Ciona intestinalis showing that the peripheral sensory neurons, whose specification is in part regulated by the coordinate activity of Notch-Delta signaling and the microRNA miR-124, exhibit a sparse spatial pattern whereby consecutive neurons may be spaced over a dozen cells apart. We perform rigorous stability and bifurcation analyses, and demonstrate that our model is able to accurately explain and reproduce the neuronal pattern in Ciona. Using Monte Carlo simulations of our model along with miR-124 transgene over-expression assays, we demonstrate that the activity of miR-124 can be incorporated into the Notch decay rate parameter of our model. Finally, we motivate the general applicability of our model to Notch-Delta signaling in other animals by providing evidence that microRNAs regulate Notch-Delta signaling in analogous cell types in other organisms, and by discussing evidence in other organisms of sparse spatial patterns in tissues where Notch-Delta signaling is active.Notch-Delta signaling is a fundamental cell-cell communication mechanism that governs the differentiation of many cell types. Most existing mathematical models of Notch-Delta signaling are based on a feedback loop between Notch and Delta leading to lateral inhibition of neighboring cells. These models result in a checkerboard spatial pattern whereby adjacent cells express opposing levels of Notch and Delta, leading to alternate cell fates. However, a growing body of biological evidence suggests that Notch-Delta signaling produces other patterns that are not checkerboard, and therefore a new model is needed. Here, we present an expanded Notch-Delta model that builds upon previous models, adding a local Notch activity gradient, which affects long-range patterning, and the activity of a regulatory microRNA. This model is motivated by our experiments in the ascidian  Ciona intestinalis in our study, develops through a cell-to-cell communication mechanism called Notch-Delta signaling. Mathematical models for Notch-Delta signaling have been developed that can explain the development of animal nervous systems with a dense arrangement of neurons. However, there are several cases where the spatial arrangement is much more sparse; we found that the peripheral nervous system of Ciona is one such example. Here, we develop an expanded mathematical model that is able to account for this sparser spacing, and furthermore demonstrate that the spacing can be widened or shortened through changing a single parameter that is influenced by the concentration of a regulatory microRNA called miR-124. The underlying differential equations contain only two variables representing the activity levels of Notch and Delta, and are thus general enough to be applicable to a wide variety of physical and biological systems that exhibit a similar sparse patterning.The nervous system of many animals, including the marine invertebrate  Differentiation of tissues during early animal development as well as tissue homeostasis during adulthood requires constant communication between cells. One of the most common ways by which cells communicate with each other is through the Notch-Delta signaling pathway Although the specific molecular factors and interactions are remarkably complex and vary among different organisms and cell types, the core Notch signaling pathway is relatively simple and is conserved across all bilaterian animals cis-inhibition of Notch by Delta within the same cell Most importantly, experimental studies have shown that neighboring cells, which communicate via Notch-Delta signaling have opposing expression patterns of these five core components With this biological background in hand, several mathematical and computational models have been developed over the years to try and quantitatively explain the dynamics of Notch-Delta signaling i.e., Notch ICD) in the cell or the quantity of downstream Hes TF i.e., a lower Hill coefficient), occasionally a spacing of two or three cells can occur e.g., cis-inhibition of Notch by Delta led to an updated model by Elowitz and colleagues that incorporated this interaction cis-inhibition was thought to facilitate Notch-Delta lateral inhibition, and indeed the expanded model resulted in faster dynamics, sharper checkerboard patterning and greater robustness to noise By contrast, in minimal models only the core molecular components and interactions, which capture the overall, essential Notch-Delta signaling dynamics, are represented in the differential equations. Unlike comprehensive models, minimal models have the advantage of being applicable to many biological contexts and are also more amenable to parameter sensitivity and stability analyses, which can shed important insight into the dynamics of the system. The first minimal Notch-Delta model was published by Monk and colleagues Drosophila thorax that give rise to microchaetes are spaced about five cells apart when fully developed Drosophila extend dynamic projections called filopodia, and that these filopodia express graded amounts of Delta along the filopoidia and allow the SOPs to reach out and activate Notch signaling in non-neighboring cells While the Monk and Elowitz models can explain the patterning in some biological systems such as ciliated cells in the early Xenopus ectoderm Ciona intestinalis. We quantify the number and spacing of ESNs in wild-type larvae, and show that our expanded Notch-Delta model accurately reproduces the experimentally observed ESN pattern Ciona intestinalis PNS, the mechanosensory bristles found in Drosophila, and the hair cells of the mammalian inner ear, are thought to have evolved from a common ciliated sensory-neuron precursor In this report, we present a minimal Notch-Delta model, which expands upon the previous Monk and Elowitz models Ciona the miRNA miR-124 downregulates Notch and all three Hes factors, and that these operate in a negative feedback loop We also demonstrate that regulation of Notch-Delta signaling by microRNAs (miRNAs) is conserved across bilaterians. The miRNAs are a class of conserved small RNAs that regulate expression of target genes through transcript destabilization, deanylation and/or translational inhibition, leading to downregulation of the protein product Ciona intestinalis, the tail epidermal sensory neurons (ESNs) differentiate from epidermal precursor cells within the dorsal and ventral midlines. Previous work in our lab and others In tion see . TherefoCiona. We began with a linear array of DrosophilaWith this quantitative experimental data in hand, we began drafting a Notch-Delta mathematical model that could adequately explain the patterning of midline ESNs in tage see , so our i.e., Notch ICD) in the cell; or it could be taken to stand for the quantity of downstream Hes TF in the cell. In addition, since the Notch-SuH-Hes cascade is linear and exhibits bistability , we can regard the states of Notch, SuH and Hes as equivalent, and can therefore consider any of these or all of these lumped together as the variable Consistent with previous minimal models, each cell tracks the activity of just two biochemical species, Delta  and led to above average levels of We wrote programs to simulate our Notch-Delta model using the Matlab When there was sufficient spacing between cells with high levels of cis-inhibition Because of the random initial conditions, different patterns of cells with high Ciona midline, we ran a Monte Carlo simulation with To determine if our model could explain the ESN pattern along the cis-inhibition, as in a previous study The parameters were chosen for the following properties. The value for ely ESNs . These cely ESNs . FinallyWe chose our Hill coefficients A stability analysis is used to determine equilibrium states of a system and the change in behavior of a system as the parameter values vary. This analysis is important because it allows us to determine the possible ESN patterns that can be produced from our model, and to rigorously determine if our model can really explain the biology. We therefore designed programs to help numerically find equilibria and allow the stability analysis of the equilibria. The stability analysis uses the Jacobian matrix analytically derived from linearizing the system (1) see .There is a unique homogeneous equilibrium for system (1). Related systems The Monte Carlo simulations showed the variety and large number of possible stable equilibria for model (1). This model can easily reproduce the stable alternating pattern of the previous Monk To help minimize the effects of the boundary, we varied the number of cells in our simulations to be as close as possible to The linear stability analysis of (1) with the parameters from i.e., differentiated ESNs.With MatLab we computed all eigenvalues and eigenvectors for each of the cases in The real part of the dominant eigenvalue, As Once The analysis above examines discrete changes in the spacing, e.g., Cells 9 and 11. Decreasing As Finally, we analyzed the change in behavior of the system as we increased the Notch decay rate parameter, nvectors , as wells  are highly stable, while the middle intervening cells (e.g. Cell 10) are in regions of lower stability. However, unlike with As in the case of l value  . The reaurcation . At , thilibrium . The behSignificantly, our analysis shows that increasing In the study of any model, it is important to determine which parameters have the greatest effects on the system. Our model is a high dimensional, nonlinear model with a large number of equilibria, so one would expect that the sensitivity of the model depends on the region of parameter space where the analysis is performed. Some equilibria will have large basins of attraction and will therefore be very robust to parameter changes, while other equilibria will have smaller basins of attractions and will be more sensitive. For this parameter sensitivity analysis, we examine variations of One measure for the sensitivity is the change in the value of the real part of the maximum eigenvalue. With the base parameters, we found Our study shows that in the case where  ,…  see . The leaand  see . Figure ibutions . We founarameter . The leaibutions . The robCiona intestinalisWe previously showed that the microRNA miR-124 is expressed in the larval midline ESNs of Ciona embryos (Here we generated transgenic embryos using this same miR-124 construct from our previous studies (Epi::miR-124) i.e., adjacent ESNs) increased as the concentration of miR-124 was increased. A magnified region of the embryo in