Archaeological survey undertaken in central Saudi Arabia has revealed 29 surface sites attributed to the Arabian Middle Paleolithic based on the presence of Levallois blank production methods. Technological analyses on cores retrieved from Al-Kharj 22 have revealed specific reduction modalities used to produce flakes with predetermined shapes. The identified modalities, which are anchored within the greater Levallois concept of core convexity preparation and exploitation, correspond with those utilized during the Middle Stone Age Nubian Complex of northeast Africa and southern Arabia. The discovery of Nubian technology at the Al-Kharj 22 site represents the first appearance of this blank production method in central Arabia. Here we demonstrate how a rigorous use of technological and taxonomic analysis may enable intra-regional comparisons across the Arabian Peninsula. The discovery of Al-Kharj 22 increases the complexity of the Arabian Middle Paleolithic archaeological record and suggests new dynamics of population movements between the southern and central regions of the Peninsula. This study also addresses the dichotomy within Nubian core typology (Types 1 and 2), which was originally defined for African assemblages. Comprehensive studies of the Arabian Middle Paleolithic are relatively recent, compared to the more established research traditions of Europe, south and east Africa or the Mediterranean Levant. In recent years, however, the Arabian Peninsula has experienced a considerable expansion of field research, aimed at the categorization of its prehistoric lithic assemblages and the investigation of its place in both human evolution and human dispersal events out of Africa sensu lato. This specific reduction strategy is defined by the production of blanks showing predetermined dimensions and shapes. This predetermination is achieved by diverse variations in core volume preparation The Middle Paleolithic lithic assemblages found in Arabia are mainly characterized by the presence of the Levallois technology tournant/semi-tournant and “frontal” débitage), although a smaller contribution of Levallois-like flake production also was noted. Middle Paleolithic industries found in the Jubbah area of Northern Saudi Arabia The discovery of the typically northeast African Nubian Levallois technology in southern Arabia represents a clear technological connection between northeast Africa and the Arabian Peninsula To expand and enhance the growing data set of Arabian Paleolithic sites, a Saudi-French archaeological project was initiated in 2011, under the direction of Dr. Jérémie Schiettecatte  and Prof. Abdulaziz al-Ghazzi . A detailed field survey was undertaken in the proximity of the modern town of Al-Kharj, central Saudi Arabia  which reMiddle Paleolithic/Middle Stone Age (MP/MSA) sites are often characterized by the Levallois methods of blank production, although some exceptions are noted. In Africa, Levallois technology remains a part of the Late Stone Age technological repertoire débitage), which can be recognized through the study of reduction patterns, or chaîne opératoirepreferential Levallois blanks.The Levallois reduction methods are marked by the production of blanks with predetermined shapes  using different methods of flaking . While the Levallois surface on a unidirectional convergent core is prepared by removals struck from the same striking platform as the preferential removal, unidirectional divergent cores are prepared by removals taken from a striking platform arranged opposite to the preferential striking platform sensu stricto, given that the preferential removal does not follow a central guiding ridge. Both studies, however, conclude that the product of this reduction is a triangular Levallois flake Bordes initially described the Levallois point production based on assemblages found in northern France and Jordan débordant elements from a distal platform. This particular preparation aims at the creation of a centrally placed distal to medial ridge, while the medial to proximal portion of the Levallois surface is prepared by centripetal removals Technological analyses undertaken on Nubian Complex sites in Egypt and north Sudan considerably add to the discussion of the dichotomy among Nubian cores Chiotti et al. Concerning the plasticity within the Nubian technology and the interchangeability between the Nubian Type 1 and Type 2 cores, Chiotti et al. : 316 argFor this study, we summarize the typo/technological characteristics that make up the Type 1, 2 and 1/2 cores under the rubric Nubian technology. The further discrimination between these core types within the Nubian assemblages is deemed unnecessary; we will refer to the specific preparation types previously associated with the core types . The site and data presented here gives insights into a largely un-sampled region of the Arabian Peninsula. The technological background to the identification of technological units discussed above serves as a guide for approaching surface site assemblages pertaining to the Paleolithic period found in central Saudi Arabia.The area surrounding the city of Al-Kharj, situated ca. 70 km southeast of Riyadh, is marked by a variety of geomorphological features including structural scarps, inselbergs, a complex drainage network, alluvial fans, outwash plains and sand dunes The flow direction of the wadis in the area is dictated by the homocline of the Arabian Shelf and the Central Arabian Graben System. The main riparian systems in the region run from the Tuwayq Escarpment, which rises abruptly to the west of the Al-Kharj area, across the Tuwayq Plateau in a general west-east course, thus serving as a conduit between the escarpment parallel to the Red Sea and the interior of the Arabian Peninsula. Towards the center of the Al-Kharj area, the wadi courses follow the aforementioned graben structures As part of the