral cortex. Recordings were also obtained from mice with diabetic neuropathy (ob/ob and db/db) between the ages of 60 and 80 days. Behavioural experiments were performed to examine mechanical and thermal nociception.   Results: Electrophysiological recordings from cortical pain pathway neurons from mature type-2 diabetic mice revealed that the endogenous neurosteroid tone is reduced compared to control. However, selected neurosteroid compounds had a more pronounced effect on the GABAA receptors of these diabetic mice. ob/ob mice exhibit mechanical hyperalgesia and allodynia, which was reduced by neurosteroids applied exogenously.   Conclusions: The reduced endogenous neurosteroid tone in ob/ob mice may be linked to their hypersensitivity. Neurosteroids may exert analgesic effects in pathological pain states by attempting to restore the physiological GABAergic inhibitory tone.
      PubDate: 2016-08-05T14:37:57Z
      DOI: 10.12688/f1000research.9034.1
      Issue No: Vol. 5 (2016)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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