Since miR-124 downregulates Notch and Hes by base pairing to their transcript a values . The varCiona, but throughout metazoans . Among these, miR-34 and miR-449 targeting of Notch in human airway epithelial tissue has been experimentally verified Drosophila, suggesting that such sensory miRNA regulation of the Notch receptor did not evolve until at least after ecdysozoans.We then bioinformatically searched for canonical target sites of these sensory miRNAs in the DrosophilaDrosophila and Ciona almost all of the Hes homologs have target sites, we observed that in vertebrates predicted targeting of Hes is much more restricted , even if the parameters are adjusted back to their original values.Finally, we provide a strong mathematical foundation for our model by performing rigorous stability analyses and bifurcation analyses of the key model parameters: the neuron spacing  is too strong in our initial model, and that tuning of the Hill coefficients may allow for production of adjacent ESNs more easily. Finally, there may be other yet unidentified local factors that counterbalance the feedback effect between neighboring cells, which we have not accounted for in our model. We will explore each of these possibilities in future studies.In order to fit our experimental observations, future work needs to be done on modifying the local interaction terms. Monte Carlo simulations of our model produce too many one-cell spacings compared to what we observe in wild-type larvae. When we adjusted the Notch decay rate parameter, Ciona, we emphasize that it can also be applied to many other biological and physical systems. At its core, we have developed a general mathematical model involving two chemical species, Ciona, this gradient is appropriate, since we do not assume these are diffusible species and are making no assumptions about the biological mechanism of long-range patterning. The presence of distal interaction greatly expands the number of possible equilibrium states of this system. Finally, as seen from our bifurcation analyses of several parameters, this is a high-dimensional system rich with at least hundreds of possible equilibrium steady states and a variety of interesting dynamics for which we have only begun to explore in this report. Since our model involves only two species and a minimal set of parameters, it is applicable not only to Notch-Delta systems, but is general enough to be applied to analogous biological and physical systems that exhibit both local and distal effects.Finally, although our model is motivated by our studies on Notch-Delta signaling in cis-regulatory and promoter region of the Acete-scute homolog, which showed expression along dorsal and ventral midlines in tailbud embryos cis-regulatory and promoter region as well as the conserved first intron of the Delta2 gene, which is expressed in the Ciona PNS  µg of each construct into fertilized and dechorionated embryos as previously described All of our transgene vectors were cloned in a pSP72 vector backbone (Promega) containing an SV40 Poly(A) site Our expanded Notch-Delta model represented by the ordinary differential equations in (1) begins with a linear array of The functions and the parameters in the model given by the ODEs in (1) are common in biochemical control models. In the cis-inhibition of The The system (1) was coded and simulated in Matlab  using the For stability analysis we need to linearize the system (1). We let We assume an equilibrium solution The Submatrices The diagonal form of the matrices Since the This term reflects the enhanced degradation of This reflects the enhanced production of For this version of the model we chose to make the boundaries substitute the average activity level for the end levels. This leads to small contributions in the For the submatrix This term reflects the enhanced degradation of Since the boundaries use the average activity level for the end levels, we obtain small contributions in the We noted that system (1) has many equilibria. For the Monte Carlo simulations we began the simulations with random low values  were counted for wild-type (wt) and miR-124 overexpression embryos . Significant differences between dorsal and ventral midlines are marked with an asterisk . Errors bars indicate SD. In the text, we consider statistical averages per midline without distinction between dorsal and ventral midlines, since overall across all experiments there are no substantial differences between dorsal and ventral counts.(EPS)Click here for additional data file.Figure S2Large ESN spacings are flanked on at least one side by a pair of closely spaced ESNs. (A) Representative image of a large (11-cell) spacing flanked on the anterior side by two neurons closely spaced. (B) Representative simulation run of our model showing the same phenomenon.(EPS)Click here for additional data file.Figure S3ESN counts and spacing distributions for changes in the parameters ,  and . (A–D) Monte Carlo simulations were performed when increasing or decreasing rameters , Fig 4, (PDF)Click here for additional data file.Figure S4Delta expression in the tail midlines detected using in situ hybridization. Delta shows specific expression in the presumptive ESNs along both the ventral and dorsal tail midlines.(PDF)Click here for additional data file.File S1MATLAB code for simulating the expanded Notch-Delta model.(TXT)Click here for additional data file.File S2MATLAB code for running Monte Carlo simulations.(TXT)Click here for additional data file.Movie S1Simulation run of expanded model leading to a stable equilibrium. The simulation begins at random low initial conditions. Because of the fast dynamics of the initial patterning, the first seconds are simulated at 5 time units per second, while the remainder of the movie is simulated at 50 time units per second.(AVI)Click here for additional data file.Movie S2Simulation run of expanded model leading to stable oscillations. The simulation begins at random low initial conditions. Because of the fast dynamics of the initial patterning, the first seconds are simulated at 5 time units per second, while the remainder of the movie is simulated at 50 time units per second.(AVI)Click here for additional data file.


The mapping of malaria risk has a history stretching back over 100 years. The last decade, however, has seen dramatic progress in the scope, rigour and sophistication of malaria mapping such that its global distribution is now probably better understood than any other infectious disease. In this minireview we consider the main factors that have facilitated the recent proliferation of malaria risk mapping efforts and describe the most prominent global-scale endemicity mapping endeavours of recent years. We describe the diversification of malaria mapping to span a wide range of related metrics of biological and public health importance and consider prospects for the future of the science including its key role in supporting elimination efforts. Like most vector-borne diseases, malaria endemicity is partly determined by the local environment that houses its human and anopheline hosts and mediates the interactions between them. This environmental dependency leads to complex patterns of geographical variation in malaria transmission at almost every scale. Risk is rarelyuniform whether considered between households in a village, villages in a district or districts in a country . The impIt is now nearly half a century since the Lysenko map was published and, during most of that period, few efforts were made to improve on it. However, initiatives such as the continent-wide Mapping Malaria Risk in Africa/Atlas du Risque de la Malaria en Afrique (MARA/ARMA) project , instigaIn this minireview we present a condensed overview of: (i) the main factors that have facilitated the recent proliferation of malaria risk mapping efforts; (ii) prominent global-scale endemicity mapping endeavours of recent years; (iii) the diversification of malaria mapping to span a wide range of related metrics of biological and public health importance; and (iv) prospects for the future of the science including its key role in supporting elimination efforts.ad hoc parasite rate data obtained, for example, from systematic literature searches. The influence of these large-scale programmes of national surveys, along with an increasing number of independent and nationally-led malaria indicator surveys, has transformed the availability of geolocated parasite rate data over the past decade  Program [ade Fig. .Fig. 2GrPlasmodium falciparum and Plasmodium vivax [Along with data on malaria infection prevalence itself, a vital component of modern disease mapping methods is the inclusion of high quality data layers describing environmental or socio-demographic variables that correlate with malaria risk and can be used as empirical covariates. The ongoing refinement of satellite and airborne remote sensing platforms, and commensurate sophistication of post-processing algorithms and computational infrastructure for storage and dissemination of the resulting imagery, has led to a huge diversity of variables being included as part of spatial malaria models, as reviewed elsewhere . In addium vivax –13. Receum vivax . With thum vivax , 15 and um vivax .The Lysenko map was constructed in the best traditions of manual cartography – with an emphasis on assimilating a wide variety of disparate data sources into a single synthesised map without any formal underlying quantitative framework. Whilst the result was an impressive summary of the state of knowledge existing at that time, this heuristic approach suffers a number of important drawbacks. Importantly, the likely accuracy of the map and how this varies from place to place can be neither measured nor communicated to end-users, placing a fundamental limitation on its use for critical public health decisions. In contrast, modern maps of malaria and other infectious diseases tend to result from formal spatial statistical models that aim to not only optimise accuracy but convey the spatially varying level of uncertainty associated with the mapped surface. The current state-of-the-art models tend to stem from a body of theory defined in the late 1990s known as model-based geostatistics (MBG) , 17. MBGNumerous studies have developed Bayesian geostatistical models to create national or multi-national maps of malaria risk, often intended to aid national malaria control programme policy decisions in specific regions and improve understanding of within-country