Saharo-Arabian desert belt, the climate of central Saudi Arabia is tied to the climate systems of the Mediterranean and the African/Asian monsoon. While the north receives moisture associated with winter cyclones driven by subtropical jet streams from the Mediterranean (northwesterly), the south is predominantly influenced by the summer incursion and northward migration of the Intertropical Convergence Zone (ITCZ). This atmospheric shift brings the Indian Ocean monsoon to the south of the Arabian Peninsula Paleoclimatic data for central Saudi Arabia indicating pluvial conditions is at present, somewhat sparse. Fluvial sediments identified near the foot of the Tuwayq Escarpment have been dated to ca. 54 and 39 kya and provide some indication of increased rainfall during MIS 3 in the general area The surface scatter of Al-Kharj 22 (or AK-22) is situated at the eastern portion of the southern fringe of the Rufa Graben ; within the Ashqar Maraghah segment. The surface site is approximately 20×60 m and lies on a slight east to west slope, flanked by inselbergs on its northern and southern faces . A low psensuThe site is composed of blank production debris with no identifiable zonations within the surface scatter. Artifact concentration within the well-delimited scatter ranges between high (more than twenty artifacts per square meter) to moderate density (between five and twenty artifacts per square meter). Cores, blanks and tools have been incorporated into a 10 to 30 centimeters thick carpet composed of aeolian sediments and small to medium sizes clasts, which have been affected by taphonomic processes. This postdepositional displacement is evident on the diversely patinated artifacts found within the aforementioned sediments. Artifact patination is reliant on raw material properties and the milieu in which the objects were deposited In arid environments, which are largely characterized by sediment erosion and subsequent displacements rather than by deposition and stabilization sensuA total of 177 artifacts encompassing cores and blanks were collected and analyzed . Of thesdébitage facial, Single platform unidirectional cores and bidirectional cores have also been identified. They present unprepared or simple facetted  striking platforms. Reduction directionality observed on the single platform cores is exclusively unidirectional; the core's working surface is placed perpendicular to the striking platform and reduced in a flat fashion  proximal platform and the distal (secondary) platform could be made. Thus, platforms placed on the core extremities are managed differently, as the proximal platform is preferential for the extraction of the Levallois triangular flake, while the other serves in the construction of distal ridges and convexities. Lateral preparations on the core's ventral surface were also observed. This feature is found associated with maintenance procedures of the Levallois surface .sensuTwo of the Nubian cores sensu. These rchaîne opératoire/operational sequence, see e.g. Nubian cores may produce more than a single preferential end product when re-preparation takes place. This re-preparation occurred using either a centripetal, distal divergent or a combination of both volume managements strategies. The diacritics coupled with valuable core refittings from Dhofar and North Africa Phase 1 is marked by the preparation of the platform and Levallois surfaces, this occurs by means of one of the set reduction schema previously identified by various researchers In Phase 2, the end product is detached from the prepared Levallois surface. This phase exploits the created convexity altering the Levallois surface in a way that the reduction of a second predetermined blank is impossible without further corrections to the Levallois surface. This does not mean that a complete preparation of the Levallois surface by either modality has to take place.Phase 3 is marked by either minor modification to the distal convexity by either distal removals or centripetal preparation. The choice of preparation method is interchangeable, in that centripetal, distal and lateral corrections to the Levallois surface are made non-exclusively.Based on these results and following the suggestion made by Chiotti et al. The site of Al-Kharj 22, in the central part of the Arabian Peninsula, provides a new point of reference for regional and interregional comparisons with assemblages from Saudi Arabia, Yemen and Oman. The archaeological investigation of central Saudi Arabia is crucial in terms of establishing comparisons between the Paleolithic records of southern Arabia with its northern provinces. Given the presence of Paleolithic sites in the Al-Kharj region The origin of Nubian Levallois technology lies in Africa and is the product of Anatomically Modern Humans The Arabian Peninsula has, up to this point, presented sites with Nubian technology across the South Arabian Highlands (encompassing the Dhofar Governorate in Oman and the Governorates of Mahra and Hadramawt in Yemen), and the area of Al-Kharj in central Saudi Arabia. Given the absolute dating of Aybut Al Auwal, southern Oman, to a later MIS 5 and the absence of bifacial technology within the Arabian samples (including the South Arabian Highland and the Al-Kharj Area), a general attribution of these assemblages to the Late Nubian Complex from Northeast Africa is possible.Usik et al. A difference between the Nubian assemblages from the South Arabian Highlands and central Saudi Arabia lies in the possible identification of the Safaha Method among the core samples from Al-Kharj 22. This technological gesture remains, up to this point, anomalous among Arabian Nubian Complex assemblages. Unfortunately, the limited sample size for Al-Kharj 22 greatly restricts interpretations and possible chrono/cultural affiliations between this particular aspect of African and Arabian Nubian lithic technology.The identification of the Nubian reduction methods at Al-Kharj 22 draws general parallels to the South Arabian sites and to the broad and reasonably well-studied regions of the Dhofar and Hadramawt plateaus. The relation between these two regions cannot be explained by technological convergence expressed by two different populations. The presence of Nubian reduction at both regions might relate to population movements between the southern and central portions of the Arabian Peninsula and northeast Africa. Concerning the directionality of the techno-cultural interchanges between Africa and Arabia, it is reasonable to argue in favor of an out-of-Africa movement, given that the Arabian archaeological record lacks a technological predecessor that would have given rise to the Nubian Complex. Geographically, approximately 1000 kilometers stretch between the northernmost occurrence of Nubian technology identified in Dhofar  and the mountainous and coastal settings of the Red Sea may yet shed some light on the conductivity of these landscapes for Nubian technology bearers. The continually expanding palaeoclimatic record of Arabia, however, suggests that humid episodes across the Peninsula were not spatially uniform; variations in the timing and extent of precipitation incursions from varying sources may mean that favorable environmental conditions could have developed asynchronously between northern, central and southern regions. Indeed, the Red Sea coastal and mountainous environments have been attributed the status of both refugium and corridor Alternatively, Nubian technology bearers may have spread across the Rub' al-Khali desert. Relict fluvial and lacustrine records from Saudi Arabia and Oman débitage and Taramsa blade production systems respectively. Activity Phase V, characterized by a Safahan assemblage has been dated by OSL to between 56.9±6.9 and 39.5±3.8 kya, whilst Activity Phase VI  has yielded 14C AMS dates of between 45,348–40,711 (2σ) cal. BP (The geomorphological observations made during field research indicates that the Al-Kharj area, with its many springs and natural water holes, likely played a role in what may be termed an ‘environmental boon’ during the desiccation following the pluvial phases of MIS 5. This may have allowed the region to become an important refugium, as has been interpreted from other archaeological Upper Pleistocene sites in Arabia All necessary permits for the Yamama/Al-Kharj fieldwork and analyses were obtained from the Saudi Commission for Tourism and Antiquities, Kingdom of Saudi Arabia.


Z-effect and reverse Z-effect are complications that arise from the surgical treatment of pertrochanteric fractures of the femur with proximal femoral nails (PFN) comprising two interlocking head screws. Such complications are induced by the migration of screws in opposite directions, which may lead to failure of the osteosynthesis.The paper describes three cases of pertrochanteric fractures that were treated with PFN with two interlocking screws that evolved to either Z-effect or reverse Z-effect. Literature-based explanations for this phenomenon are provided together with recommendations of how to avoid such complications.Although intramedullary fixation is an established method of treatment of femoral intertrochanteric and subtrochanteric fractures, the evolution of the procedure may include complications associated with the migration of the interlocking head screws. The occurrence of Z-effect and reverse Z-effect has not been completely elucidated, but the main causes of such complications are probably fracture fixation in varus position, severe medial comminution, inappropriate entry point of the nail and poor bone quality. The incidence of fractures of the proximal femur has increased considerably over the last few decades as a consequence of the greater longevity of the population . FemoralIn the present paper, we describe the complications observed in three patients arising from surgical treatment of FPF with proximal femoral nails (PFN) comprising two interlocking head screws that migrated in opposite directions (Z-effect and reverse Z-effect). The possible causes of these complications and relevant preventive methods are discussed.®, Campinas, SP, Brazil) one day after the trauma. The femur fracture was classified as level 3 on the abbreviated injury scale (AIS), whereas the injury severity score (ISS) was level 9 without any associated injuries. After 10 months, the patient evolved with varus consolidation, chronic osteomyelitis and migration of the proximal interlocking screws in different directions with the caudal screw migrating laterally (characteristic of the Z-effect). Because of the protruding inferior screw, it was necessary to remove the implant and to treat the chronic osteomyelitis. Radiographic images are presented in Figure A 44-year old male doctor (with no comorbidities), who had been injured in a car accident, presented subtrochanteric fracture (AO/OTA 32-B1) of the right femur and was submitted to osteosynthesis with PFN (Hexagon®) 36 hours after the trauma and evolved with migration of the proximal interlocking screws in opposite directions. The superior screw dislocated laterally, and varus collapse led to perforation of the femoral head by the inferior screw (reverse Z-effect). Since consolidation of the fracture had occurred, the implant had to be removed three years after osteosynthesis. The patient mobilized in the confines of his domicile with the aid of a walking stick. Radiographic images are presented in Figure A 68-year old retired male (a diabetic and well-controlled hypertensive patient) with a history of falling, presented intertrochanteric fracture of the right femur (AO/OTA 31-A2.2). The patient was submitted to osteosynthesis with PFN (Hexagon® (75 mg). The patient was submitted to osteosynthesis with PFN  one day after