patterns of spatial heterogeneity in malaria transmission and burden –38. AddiP. falciparum in 2009 by the Malaria Atlas Project [PfPR surveys, some important methodological advances were made [PfPR of a wider suite of 20 environmental and socio-demographic covariates to be incorporated, substantially improving predictive accuracy and the level of spatial detail that could be resolved.The first attempt to map malaria endemicity at global scales using MBG techniques was completed for  Project . This wa Project , delinea Project , and met Project  and the ere made . Early cP. vivax prevalence was produced by the Malaria Atlas Project [P. falciparum, the unique epidemiology [P. vivax is absent due to the near-fixation in the population of Duffy negativity – a genetic blood disorder that conveys near total protection from P. vivax infection. A detailed literature review, however, demonstrated the presence of the parasite in nearly all Africa countries. Rather than branding large swathes of the continent as being vivax-free, a more elaborate approach was developed that drew from data on both PvPR and population prevalence of the Duffy genetic trait [P. vivax, which suggested that morbidity and fatalities caused by P. vivax may be substantially underestimated [In that same year, a corresponding global endemicity map of  Project   in an MBG model to generate cross-sectional risk maps for the years 2000, 2005 and 2010 [PfPR in nearly all endemic Africa countries between 2000 and 2010, but in many cases these declines were relatively modest.These maps provided new benchmark evaluations of the contemporary landscape of malaria risk worldwide. For the first time, international policy makers could draw upon a standardised methodology that allowed meaningful country-to-country comparison of malaria risk exposure for national populations. Since the publication of these 2010 maps, there has been an increasing interest in extending the methodologies to allow prediction of risk both geographically and through time, motivated in part by the need to evaluate progress towards international targets set for the year 2015 . By mappnce 2000 . This anand 2010 . This anPfPR, in the context of any changes in underlying environmental conditions. This work provided important evidence on the impact of large-scale control efforts in Africa since the turn of the Millennium.A more recent study by the Malaria Atlas Project has also sought to evaluate changing risk patterns in Africa, for the more recent year of 2015, with some important differences in input data and approach  in Africa 2000–2017: coverage, system efficiency and future needs to achieve international targets, unpublished). Most significant was the development and incorporation of detailed spatio-temporal reconstructions of coverage patterns for the major malaria control interventions over the same time period : insectiR) and the burden of morbidity due to malaria in pregnancy.The developments in mapping malaria infection prevalence, described above, have spawned a larger and more diverse body of work, allowing maps of parasite rate to be used as an input to predict the distribution of a wide range of other malariometrics with distinct utility to biologists, epidemiologists and decision-makers. These have included the mapping of clinical incidence rates, entomological inoculation rates (EIRs), the basic reproductive number  is typically measured by one of two approaches: either by using direct data on observed cases detected via routine surveillance systems; or by using maps of infection prevalence and using a model to convert this metric into a plausible value of clinical incidence at each mapped location (known as the ‘cartographic’ approach). In much of sub-Saharan Africa, and in particular those countries with the higher malaria burdens, routine surveillance data are not considered sufficiently robust to use as a basis for estimating clinical incidence or evaluating trends through time . The devgression –50, and gression . In 2015PfPR [PfPR maps to describe the global distribution of the basic reproductive number, R, for P. falciparum malaria. R quantifies the potential of P. falciparum to spread throughout a population  and provides important insights into, for example, the magnitude of impact that control efforts must have at each location in order to drive transmission towards elimination.The EIR, or entomological inoculation rate, describes the number of expected bites from infected mosquitoes per person per unit time and is often used as a standardised measure of transmission intensity . Work haPfPR . In an aPfPR . The samP. falciparum [P. vivax endemicity [Estimates of the number of pregnant women at risk of malaria infection globally have been made  by combilciparum  and P. vdemicity , respectLong-term international policy around malaria control is increasingly reoriented to achieve progressive elimination of malaria country-by-country with the ultimate goal of reaching eradication of the disease , 56. An Further challenges in defining geographic patterns of risk arise from the issue of human movement. When cases become rare, the relative contribution of imported malaria – infections originating outside the eliminating country – tends to increase until they can become the primary reason for transmission being sustained. This complicates the description of risk patterns and necessitates an understanding of human movement alongside data on observed infections. In a study in Namibia, Tatem et al. integrated mobile phone data (which can serve as a proxy for human movement patterns) with case-based risk maps to predict hotspots of transmission in generally low-transmission settings . Other wThis review has summarised the evolution of malaria risk mapping over the past decade and the improvements in data availability, computational power and methodological developments that have facilitated it. This ongoing development has transformed malaria risk mapping from an art to a science, and can now bring mature and statistically robust approaches to bear on a diverse range of cartographic questions. As the global malaria landscape continues to change over the coming years, these geospatial approaches must continue to evolve in order to provide accurate descriptions of change, insight into the many factors driving those changes and, ultimately, to continue to contribute to evidence-based malaria control and elimination activities worldwide.


The choice of disease-specific versus generic scales is common to many fields of medicine. In the area of traumatic brain injury, evidence is coming forward that disease-specific prognostic models and disease-specific scoring systems are preferable in the intensive care setting. In monitoring prognosis, the use of a calibration belt in validation studies potentially provides accurate and intuitively attractive insight into performance. This approach deserves further empirical evaluation of its added value as well as its limitations. Critical Care, Raj and colleagues [In the previous issue of lleagues  report aScoring systems such as the Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores are commonly used in the intensive care setting to quantify the impact of disease severity and to benchmark the quality of delivered health care. These scoring systems are developed for use in the general ICU environment and are not disease specific. TBI is a very heterogeneous disease in terms of cause, pathology, severity and also in expected outcome. Disease-specific prognostic models for moderate and severe TBI have been developed and validated. These include the CRASH (Corticosteroid Randomisation After Significant Head Injury)  and the The performance of prognostic models is commonly evaluated by discrimination and calibration. Discrimination concerns the ability to distinguish between survival and death or favourable and unfavourable outcome. It is generally assessed by calculating the area under the receiver operating characteristic curve (AUC). Discrimination is influenced by both the validity of the model for a specific population  and the case mix of the validation population ,7. If thCalibration evaluates the agreement between observed and predicted outcome and can be graphically presented in plots. The often used Hosmer-Lemeshow test considers deciles of patients with similar risk, and reflects the average concordance of expected outcome compared to the observed outcome analyzed. Limitations of the Hosmer-Lemeshow test mentioned by the authors include that it may be non-informative in large data sets , and that the division of the patient cohort into deciles does not account sufficiently for the individual patient.As a relatively new instrument to assess calibration, the authors utilised a calibration belt. This approach was developed and tested within the GiViTI consortium in Italy  and was taken forward in a larger ICU network named Prosafe through EU funding (PHEA 2007 331). These studies are now coordinated in the CREACTIVE Project . Within this project, TBI-specific prognostic models will be developed to be used as a benchmark for quality of care assessment in individual ICUs. The calibration belt relates the observed and the expected probability of a dichotomised outcome. Importantly, the calibration belt calculates the 80% confidence interval and the 95% confidence interval surrounding the calibration curve. This instrument thus potentially provides accurate and intuitively attractive insight into calibration performance. As with any new instrument, however, its validity has to be demonstrated in broad settings and validated by other groups. Limitations may only become apparent with greater experience. It is not quite clear how dependent the calibration belt and, in particular, the calculated confidence interval may be upon the relative number of patients with specific prognostic risks. Adding the distribution of patient numbers across the plotted curves would provide additional insight. Notwithstanding this potential limitation, this approach in which disease-specific aspects are combined in an intuitively attractive novel instrument is worthy of further exploration and validation.AUC: Area under the receiver operating characteristic curve; CRASH: Corticosteroid randomisation after significant head injury; GCS: Glasgow coma scale; IMPACT: International mission for prognosis and analysis of clinical trials in TBI; TBI: Traumatic train injury.The authors declare that they have no competing interests.