the trauma and evolved with fracture consolidation in a favorable position. After surgery, the patient returned to normal functional activities but the superior screw migrated laterally after 6 months. Although the inferior screw remained in the normal position the cranial screw migrated, probably owing to poor bone quality. The superior screw was removed after consolidation of the fracture. Since the sliding screw was well positioned with regard to the tip apex distance, and the fracture was adequately reduced, no failure in osteosynthesis occurred. Radiographic images are presented in Figure An 80-year old housewife was injured in a fall resulting in lateral trauma of the left hip that was diagnosed as an intertrochanteric fracture of the left femur AO/OTA 31-A2.1). The patient had a history of ischemic cardiomyopathy and had undergone angioplasty and vascular stenting, and was receiving a daily dose of Clopidogrel1-A2.1. TThe treatment of proximal femoral fractures remains a challenge for trauma surgeons. The high rate of complications (> 30%), together with the large variety of techniques currently available, demonstrate that this problem has yet to be resolved satisfactorily .Femoral proximal fractures are treated surgically with the dual objectives of avoiding clinical problems resulting from bed confinement and of providing the patient with a quality of life similar to that enjoyed pre-injury.Surgical stabilization of the fracture is of crucial importance and can be achieved through the application of either intra- or extramedullary implants. There are, however, conflicting opinions regarding the type of implant that is most appropriate. For unstable fractures, intramedullary implants generally present biomechanical advantages over their extramedullary counterparts ,3, and nThe use of intramedullary implants comprising a single proximal interlocking screw results in significant rates of rotational instability and varus collapse of the fracture -7. AdditThe Z-effect involves the lateral migration of the inferior screw, varus collapse of the fracture and perforation of the femoral head by the superior screw. The reverse Z- effect involves the lateral migration of the superior screw accompanied by the medial migration of the inferior screw. The first account of the Z-effect has been attributed to Werner-Tutshcku et al. , who repAlthough the literature describes the Z-effect and reverse Z-effect as the migration of proximal interlocking screws in opposite directions, in practice, sometimes only one screw actually migrates and the fracture undergoes an accommodation process that may lead to the perforation of the femoral head by the screw that remains in the normal position. Although the cause of this complication has been explained by varus collapse of the fracture and the lack of medial cortical support, its precise etiology requires further clarification .Strauss et al.  have repIn an attempt to solve this problem, implants have been devised that include specific safety features aimed at avoiding screw migration . AdditioIn this paper, we report the unfavorable evolution of three patients undergoing osteosynthesis of proximal femoral fractures with intramedullary nails comprising two interlocking head screws. The retrospective analysis of these patients leads us to believe that the problems resulted from a series of factors including loss of medial support, varus collapse, inadequate entry point of the nail, and poor bone quality, or a combination of all such factors. Elucidation of the reasons for the occurrence of the reverse Z-effect observed in some types of fractures is still pending and requires further investigation.Although intramedullary fixation is an established method for the treatment of FPFs, it may evolve with complications including the migration of the interlocking head screws. Such an unfavorable evolution can be minimized by careful selection of the correct entry point of the nail and reduction of the fracture in order to avoid fixation in varus. For fracture patterns in patients presenting severe osteoporosis or medial comminution, the use of helical blades is recommended.AIS: abbreviated injury scale; AO/OTA: Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association; FPF: femoral pertrochanteric fractures; ISS: injury severity score; PFN: proximal femoral nailThe Ethical Committees of the hospitals involved approved the study. Written informed consent to publish the case reports and the accompanying images was obtained from all of the patients concerned. Copies of the written consents are available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.RESP and DB were responsible for developing the idea of this study. RESP, EOSJ, LENS, VG, DB and FBR contributed to the study design. RESP, EOSJ and DB were involved in reviewing records and in data acquisition. RESP, EOSJ, VG and DB performed the literature review and drafting of the manuscript. All authors were involved in reviewing and editing the manuscript and all have approved the final manuscript.RESP obtained his Masters Degree at the Medical School of Universidade Federal de São Paulo. He is Assistant Professor in the Locomotor System Department of Universidade Federal de Minas Gerais.EOSJ is a Medical Resident of the Orthopedic and Trauma Service of Hospital Felício Rocho.LENS is Fellow Physician in the Hip Surgery Group of Hospital Felício Rocho.VG obtained his Masters Degree at the Medical School of Universidade Federal do Rio de Janeiro and is Fellow Physician in the Trauma Group of Hospital Municipal Miguel Couto.DB obtained his Masters Degree at the Medical School of Universidade Federal de São Paulo and is now a Fellow Physician of the Orthopedic Trauma Group at this Institute.FBR obtained the Title of 'Livre Docente' and is a Professor at the Orthopedic and Trauma Department of Universidade Federal de São Paulo.


GABAergic interneurons (INs) in the dorsal lateral geniculate nucleus (dLGN) shape the information flow from retina to cortex, presumably by controlling the number of visually evoked spikes in thalamocortical (TC) cells, and refining their receptive field. The dLGN INs exhibit a rich variety of firing patterns. Depolarizing current injections to the soma may induce tonic firing, periodic bursting or an initial burst followed by tonic spiking, sometimes with prominent spike time adaptation. When released from hyperpolarization, some dLGN INs elicit rebound bursts, while others return more passively to the resting potential -3.A full mechanistic understanding that explains the function of the dLGN on the basis of neuronal morphology, physiology and circuitry is currently lacking. One way to address this question is to develop and investigate mathematical models of the involved cells and their interactions. While detailed models of the well studied TC cells exist, previous models of the less studied dLGN INs are simplified and use only passive dendritic properties. Several ion channels are present in the dendrites of dLGN INs -6, and mNEURON (http://neuron.duke.edu/) was used for the model. The conductance values were constrained by somatic voltage recordings from two dLGN INs under 8 experimental conditions. The model reproduces qualitative features in the experimentally recorded response patterns, as well as quantitative data on the firing frequency as a function of injected current. We show that relative differences in conductance values, rather than differences in ion channel composition, explain the differences in the response properties of the two neurons, and can account for the various response patterns listed above. The model lays the foundation for studying the function of the dLGN IN and its interactions with TC cells within a network context, and does also in its own right give new insights in the properties of dLGN IN activity.We here present a detailed compartmental model of a dLGN IN with a detailed morphology and active dendritic, as well as somatic, conductances. The simulation tool


Over the past decade or two biology has become increasingly quantitative and concepts from mathematical and physical sciences have in turn increasingly influenced biology Knight, . As a reThe International Workshop on Quantitative Biology (IWQB2012) organized in conjunction with the 5th annual meeting of the Japanese Society for Quantitative Biology (Q-BioJP) was held on November 22nd, 2012 in Tokyo.An opening remark by Prof. Yasuyuki Sakai, Institute of Industrial Science, University of Tokyo, highlighted the scientific importance of quantitative biology for mechanistic understanding of living processes. Prof. Sakai emphasized the need to extend the technical and conceptual knowledge gained into applications area for the benefit of human medicine.The day's talks were kicked off with a session on mesoscopic structures and their regulation. Prof. Madan Rao  opened this session with captivating description of the physical principles that govern the functional organization and dynamics of molecules on the cell surface. Dr. Chun-Biu Li  described his novel approach on how one could develop objective kinetic scheme to identify network properties that are entirely supported by data in a parameter-free manner. Dr. Ziya Kalay  ended the session with an elegant description of a basic theoretical framework on molecules' movement on membrane surfaces that could be used to predict reaction bursts.A live relay of how automated fermentation systems yield data on membrane and metabolite dynamics by Dr. Douglas Murray  opened the second session on application of engineering in quantitative biology. By presenting novel wet systems with two or three oscillators, Dr. Yannik Rondelez (CNRS-University of Tokyo) showed the origin of direct and hidden coupling of network interactions and how the layer of hidden coupling allows the building of “winner-take-all” network.Over an extended lunch, an interactive poster session with 29 presenters was held. Poster highlights include modeling and simulation of biochemical reactions, molecular crowding, single molecule imaging, metabolic pathway analysis, chromatin dynamics, quantitative measurement of RNA, micro-fluidic devices and bioimage informatics. Engaging discussions at the poster session stressed the need for such small-scale workshops to promote cross-disciplinary interaction. Several participants acknowledged the seeding of new collaborative bridges at the poster session.C. elegans embryos. Prof. Antonio Celani  described how the complex problem of sensory response in bacterial chemotaxis can be tackled both at a mechanistic level of signal transduction from receptor to motor and at a behavioral level as response to the molecular response using Bayesian inference. Dr. Timothy Stasevich  elucidated model parameters for RNA polymerase II transcription dynamics using various quantitative data obtained from FRAP (fluorescence recovery after photo bleaching) and FabLEM (Fab-based live endogenous modification labeling) in living cells.Building new ways to push the frontiers of data assimilation is pivotal for advances in quantitative biology and this was the focus of the next session. Dr. Hiromichi Nagao  introduced a Bayesian estimation method to systematically estimate simulation parameters with a data-driven manner, and reported its application to estimate force distribution for cytoplasmic streaming in C. elegans. Dr. Viji Draviam  presented a collaborative work with the Funahashi group  on the importance of astral microtubule pause frequency in translating cell shape cues into spindle rotating forces during human cell division.The final session of the meeting on chromosome and spindle dynamics started with Prof. Tomoyuki Tanaka's  presentation of ingenious experiments demonstrating the steps through which a microtubule captures chromosome. This was followed by a tour-de-force presentation of Shugoshin's role in monitoring centromeric tension and preventing errors in chromosome-microtubule attachment by Prof. Yoshinori Watanabe . Dr. Akatsuki Kimura  quantified and formulated the relationship between spindle length and width in The meeting ended with final remarks by Prof. Madan Rao who commented on the success of the day's meeting in building new interactions and also stressed on the need for similar future meetings to promote interaction between researchers in Asian and European countries.Researchers with a wide range of expertise had contributed to the success of the day Figure . Partici