The formation of the East African Rift System has decisively influenced the distribution and evolution of tropical Africa’s biota by altering climate conditions, by creating basins for large long-lived lakes, and by affecting the catchment and drainage directions of river systems. However, it remains unclear how rifting affected the biogeographical patterns of freshwater biota through time on a continental scale, which is further complicated by the scarcity of molecular data from the largest African river system, the Congo.We study these biogeographical patterns using a fossil-calibrated multi-locus phylogeny of the gastropod family Viviparidae. This group allows reconstructing drainage patterns exceptionally well because it disperses very poorly in the absence of existing freshwater connections. Our phylogeny covers localities from major drainage basins of tropical Africa and reveals highly disjunct sister-group relationships between (a) the endemic viviparids of Lake Malawi and populations from the Middle Congo as well as between (b) the Victoria region and the Okavango/Upper Zambezi area.The current study testifies to repeated disruptions of the distribution of the Viviparidae during the formation of the East African Rift System, and to a central role of the Congo River system for the distribution of the continent’s freshwater fauna during the late Cenozoic. By integrating our results with previous findings on palaeohydrographical connections, we provide a spatially and temporarily explicit model of historical freshwater biogeography in tropical Africa. Finally, we review similarities and differences in patterns of vertebrate and invertebrate dispersal. Amongst others we argue that the closest relatives of present day viviparids in Lake Malawi are living in the Middle Congo River, thus shedding new light on the origin of the endemic fauna of this rift lake. The formation of the East African Rift System (EARS) played a decisive role in the evolution of Africa’s tropical fauna and flora. The climatic, geological, and hydrological consequences of the rifting processes are critical to understand the emergence of the endemic species of the savannahs and the Great Lakes as well as the origin of humankind. Rifting created, disrupted, redirected, and connected major freshwater systems .The three largest drainage systems in present-day Central Africa are the Congo-, the Nile-, and the Zambezi system Figure . The ConMost suggestions of palaeohydrological connections in tropical Africa are based on circumstantial evidence in combination with general models of rifting and uplifting  rather tHere we study the historical biogeography of the freshwater gastropod family Viviparidae, a taxon widely distributed in the lotic and lentic environments of tropical Africa . This faWe obtained samples from the major drainage systems in the region, i.e. that of the Nile, the Okavango, the Zambezi as well as the Upper and Middle Congo. Using Bayesian multi-locus phylogenetic analyses and a fossil-calibrated, relaxed molecular clock we studied the diversification and distribution of viviparids in Africa. In light of the impact of the evolution of the EARS on African hydrographic systems and the dependence of our model organism on these systems to disperse, we expect a deep phylogenetic separation between viviparid species east and west of the western branch of the rift system. We furthermore hypothesize this separation to temporarily coincide with the disruption of freshwater migration routes across the evolving rift.Neothauma group from Lake Tanganyika . We thus tentatively name specimens with an ambiguous status in current systematics using ‘confer’ (cf.) to emphasize that taxonomic revisions are required.The phylogenetic structure revealed by Figure  equator . The typWe focus on estimates for the ages of the following three nodes in Clade I Figure : Split AThe phylogenetic reconstruction reveals two, geographically highly disjunct sister-group relationships in Clade I Figures  and 3-4:In order to explain our findings we integrated our phylogenetic information with literature data on palaeohydrographical connections to provide a synthesized, spatially and temporarily explicit model of historical freshwater biogeography in tropical Africa. Subsequently, we review recently published studies on African fish biogeography and evaluate similarities and dissimilarities of vertebrate and invertebrate dispersal patterns.Changes in the structural geology of East Africa associated with uplifting and rifting  as well (1) The earliest African viviparid fossils were found in tropical regions  Additio. We thus2) Subsequently this ancestral lineage split into the Congo-Malawi- and the Victoria-Okavango-cluster  In the Late Miocene/Early Pliocene the Okavango group started to separate from the Victoria group  Subsequently the connection between Lake Malawi and the Chambeshi/Upper Congo system ceased, which separated the Congolese from the Malawian Bellamya fauna to that of the Middle Congo. In light of the well-supported reciprocal monophyly of both groups we argue that the separation of the Congo-Malawi-cluster  nor ß et al. . In any Neothauma is currently endemic to Lake Tanganyika, this has not been the case from the Late Miocene to the Early Pleistocene when the genus radiated in Palaeolake Obweruka [Neothauma lineage from Lake Tanganyika evolved fairly isolated from the African Bellamya .A striking difference between viviparid and fish patterns lies in the phylogenetic relationships of taxa from the modern Lake Victoria region: fish specimens from the Lake Victoria region cluster generally with other East African species, e.g. ,50,52,53Eventually, the rifting process separated the two viviparid clusters into the four modern groups  subsequently to Split A. Each of these groups is (much like in fish) confined to one side of the western branch of the EARS.This pattern and comparative biogeography sheds new light on freshwater migration corridors over the emerging rift. African tigerfish, for example, were suggested to have migrated during the Late Miocene along an east–west corridor from the Tanzanian Rufiji-Ruaha system via the Luangwa to the Upper Zambezi and the Okavango , crossinWith the exception of some branches in Clade II, our phylogeny generally features strict regional monophyly—a pattern often absent in biogeographical studies of fish in tropical Africa, e.g. ,12,55. TBellamya, as our work reported considerable incongruences between traditional taxonomy and the results of molecular phylogenetic analyses, e.g. [The decisive phylogenetic pattern notwithstanding, further sampling is required to substantiate the proposed model. In particular, more sampling from the central Congo area is desirable despite logistic challenges, e.g., to search for putative remnants of the Victoria-Okavango-cluster  is reported from the Upper Miocene Kakara Formation from the western branch of the East African Rift System and is 10–11 My old [Neothauma clade . Uncorrelated lognormal relaxed clock models were chosen to account for lineage specific rate heterogeneity within each partition; mixing of the Markov chains was monitored with Tracer 1.5 [We ran five independent Bayesian phylogenetic reconstructions (partitioned into the four DNA fragments) in BEAST 1.75  to ensur9 My old . To impl9 My old -68. The 1 My old ,69. For acer 1.5 .Ancestral area/state reconstructions as implemented in, e.g., Lagrange, BEAST and Mesquite are not feasible with the present datasets for two reasons. First, the basal topology of the African viviparids is unresolved, whereas a dichotomy is needed to reconstruct the ancestral state and the dichotomy-enforcing algorithm of BEAST would result in low node supports. Secondly, the four major groups of Clade I  form a dichotomous topology Figure , resultihttp://purl.org/phylo/treebase/phylows/study/TB2:S15381.The data sets supporting the results of this article are available in the treeBASE repository, EARS: East African Rift System; BPP: Bayesian posterior probabilities; cf.: Confer; mrca: Most recent common ancestor; My: Million years; CI: Confidence interval; COI: Cytochrome oxidase subunit I; LSU rRNA: Large subunit of ribosomal RNA.The authors declare that they have no competing interests.RS analysed the data, developed the model and led the writing of the manuscript. BVB developed the fossil framework of the study and contributed to the model building and writing. FR, TvR, and CA designed and coordinated the study; TvR and CA provided the DNA sequences. Material was collected by FR, BVB, and RS. All authors read and approved the final manuscript.All DNA sequences used in this study are available from NCBI GenBank. Accession numbers are provided in Table The supplementary file contains additional information on the phylogenetic analyses conducted during this study. We furthermore provide the results of the separate analyses of nuclear and mitochondrial data.Click here for fileThe supplementary file contains additional information on the fossil record of the African Viviparidae and the dating constrains employed in the phylogenetic analysis of this study.Click here for file


There have been developments and applications of osteogenic biomaterial substitutes in dentistry to replace missing dentition or to reinforce existing dentitions. The dentistry in practice has evolved into new treatment modality with the development and application of novel biocompatible materials. The examples are dental implants, bone graft materials, surgical plates, and any modification to increase biocompatibility and stability in dentition. These materials cover everything from replacing the missing teeth and/or degenerated supporting structures to the induction of new bone formation. Also, the osseointegrated materials further allowed orthopedic force application on these materials as skeletal anchorage to control tooth movements. Currently, modifications of the surface treatment or combination of osseoinductive materials to improve potential osseointegration are continuously endeavored.This special issue delivers original research on different aspects, studies on the application of the novel biomaterials to fill bone defect rapidly with new bone, improvement of osseointegration through variety of surface treatment, and the possibility of alumina toughened zirconia for the new implant material, and also covers clinical research on a modified dental implant as a gateway to the human body: implant mediated drug delivery system.First, we discuss the studies of novel biomaterial application for new bone formation in bony defect. Rapid bone defect filling with normal bone is a challenge in orthopaedics and dentistry. A study by S. Ansari et al. developed a strategy for bone tissue engineering that entails application of immobilized anti-BMP-2 monoclonal antibodies (mAbs) to capture endogenous BMPs in vivo and promote antibody-mediated osseous regeneration (AMOR). These data have potential implications for the mechanism of action of AMOR, suggesting that anti-BMP-2 may capture endogenous osteogenic BMPs, which may in turn mediate de novo bone formation. Strontium ranelate (SrRan) has been shown to in vitro decrease bone resorption and increase bone formation and represents a potential agent with the capacity to accelerate bone defect filling.G. Zacchetti et al.'s study demonstrates that Sr is integrated both in cortical and in trabecular bone healing of the defect in SrRan-treated rats and improves the bone material level properties of the healing bone mainly after 4 weeks of treatment. These results open up new perspectives for the use of SrRan in clinical studies as a pharmacologic agent with a potential beneficial effect on bone defect repair.A. Monje et al.'s comprehensive systematic review aimed at assessing the feasibility of allogeneic block grafts by means of survival rate, histologic analysis, and causes of failure, for augmentation of the atrophic maxilla, provides a current state of the art about this treatment modality. Therefore, this study can be of a very meaningful importance for clinicians in the decision making of selecting the ideal source for bone block grafting.This special issue illuminates the clinical evaluation of the bone graft materials that have been used conventionally and introduces the histological identification of changes in tissue adjacent to the biomaterials through three original research articles. Particularly, clinical experiment on the management of the thin alveolus which has been considered as tooth movement limitation in orthodontics and the scientific analysis of the methods have been discussed in depth.Alveolar augmented corticotomy is effective in accelerating orthodontic tooth movement, but the effect only lasts for a relatively short time. A study by D.