There is currently no standard way of defining malaria seasonality, resulting in a wide range of definitions reported in the literature. Malaria cases show seasonal peaks in most endemic settings, and the choice and timing for optimal malaria control may vary by seasonality. A simple approach is presented to describe the seasonality of malaria, to aid localized policymaking and targeting of interventions.A series of systematic literature reviews were undertaken to identify studies reporting on monthly data for full calendar years on clinical malaria, hospital admission with malaria and entomological inoculation rates (EIR). Sites were defined as having 'marked seasonality' if 75% or more of all episodes occurred in six or less months of the year. A 'concentrated period of malaria' was defined as the six consecutive months with the highest cumulative proportion of cases. A sensitivity analysis was performed based on a variety of cut-offs.Monthly data for full calendar years on clinical malaria, all hospital admissions with malaria, and entomological inoculation rates were available for 13, 18, and 11 sites respectively. Most sites showed year-round transmission with seasonal peaks for both clinical malaria and hospital admissions with malaria, with a few sites fitting the definition of 'marked seasonality'. For these sites, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. The use of monthly EIR data was found to be of limited value when looking at seasonal variations of malaria transmission, particularly at low and medium intensity levels.The proposed definition discriminated well between studies with 'marked seasonality' and those with less seasonality. However, a poor fit was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this definition on a wide-scale, using routine health information system data where possible, to aid appropriate targeting of interventions. Malaria remains the world's most important tropical parasitic disease, and one of the major public health challenges in the poorest countries of the world, particularly in sub-Saharan Africa. With the new move towards malaria eradication and the Knowing the duration, start and end of the malaria transmission season is important in terms of planning control strategies. For example, to maximize impact, Indoor Residual Spraying (IRS) should be carried out prior to the onset of the malaria season. Also, the cost-effectiveness of some malaria control strategies may be influenced by the intensity of seasonality. For example, in a setting where transmission only occurs during four months of the year, giving intermittent preventive treatment (IPT) to pregnant women (IPTp) or infants (IPTi) all year round would be less cost-effective than in a perennial transmission setting.et al, submitted).Most malaria endemic settings have "seasonal peaks" of malaria cases, which are usually described in terms of the duration and timing of the rains during a given study period. However, this may vary from year-to-year, giving a variety of subjective descriptions of seasonality for a single site. For example, in Manhica (Mozambique), malaria has been described as being perennial with "some" , "substaTo date, several attempts have been made to describe the seasonality of malaria endemic areas such as the Climate and Malaria Resource Room (CMRR)  and MappMore recently, a different approach to define seasonality was carried out by Mabaso and others who aimed to predict seasonality from environmental covariates. They defined a seasonality concentration index to model the relationship between environmental covariates and seasonality in malaria incidence and EIR Given that the intensity and seasonality of malaria transmission varies widely within and between countries in sub-Saharan Africa, the choice and timing of malaria control interventions might be different across distinct epidemiological contexts. This paper aims to present a simple method for describing the seasonality of malaria disease in a given site, to assist policy makers in deciding when and where malaria interventions should be delivered.Plasmodium falciparum and reporting on clinical malaria from community-based studies, hospital admissions with malaria, or entomological inoculation rates (EIR) for each month during a full calendar year were included  online abstracting databases, the WHO publication Library , and theon average 50% of malaria episodes would be expected to occur within any given 6 months of the year. Conversely, in areas with seasonal peaks much more than 50% of malaria cases would be concentrated during the six-month period that includes the seasonal peak. To identify where this occurred, the percentage of cases occurring in each month of the year was calculated for each study. The cumulative percentage of all hospital admissions with malaria, clinical malaria incidence, EIR data and the number of months in which they happened were used to explore different definitions of 'marked seasonality'. Studies were defined as having 'marked seasonality' if 75% or more of the episodes occurred in 6 or less months of the year (definition A). Sites were defined as showing 'borderline marked seasonality' if 75% or more of the episodes occurred in seven months of the year.Studies were only included if they had at least 50 cases of clinical or severe disease and monthly data for a full calendar year. To derive a definition of malaria seasonality, it was assumed that in areas with no seasonal peaks, concentrated period of malaria". Although age ranges varied by study, the analyses were conducted separately for each site and were, therefore, internally consistent.The cumulative percentage was calculated for each consecutive six-month period in turn, using a rolling starting month, e.g. from January to June, then February to July, then March to August, and so-on up to December to May. The six-month combination that gave the highest cumulative percentage was defined as a "Given the variability of EIR data collection methods, studies were screened for quality inclusion criteria based on methods of mosquito collection, frequency of sampling, method of sporozoite collection, and number of mosquitoes caught, tested and sporozoite