-Y. Lee et al. demonstrated the stable results in a long-term (12 weeks) experiment using xenograft materials in beagle experiment. Absorbable collagen membrane could control the texture of bone surface.K.-B. Lee et al. researched the different types of bone graft materials on the treatment effect of augmented corticotomy. The remarkable thing is that not only allograft or xenograft but also synthetic graft material showed comparable new bone formation. Augmented corticotomy showed stable results regardless of the graft material types, and in particular synthetic bone material showed dramatic new bone formation.The study of H.-J. Choi et al. was to investigate the underlying biology of the immediate periodontal response to orthodontic tooth movement after the augmented corticotomy with alloplastic bone grafts. The results demonstrated that measurable tooth movement began as early as 3 days after the intervention in beagle dogs. Based on the results and histological findings, augmented corticotomy-facilitated orthodontic tooth movement might enhance the condition of the periodontal tissue and the stability of the outcomes of orthodontic treatment.There has been increased interest in search of the new biomaterial for dental implant. We would like to examine the possibility of alumina toughened zirconia for the new implant material through several articles.S. Y. Kim et al.'s study classified the influence of different topographies and hydrophilicities of Ti surfaces on the expression of various functional factors in PDLSCs involved in osteogenesis in the absence of osteogenic supplements and evaluated biomarkers of cellular activity, including the expression of transcription factors and signaling molecules of PDLSCs on the Ti surfaces.The relevance of J. Markhoff et al.'s research was to develop a glass solder matrix for coating zirconia ceramics to improve osseointegration of ceramic dental implants with adequate mechanical properties at once. Thereby, the existing advantages in esthetic appearance and hypersensitivity of ceramic dental implants in contrast to metallic implants may become effective in clinical application in the near future.α,25(OH)2D3 had a major role in enhancing these effects that was sex depended.The results of R. Olivares-Navarrete et al.'s study indicate that effects of the complex SLA topography are greater than the effect of acid etching or grit blasted on regulation of osteogenesis, osteoclastogenesis, and angiogenesis on multipotent BMCs and committed osteoblasts. 1Alumina-zirconia composites have attracted significant interest in the past few years for orthopedic and dental use. Although yttria stabilized zirconia is the only ceramic currently employed for dental implant fabrication, several reasons suggest that alumina-zirconia composites may conveniently substitute this monolithic material. Here, F. Mussano et al. report the results of the experiments performed in vitro and in vivo to assess the behavior of alumina toughened zirconia (ATZ) dental implants. It is important to underline that ATZ is different from zirconia-toughened alumina (ZTA) due to the relative percentage of the two materials and the consequent mechanical and possibly biological properties.Another topic enlightened in this special issue is dental implant. It is about neither improving osseointegration potential nor improving functional occlusion of implant, but it is a preliminary study on the prospect of dental implant as a drug delivery system. In an article by Y.-S. Park et al., they developed and proposed a new implant mediated drug delivery system (IMDDS) through a modified titanium implant. In the nearest future, the IMDDS may provide a novel approach to treat patients with chronic diseases.In conclusion, we debated about the current status of osteogenic biomaterials in contemporary dentistry, the osteogenic biomaterial types, the application of the material, and the future study. We would like to suggest a right direction of osteogenic biomaterial in this special issue because comprehension of recent advances in biomaterial of dentistry would lead to appropriate applications of these biomaterials and successful strategies to improve treatment outcomes to better serve patients.Seong-Hun KimJae-Pyung AhnHomayoun H. ZadehEric J. W. Liou


Thunnus thynnus), the reproduction and spawning biology remains poorly understood, especially in the NW Atlantic. At present, the eastern and western spawning populations are believed to exhibit different reproductive characteristics and, consequently, stock productivity. However, our study suggests that the two spawning populations, the Gulf of Mexico and the Mediterranean Sea, could show similar reproductive features and spawning strategies. Between 2007 and 2009, gonad samples from female Atlantic bluefin tuna were collected in the northern Gulf of Mexico (n = 147) and in the western Mediterranean Sea (n = 40). The histological and stereological analysis confirmed that sampled eastern and western bluefin tuna exhibit the same spawning duration (three months) but the spawning in the Gulf of Mexico begins one month earlier than in the Mediterranean Sea. Western bluefin tuna caught in the peak of the spawning season (May) showed a similar spawning frequency (60%) to the spawning peak observed in the Mediterranean Sea (June). Fecundity for the Gulf of Mexico fish (Despite attention focused on the population status and rebuilding trajectory of Atlantic bluefin tuna ( Thunnus thynnus, L. 1758) remains poorly understood despite the high economic value of this fishery and its exploitation throughout the Atlantic Ocean and the Mediterranean Sea. These uncertainties directly affect our understanding of the recruitment and productivity of the stock and could result in inefficient management of the fishery. The International Commission for the Conservation of Atlantic Tunas (ICCAT) manages the population as two stocks (eastern and western), separated at The reproductive biology of Atlantic bluefin tuna , lipid-stage (LSF), vitellogenic (VF), and oocyte maturation follicles (OMF), which consisted of migratory-nucleus (MNF) and hydrated (HF) follicles. Additionally,  counted . Based oSpawning frequency was estimated by the postovulatory follicle method K is a size distribution coefficient, K previously calculated for ABFT were used for this study N) was calculated by extrapolating A stereological model-based method was applied to estimate numbers of the different categories of follicles according to the formula, Comparisons of means of the stereological and biometrical parameters among years were performed using the Kruskal-Wallis test, and parameters with no significant difference were regrouped by month  females was less than 20% of our sample except in 2007 (28.0%). The proportion of active non-spawning (ANS) females was 20.0% (2007), 50.0% (2008) and 30.0% (2009). The proportion of active spawning (AS) females was consistent at about 50% for all years . Given tWhen ovary samples were arranged by month, consistent differences in the reproductive condition were observed with increasing maturation throughout the sampling period . In the Spawning fraction in the GMX was estimated to be 0.45 throughout the sampling period as 49 out of 108 mature females contained POFs in their ovaries. When this parameter was calculated by month, the proportion of females with POFs caught in April was lower than that in May and June. When the spawning frequency was calculated considering only AS females, its value increased significantly and remained similar among months. The spawning fraction in the MED samples was higher (0.60) than in the GMX .NLSF) and the relative number of LSF (NgLSF) estimated in GMX fish in April was significantly higher than in June. In general, stereological counts of LSF quantified in the MED showed significantly lower values than those from the GMX sampled in April and May. Although the mean number of VF per NVF) remained unchanged in the GMX, the relative number of VF (NgVF) was significantly lower in June than in May. NVF estimated in the MED were similar to the GMX values in June; however, because eastern fish were smaller than western fish on average, the relative number of VF (NgVF) was much higher for MED fish. The low number of females with MNF and HF is likely the cause for finding no significant differences for these stages throughout the sampling period in the GMX. The highest number of POF  occurred at the beginning of the sampling period (April) and the lowest values were observed in June; however, no significant differences were found either among months or between the spawning areas. The realized fecundity estimated as the mean absolute number of POFs . Such restrictions prevent comprehensive size sampling of spawning ABFT in the GMX and hinder the determination of the spatial and temporal extent of western spawning Histological analysis of gonad samples from the spawning grounds throughout the spawning season is essential for evaluating the reproductive condition and performance of ABFT. Additionally, systematic sampling across the extent of the spawning grounds allows the study of temporal variations in key reproductive parameters, such as sex ratio, proportion of mature fish, spawning frequency, and spawning periodicity and fecundity. This information was lacking for the western stock resulting in large uncertainties for stock assessment and evaluation of productivity As a result of the bycatch sampling, previous studies have lacked small/medium fish  Prior to the US moratorium, catch records indicated the presence of only giant ABFT  individuals, 31% of samples collected in April were AS individuals. As the spawning season progressed, the number of AS females increased and peaked in May (60%). The In spawning fish, atresia is a natural mechanism for regulating the number of eggs spawned. Alternatively, massive atresia can indicate a cessation of oocyte maturation and/or spawning activityWhile ABFT have been observed on the western spawning grounds for months during the spawning season The relatively low proportion of GMX females with POFs in their ovaries , but spawning in the northern GMX occurs one month earlier than in the western Mediterranean spawning ground. This is likely due to specific oceanographic conditions and the early warmer temperatures observed in the GMX (data from CCA-UNAM). In this study, we have observed similar values in bluefin reproductive parameters showing that the spawning condition of Mediterranean spawners from mid-June to mid-July is comparable with the reproductive peak observed in the GMX in May. Depth and temperature associations of electronically tagged ABFT entering the GMX in winter also suggest that it also serves as a foraging ground A more holistic view of the population dynamics of ABFT requires life history characteristics, reproductive profiles, and spawning areas and periodicity to be well defined, especially since they undoubtedly will change with shifts in climate and ocean productivity


To assess whether reports from reviewers recommended by authors show a bias in quality and recommendation for editorial decision, compared with reviewers suggested by other parties, and whether reviewer reports for journals operating on open or single-blind peer review models differ with regard to report quality and reviewer recommendations.Retrospective analysis of the quality of reviewer reports using an established Review Quality Instrument, and analysis of reviewer recommendations and author satisfaction surveys.BMC Infectious Diseases and BMC Microbiology are similar in size, rejection rates, impact factors and editorial processes, but the former uses open peer review while the latter uses single-blind peer review. The Journal of Inflammation has operated under both peer review models.BioMed Central biology and medical journals. BMC Infectious Diseases, 200 reviewer reports submitted to BMC Microbiology and 400 reviewer reports submitted to the Journal of Inflammation.Two hundred reviewer reports submitted to BMC Infectious Diseases, BMC Microbiology and the Journal of Inflammation). For BMC Infectious Diseases, the overall quality of reviewer reports measured by the Review Quality Instrument was 5% higher than for BMC Microbiology (p=0.042). For the Journal of Inflammation, the quality of reports was the same irrespective of the peer review model used.For each journal, author-suggested reviewers provided reports of comparable quality to non-author-suggested reviewers, but were significantly more likely to recommend acceptance, irrespective of the peer review model (p<0.0001 for BMC Infectious Diseases were of higher quality than single-blind reports for BMC Microbiology. There was no difference in quality of peer review in the Journal of Inflammation under open peer review compared with single blind.Reviewers suggested by authors provide reports of comparable quality to non-author-suggested reviewers, but are significantly more likely to recommend acceptance. Open peer review reports for  BMC Microbiology operates single-blind peer review while BMC Infectious Diseases operates open peer review).This is the first study to compare quality of peer review between two journals that are very similar in most aspects but differ in peer review model .It is the first study to analyse the effect of change in peer review model across a single journal , resulting in a well-powered study in three different journals publishing research in both biology and medicine.BMC Infectious Diseases and BMC Microbiology, and did not confer about their ratings for individual reports for any journal.We observed moderate agreement between raters for peer review report quality, although the raters did not discuss the rating for Journal of Inflammation section of the study than that used for the BMC Infectious Diseases and BMC Microbiology section, due to insufficient number of manuscripts fulfilling the inclusion criteria.We had to use a different study design for the Most scholarly journals operate one of three types of peer review models: single blind, where the reviewers know the identity of the authors but not vice versa; open peer review, where authors and reviewers both know each other's identity, or double-blind peer review where the author and reviewer names are both blinded. Some journals publish reviewer reports (signed or anonymous) and authors’ responses together with accepted articles. Many journals allow, or in some cases require, authors who submit manuscripts to suggest potential reviewers. This information is available to editors who are responsible for selecting appropriate reviewers.Previous studies have compared quality of reviewer reports under open and single-blind peer review across various journals,The objective of this study was to assess whether the reviewers suggested by the authors are biased in their assessment of a manuscript, and whether the quality of their reports is different from reports prepared by reviewers suggested by editors. A second objective was to compare open peer review with single-blind peer review. This study was the first to analyse a large number of reviewer reports  in both medical and biology journals, and compare quality of reviewer reports between open and single-blind peer review models and between author-suggested and non-author-suggested reviewers.The initial findings from this research were presented in poster format at the 7th Peer Review Congress in Chicago in 2013. The poster has been deposited on F1000 Posters.10BMC Microbiology, which operates single-blind peer review, and BMC Infectious Diseases, which operates open peer review. BMC Microbiology and BMC Infectious Diseases were launched in 2000 as part of the BMC series of journals.BMC Microbiology and BMC Infectious Diseases are similar in terms of size, impact factors and rejection rates, and cover similar subject areas . This was achieved by searching the journal's database for consecutive submissions in the analysed period 2010–2011. The Journal of Inflammation published fewer original research articles and a larger proportion of review articles and case reports that were not suitable for our analysis. In the Journal of Inflammation, we analysed 200 reviewer reports for research manuscripts submitted consecutively counting back from the date of change of peer review model (under open peer review), and 200 counting forward (under single-blind peer review). There was an insufficient number of research article submissions that had two reviewers, one suggested by the authors and one by another party. We analysed 193 manuscripts, in total, that had between one and five reviewers. As a result, for the Journal of Inflammation, we analysed reports spanning a longer period of time (2007–2011), and the number of reports provided by author-suggested reviewers was not equal to that provided by non-author-suggested reviewers . In each of eviewers .BMC Microbiology and BMC Infectious Diseases, formal discussions were not held between the raters on how to use the RQI. However, before analysing reports for the Journal of Inflammation, the raters agreed on the criteria for each score on the RQI before rating the peer review reports (see Discussion section).Each peer review report was rated using an established Review Quality Instrument (RQI)For the journals studied, peer reviewers could choose one of six recommendations suggested in the reviewer form, or choose not to provide recommendation. To facilitate the analysis, we grouped these recommendations into four categories .All corresponding authors were asked to complete author surveys after publication of their article . The survey consists of 18 questions related to different aspects of the editorial and production processes, of which one is, ‘How helpful were the reviewers’ comments?’. The authors were asked to score their answers to the questions on a scale from 1 (very poor) to 5 (very good). We compared the authors’ ratings for the question on the helpfulness of peer review comments compared to scores for other questions.It was previously shownBMC Microbiology and BMC Infectious Diseases (in which each article had one reviewer of each type), and using the unpaired test in the Journal of Inflammation. Bonferroni correction was applied for eight tests in each journal.Inter-rater agreement was measured by weighted κ with quadratic weights. For each article and reviewer, the mean of the two rater scores was then used in subsequent analyses. Review quality was compared between open and single-blind review models using the unpaired Mann-Whitney U test. Review quality was compared between author suggested and other reviewers, using the paired Mann-Whitney U test in To test whether author-suggested reviewers were more positive than other reviewers, we coded reviewer recommendations as reject=0, revise=1, or accept=2, and treated this value as the response in linear regression with reviewer type (author suggested or other) as the predictor. Interaction terms with review model (open or single blind) were included in exploratory analysis but dropped if found to be non-significant.Association of reviewer recommendations with the review model was tested in logistic regression with review model (open or single blind) as the response, and reviewer recommendation coded as a three-level categorical predictor .Association of reviewer recommendations with the final decision was tested in logistic regression with the final decision as the response and reviewer recommendation coded as a three-level categorical predictor  with different effects for author-suggested and non-author-suggested reviewers. Interaction terms with review model (open or single blind) were also included in exploratory analysis but dropped if found to be non-significant.In all regression analyses, each review was treated as one observation and cluster SEs used to allow for multiple reviews of each paper.Responses to author surveys were tested using the two-sample Mann-Whitney U test.All analyses were conducted in R.The analysed journals and reports are shown in tables 1BMC Microbiology and BMC Infectious Diseases, with weighted κ values generally around 0.4 or higher. For the Journal of Inflammation, where the raters agreed on the criteria for each score of the RQI before rating the reports, the agreement was stronger for six of eight questions, but still in a moderate range (see online supplementary table S1). Our agreements were lower than found in previous studies using the RQI,We found moderate agreement between the raters for BMC Infectious Diseases (open peer review) compared with BMC Microbiology , 5 (constructiveness) and 6 (supplying appropriate evidence