positive. This led to the exclusion of one study where the methods were not fully described . FurtherSites that reported monthly data for a variety of outcomes were compared to see whether they showed a consistent definition of seasonality across outcomes. Further consistency checks included a comparison of the first and last month of the concentrated period of malaria  with the first and last month of the rainy season (as reported in the literature) and with the first and last month of the malaria season based on the MARA predictions. Finally, to examine the robustness of our 'marked seasonality' definition, a sensitivity analysis was performed to test a variety of cut-offs against the original definition "A" .Annualized EIR data broken down by month were available from 11 sites,17-26. FIndividual-level data from nine sites with longitudinal data on more than 50 clinical malaria episodes were available for analysis -37. In aEighteen hospital-based sites across sub-Saharan Africa (20 studies) with data from full calendar years on hospital admissions with severe malaria were available for analysis , Maputo (Mozambique), Macha (Zambia), Maiduguri (Nigeria), and Huruma (Tanzania). 'Borderline marked seasonality' was seen in Kumasi (Ghana), Blantyre , and Same (Tanzania). More regular transmission with minor seasonal peaks was found in the remaining sites , results showed some discrepancies as not all outcomes consistently fitted our 'marked seasonality' definition. In Maputo, more than 75% of all hospital admissions with malaria were found to be concentrated between December and May, whereas EIR data did not meet the proposed 'marked seasonality' definition. Conversely, Kilifi (Kenya) showed 'marked seasonality' when EIR data were analysed, but 'no marked seasonality' in the two studies reporting on all hospital admissions with malaria. These results suggest that EIR data are less reliable for assessing malaria seasonality than malaria morbidity outcomes.The range of months of the concentrated period of malaria for all sites that showed 'marked seasonality' of clinical malaria and of hospital admissions with malaria were found to be concordant and fully overlapped with the duration and timing of the rainy season as reported in the literature and/or the first/last month of seasonality as estimated by MARA climate suitability models . As expected, when the cut-off for cumulative proportion of cases was reduced to ≥ 70% of episodes in ≤ 6 months (definition C) a few additional sites were found to fulfil the criteria for 'marked seasonality' . Conversely, when the cut-off for cumulative proportion of cases was increased to ≥ 80% (definition D), Blantyre was no longer considered to show 'borderline marked seasonality'. These results suggest that a consecutive period of 5-6 months gives a consistent seasonality pattern.In this paper, a standardized and practical approach for defining seasonality of malaria is presented based on a simple statistical analysis of the monthly distribution of malaria disease from a wide range of epidemiological settings across malaria endemic countries. A proposed definition of 'marked seasonality', where 75% or more of the episodes occurred in six or less months of the year, appeared to discriminate well between studies with 'marked seasonality' of cases and those with a more regular distribution of cases and perhaps one or two seasonal peaks. Furthermore, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. With regards to monthly EIR data, however, a reliable assessment of seasonality could only be made in sites with high transmission (i.e. > 100 ibpppy), where monthly EIR data was greater than 0 for most consecutive months of the year. The 'concentrated period of malaria' in less intense transmission settings is difficult to interpret as it is not clear whether there is actually no transmission during those months of the year or whether monthly EIR measurements in these areas suffer from poor sensitivity . FurtheFor example, Kilifi (Kenya) was found to show 'borderline seasonality' when monthly EIR data was analysed, but 'no marked seasonality' in the two sites reporting data on all hospital admissions with malaria. This discrepancy might also be due to the fact that Kilifi is usually reported as having two rainy seasons,51-55. TThe range of months of the concentrated period of malaria for sites showing 'marked seasonality', were found to be concordant with both the rainy periods reported in the literature and first/last month of the MARA seasonality database indicating that our approach works well for identifying these aspects of seasonality in these study settings . The use of a standardized definition of malaria seasonality in these comparative studies has improved our ability to discriminate studies with 'marked seasonality' from those with more regular transmission and seasonal peaks.A common definition of malaria seasonality is also crucial for the comparability of studies. The proposed method has already been applied to describe the age-pattern of malaria of differing severities across a range of transmission settings on a series of pooled analyses of existing data  -when working well-have been shown to provide consistent seasonal variation in the number of cases seen at outpatient clinics, coinciding with the pattern of malaria transmission . AlthougCurrently, there is no standard way of defining malaria seasonality resulting in a wide range of definitions reported in the literature. Where there is considerable seasonality, optimal timing of control becomes particularly important. Here a simple approach for describing the seasonality of malaria is presented, that discriminates well between studies with 'marked seasonality'  and those with less seasonality. This method also helps to identify the start and end of a 'concentrated period of malaria' at a local scale, which could inform policy makers about the optimum timing and frequency of deployment of malaria control interventions. A poor fit, however, was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this method, using routine health information system data.EIR: Entomological Inoculation Rate; Ibpppy: infective bites per person per year; IPT: intermittent preventive treatment; IRS: indoor residual spraying; MARA: Mapping Malaria Risk for Africa.The authors declare that they have no competing interests.ARF, JAS & IC conceived and designed the analyses, ARF & LS collected the data, ARF analysed the data. All authors contributed to the writing of the manuscript and approved the final version.Comparison of malaria concentrated periods  with the month interval of the rainy season as defined by the literature and/or by MARA for sites found to show 'marked seasonality'. Sites were defined as having 'poor agreement' if the 'concentrated period of malaria' did not fully overlapped with either the reported rainy months or the MARA maps. Conversely, sites were defined as having 'good agreement' if the 'concentrated period of malaria' fully overlapped with at least one of them.Click here for fileTable summarising results from sensitivity analyses looking at different season lengths  and different cumulative proportion cut-offs. Cumulative percentages for definition A  is also shown for comparison purposes.Click here for file