to substantiate comments) of the RQI, there was a significantly higher score for Journal of Inflammation, however, no significant differences were seen in review quality between open and single-blind models (see online supplementary table S2).For the BMC Infectious Diseases (open peer review) than the scores obtained by reviewers in BMC Microbiology (single-blind peer review). However, these differences are not significant when adjusted for multiple testing. No other questions showed significant differences between author-suggested and non-author-suggested reviewers (see online supplementary tables S3 and S4).There is nominally significant evidence that non-author-suggested reviewers obtained higher scores on Q6 (how well the reviewer substantiated their comments) and Q7 (comments on the author’s interpretation of results) in Journal of Inflammation, a nominally significant difference in review quality was seen for Q3 (comments on strengths and weaknesses of the method), but this was not significant after correction for multiple testing. No other significant differences were seen in review quality between author suggested and other reviewers (see online supplementary table S5).In the BMC Infectious Diseases (open peer review) and BMC Microbiology (single-blind peer review) the numbers of reviewer recommendations of each kind were similar, suggesting a lack of difference between open and single-blind peer review models . About two-thirds of author-suggested reviewers recommend acceptance and only 2–5% recommended rejection . Again, there was no significant difference between open and single-blind review models  compared with the author-suggested reviewer (p=1.3×10−5). There were no differences between BMC Infectious Diseases and BMC Microbiology in this respect. However, in the Journal of Inflammation, there was no significant difference between author-suggested and non-author-suggested reviewers in predicting the final decision.We found 13 manuscripts in BMC Microbiology (single-blind peer review), 685 for BMC Infectious Diseases (open peer review) and 49 (open peer review) and 47 (single-blind peer review) for the Journal of Inflammation.We analysed all author surveys that were available at the end of September 2013: 741 surveys for BMC Infectious Diseases felt that reviewer comments were more helpful than did the authors in BMC Microbiology . However, most other questions relating to managing other editorial and production processes on the manuscript tended to be scored more favourably (p<0.05) as well.Authors in Journal of Inflammation, we did not find statistically significant differences between surveys returned by authors of manuscripts that underwent open or single-blind peer review, for any question regarding the editorial and production processes.For the BMC Infectious Diseases (open peer review) and BMC Microbiology (single-blind peer review), two journals that differ in peer review model but are otherwise very similar. We also assessed the effect of change in peer review model within a single journal, the Journal of Inflammation, which has changed its peer review model. It gave us unique opportunity to assess the impact of the peer review model on the quality of peer review and recommendations made by the reviewers. In the analysed journals, we were also able to compare the quality of reports and recommendations provided by reviewers suggested by the authors, compared with reviewers suggested by other parties . The large sample size of analysed reports ensured statistically robust results.The peer review process in journals has been criticised for being slow, inconsistent and biased.BMC Infectious Diseases (open peer review) compared with BMC Microbiology (single-blind peer review), but we did not find a difference for the open versus single-blind review in the Journal of Inflammation. These results suggest that it may be advantageous to use open peer review but they do not undermine the validity of using the single-blind approach.The main findings are that the quality of peer review reports was slightly higher in quality of peer reviewer reports written by author-suggested reviewers compared with those written by reviewers suggested by other parties, but in all three journals the reviewers suggested by the authors were much less likely to recommend rejection and more likely to recommend acceptance than reviewers suggested by other parties. Overall reviewer recommendations were similar in BMC Infectious Diseases compared with BMC Microbiology, suggesting no difference between open and single-blind peer review. However, in the Journal of Inflammation, we found that reviewers were more likely to recommend acceptance under open peer review as compared with under single-blind peer review. Author satisfaction was higher for BMC Infectious Diseases compared with BMC Microbiology, including the response to the question regarding the helpfulness of comments from peer reviewers. In the Journal of Inflammation, there was no difference in author satisfaction between the periods of time when the journal operated on open or single-blind peer review.In none of the three analysed journals did we find a difference in BMJ was one of the first journals to open up peer review in 1999.BMJ study found no significant differences between the anonymous and non-anonymous reviewers with regard to the quality of their reports.2The single-blind peer review model is the most common model of peer review used in journals in the field of biology and medicine. The British Journal of Psychiatry.BMC Microbiology (single-blind peer review) and in BMC Infectious Diseases (open peer review). Moreover, the signed reviewer reports scored significantly higher on the same two questions as our open reports for BMC Infectious Diseases (Q3 regarding methodology and Q5 regarding constructiveness of comments). It was also very encouraging to see that, of the 322 reviewers, as many as 245 (76%) agreed to sign their reports for the British Journal of Psychiatry.13Another study of open peer review, using a modified version of the RQI,Under open peer review, reviewers are more accountable for their reviews, which may account for the higher scores we observed for Q3 (discussing the strengths and weaknesses of the method), Q5 (the more constructive reports) and Q6 (supplying appropriate evidence to substantiate the comments), which led to a 5% improvement of the overall score (p=0.042).BMC Infectious Diseases compared to reviewer reports for BMC Microbiology, although it did not reach statistical significance .There is another possible explanation for the higher score that reviewer reports obtained on open peer review for Question 3 . Medical research follows several distinct types of defined study designs  and BMC Microbiology (single-blind peer review), recommendations made by non-author-suggested reviewers were a better predictor of the final decision to accept or reject the manuscript than recommendations made by author-suggested reviewers. It seems that these reviews carried more weight with journal editors (unconsciously or consciously).Author-suggested reviewers tend to provide more favourable recommendations than other types of reviewers. This result is consistent for the three journals we analysed, irrespective of the peer review model. This is also consistent with previous studies on this topic.Journal of Inflammation, we found that reviewers provided significantly more favourable recommendations under open peer review. This effect was found in some of the previous studiesJournal of Inflammation is smaller than BMC Microbiology or BMC Infectious Diseases, and its analysed reports span a longer period of time, from September 2007  to September 2011. The change in peer review model was also accompanied by a change in editorship and coincided with the journal receiving its first impact factor. It is possible that these factors impacted on how the peer reviewers were selected, and how they perceived the journal and made recommendations.In the BMC Infectious Diseases (open peer review) gave slightly higher scores for the question on the helpfulness of reviewers’ comments, compared with BMC Microbiology authors (single-blind peer review). However, they also gave higher scores for every other question, so it may be the case that the overall editorial process was perceived to be better at BMC Infectious Diseases, or that it simply reflects different priorities among research fields. The score for the Journal of Inflammation regarding helpfulness of peer reviewers’ comments was higher for open than for single-blind peer review, but did not reach significance.Authors on The RQI17BMC Microbiology (single-blind peer review) and BMC Infectious Diseases (open peer review), formal discussions on how to use the RQIJournal of Inflammation, the raters explicitly discussed the rating scale and agreed broadly on how they would score individual questions in general terms. Following this, we found improved rater agreement for all questions (see online supplementary table S1). However, the raters did not confer about the ratings for individual reports for any journal. The raters were not blinded to the identity of the reviewers. However, as the raters were not involved in managing peer review on these journals, the names of the reviewers were not familiar.We found only a moderate level of agreement between the raters of the quality of referee reports. Prior to rating the quality of reports for Journal of Inflammation as used for BMC Infectious Diseases and BMC Microbiology. The Journal of Inflammation did not have a sufficient number of manuscripts reviewed by two referees, one of whom was suggested by the authors and one not. As a result, we did not have an equal number of reports from author- and non-author-suggested reviewers.We were not able to use exactly the same research design for the Journal of Inflammation. Although we analysed all available author surveys, it is possible that the lack of statistical significance of the results is due to the low number of available surveys rather than the lack of impact of peer review model.Another limitation of the study is the low number of author surveys available for the BMC Microbiology and BMC Infectious Diseases because the journals have a similar profile (Journal of Inflammation may reflect temporal trends, such as the change of editorship noted above. To reduce the impact of such biases we selected articles sequentially by order of submission, starting from the date of change of review model.We chose  profile  and the This study is the first to investigate the effect of author-suggested peer reviewers and openness of peer review, on the quality of peer review in the same journal and between very similar journals in the field of biology as well as medicine. We show that, in agreement with previous studies,Author-suggested reviewers tend to recommend acceptance more often than non-author-suggested reviewers, but the quality of peer review reports is similar regardless of the source of peer reviewer suggestions, which is also in agreement with previous reports.9


Telepractice is the application of telecommunications technology to the delivery of telehealth services via the online connection of clinicians, clients, and patients for assessment, intervention, or consultation. This article describes a pilot project in which speech-language pathology students in a university training program gained experience in working with culturally diverse preschool students using telepractice technology. The preschool students benefited by making gains in communication skills, while the university students acquired competency in the use of telepractice and in working with children whose cultural and linguistic backgrounds were outside of their experience. To assess the training experience, a Likert-scale survey administered to student clinicians revealed a high degree of satisfaction and improved familiarity with the use of telepractice, and an increased comfort level working with multi-cultural populations. University students completing certification requirements for the American Speech-Language and Hearing Association (ASHA) as speech-language pathologists must complete 400 clock hours of supervised clinical experience . AccordiStudents need to understand the cultural and socioeconomic factors that impact the daily lives of their clients as well as the beliefs and values of the communities in which the clients live .A pilot study examining such partnerships was conducted by Speech-language pathologists work in a variety of settings. According to the most recently published membership survey by the American Speech-Language Hearing Association , over haGiven the increased diversity of the children that speech-language pathology students will likely encounter when entering the workforce, it is crucial that during their clinical training, they gain direct clinical experience with multi-cultural individuals whose backgrounds differ from their own. For some university clinics, providing experiences with culturally and linguistically diverse populations within the same geographic region as the program may pose a challenge . In addiAccording to the American Speech-Language-Hearing Association, telepractice is “the application of telecommunications technology to the delivery of speech-language pathology and audiology professional services at a distance by linking clinician to client/patient or clinician to clinician for assessment, intervention, or consultation” . The two most readily accessed modes of telepractice involve synchronous methods  and asynchronous methods (involving the transmission of captured data). By applying telecommunications technology to deliver professional services from a distance, “there are no inherent limits to where telepractice can be implemented” . Research to date indicates that the use of telepractice yields clinical outcomes and patient satisfaction consistent with results obtained through traditional in-person service delivery models .There is a growing base of evidence demonstrating the success of telepractice as a method of speech-language therapy service delivery in the schools . In a paParticipants in the telepractice program included eight undergraduate university speech-language pathology students enrolled in their first clinical experience. Each student was supervised by a licensed and certified speech-language pathologist. Four preschool-aged children received speech and language services twice weekly for eight weeks through a telepractice partnership between the university and their preschool.Stockton University operates a speech and hearing clinic that serves approximately 35 clients per semester. The clients receive treatment from student clinicians under the direction of licensed and certified (in speech-language pathology) faculty members. The students periodically receive experience in conducting speech, language and hearing screenings at community health fairs and at local preschool and daycare centers located near the university. The clinic is located in a suburban area in southern New Jersey.During the 2013–2014 academic year, the university program received a request to provide speech, language, and hearing screenings to approximately 50 preschool aged children in a non-profit, early learning center (ELC) located approximately 60 miles from campus. The ELC is located in an inner city in the Mid-Atlantic region and is unique in the fact that its students represent children at risk secondary to abuse or neglect. The ELC is accredited by NAEYC, the National Association for the Education of Young Children. More than 75% of the children attending the ELC are classified as an ethnic minority, either speaking a non-standard dialect of English or residing in a bilingual home. Thus, the children attending the ELC were both ethnically and linguistically diverse, with cultural and socio-economic backgrounds different from those of the university students.In response to the request for screenings, a faculty member accompanied several students to the ELC to conduct the screenings. At that time, four children were identified as needing full evaluations. Results from these evaluations determined that speech-language therapy was indicated for all four children. Three of the children demonstrated speech sound disorders and the fourth child demonstrated both a speech sound disorder and deficits in oral language. The children were initially referred for services through the local school district, but the ELC director was informed that they would be placed on a waiting list for services due to personnel shortages.Due to the distance between the ELC and the university, it was not feasible for the children to attend therapy at the university speech and hearing clinic. As a result, a pilot project was developed through which the preschool-aged children could receive free services through the university via telepractice.Telepractice equipment was set up both at the clinic and the ELC. Both sites were already equipped with computers and an internet connection. Additionally, each site was equipped with a Logitech HD Pro Webcam C920 (1080p Widescreen) for teleconferencing and recording capabilities. The teleconferencing application chosen was VSee, presumed to support HIPAA compliance. VSee is defined as “a proprietary low-bandwidth, group video chat and screen-sharing software tool being used as a HIPAA compliant alternative” to other videoconferencing platforms , para.1.Eight student clinicians, working in pairs, were assigned to the children. These students collaborated on developing therapy plans and materials under the direction of supervising faculty members. During the therapy sessions, one student would interact with the preschool student via the telecommunication system, while the other would document quantitative data on the child’s performance in therapy. The university students would alternate the task of interacting with the preschool child and collecting data. At the end of the intervention period, supervisors used course grades based on pre-determined clinical competencies and child outcomes as measures of each student’s ability to provide services via telepractice to a multi-cultural pediatric population.Each week, quantitative treatment plans were developed and were shared electronically  with staff at the ELC. Materials such as worksheets or stimulus pictures were also electronically sent to the ELC on a weekly basis. Some of the learning activities involved matching, sound discrimination and identification, imitation, and labeling. The students successfully adapted both therapy materials and behavior management plans typically used in in-person settings for the telepractice mode of service delivery.At the ELC, an adult facilitator was present during the treatment sessions, seated next to the child. The facilitator’s role included: (a) physical presentation of therapy materials; (b) clarification of instructions between the child and the clinician; and, (c) providing additional skill modeling as needed. Each session was scheduled for twenty minutes, twice weekly. Telecommunication was additionally used to communicate with the children’s teachers. Written progress reports and home practice activities were sent home periodically to families throughout the intervention period.The student clinicians completed a 5-point ascending Likert-scale survey that targeted two parameters: (1) student-clinician familiarity and satisfaction with the use of telepractice; and, (2) student-clinician familiarity and satisfaction with working with multi-cultural populations outside of their clinical experience. Survey questions are presented in Based on quantitative post-evaluation findings and progress notes, all four children demonstrated improvement over the course of the academic year on their speech and language objectives. At the end of the academic year, all of the children successfully transitioned to kindergarten, where any residual speech or language needs could continue to be addressed via telepractice. Detailed participant data are not included since clinical training is the focus of this pedagogical note.An informal assessment of the participating student clinicians  revealed a high degree of satisfaction and improved familiarity with the use of telepractice, and an increased comfort level working with multi-cultural populations. This is demonstrated in the Based on the success of the pilot year, the telepractice partnership with the ELC continued the following year; four additional children were identified as having speech-language deficits and were added to the telepractice caseload. The goal of the clinic supervisors was to add an additional four student clinicians to the telepractice program.One challenge encountered was the limited bandwidth speed of the ELC. The video transmission of the session would occasionally freeze, while the audio portion would remain intact. Also, there was some initial turnover in the role of the facilitator. Turnover was reduced by identifying a university student who lived near the ELC and was interested in gaining experience working with children.A limitation of this investigation was the small sample size of student clinicians involved in the project (four); however, the clinic supervisors wanted to ensure continuity of care by having the same student clinician provide services to the student. As this was the clinic’s first attempt to initiate this pilot program, the attending supervisors also felt that monitoring a small group of students would enable the team to document and troubleshoot initial difficulties more readily, thereby maximizing the quality of service provided.Speech-language pathologists entering the workforce must be prepared to meet the needs of a culturally and linguistically diverse client population. The standards for certification of the Having direct clinical experience is related to students’ self-efficacy as clinicians . Self-efTelepractice holds much promise as an educational tool for university programs. The cost to employ a telepractice program is relatively small. The advantages include increased exposure to diverse client populations, decrease in time and money spent on travel for both clients and service providers, and access to services by those who may otherwise be underserved.