In patients who undergo low anterior rectal resection, the fashioning of a covering stoma (CS) is still controversial. In fact, a covering stoma (ileostomy or colostomy) is worsened by major complications related to the procedure, longer recovery time, necessity of a re-intervention under general anesthesia for stoma closure and poorer quality of life. The advantage of Ghost Ileostomy (GI) is that an ileostomy can be performed only when there is clinical evidence of anastomotic leakage, without performing further interventions with related complications when anastomotic leak is absent and therefore the procedure is not necessary. Moreover, in case of anastomotic dehiscence and necessity of delayed stoma opening, mortality and morbidity in patients with GI are comparable with the ones that occur in patients which had a classic covering stoma. On the other hand, is simple to think about the possible economic saving: avoiding an admission for performing the closure of the ileostomy, with all the costs connected  represents a huge saving for the hospital management and also raise the quality of life of the patients.In this study we prospectively analyzed 20 patients who underwent anterior extra-peritoneal rectum resection for rectal carcinoma with TME and fashioning of GI realized with or without abdominal parietal split.In the group of patients that received a GI without split laparotomy mortality was absent and in one case an anastomotic leak occurred. In the group of patients in which GI with split laparotomy was fashioned, one death occurred and there were one case of infection and one respiratory complication. Clinical follow-up was 12 months.The use of different techniques for fashioning a GI do not present significant differences when they are performed by expert surgeons, but further evidence is needed with more randomized trials, in order to have more data supporting the clinical observation. The surgical treatment of lower rectal cancers has evolved from abdominoperineal resection to proctectomy with TME and colo-anal anastomosis. The main drawback of colo-anal anastomosis is the risk of leakage, which is reported to occur in 2.9%-20% of cases .A covering stoma (CS) after low anterior rectal resection reduces the incidence of anastomotic leak and urgent re-intervention for complications related to colorectal anastomosis .Even if a covering stoma is performed by the vaste majority of surgeons in order to protect the colorectal anastomosis, the decision of creating a CS is yet left to the personal experience of the surgeon which will analyze, during the operation, the safety of the anastomosis evaluating the blood supply and the eventual tension .The presence of defunctioning stoma has more advantages in the subgroup of patients that are at high risk of anastomotic leak: patients with low anastomosis or that previously underwent radio-chemotherapy .Nevertheless, the advantages of a CS are reduced by the stoma-related complications or by the necessity of a re-intervention for the closure of that stoma, with subsequent increase of costs and recovery time. The overall incidence of clinical leak is 8%, therefore CS is confectioned and opened in 92% of cases, in the vaste majority of them, if analized retrospectively, with minimal or no clinical usefulness .®) and observed daily. In case of clinical evidence of anastomotic leak [Some surgeons have recently suggested the creation of a pre-stage ileostomy (Ghost Ileostomy - GI) : an intetic leak , the GI Confectioning of GI can be performed with different techniques. The aim of our study is to evaluate the surgical techniques that are currently employed and analyze the eventual benefits and complications that each procedure carries.We prospectively analyzed 20 patients who underwent anterior extra-peritoneal resection of the rectum for rectal carcinoma with TME and fashioning of GI realized with or without abdominal parietal split.® stitch and the thread was then exteriorized with a Reverdin needle through the abdominal wall in the right iliac fossa. The intestinal loop was verified to be not under tension by the operating surgeon and then left just under the fascial layer ready to be eventually exteriorized. The Prolene® thread was then stitched to the skin with non-absorbable suture stitches  and sex 12 males), and rectal adenocarcinoma was staged in both groups as T2-T3 localized at ≤ 10 cm from anal verge. In all the patient staged as T3 (N = 9) neoadjuvant radio-chemotherapy was performed. Laparotomical extra-peritoneal anterior resection (AR) of the rectum with TME was performed within 6 weeks after radio-chemotherapy. A GI was fashioned after AR and the realization of the colorectal anastomosis. In the group of patient where a GI without abdominal parietal split was realized (N = 10), the second-to-last ileal loop was intraoperatively marked with a Prolene2 males, -86 yearsIn the group of patients that received a GI without split laparotomy, in one case an anastomotic leak occurred, for which surgical intervention under general anesthesia was required and a traditional loop ileostomy was fashioned. The leakage occurred in post-operative day 7 with findings of fecaloid material mixed with pus coming out from the peri-anastomotic drainage positioned during the surgical intervention. The patient was put under Total Parental Nutrition (TPN) and a full course of antibiotic therapy. Seven months later the patient underwent the closure of the ileostomy with good results. Mortality was absent.In the group of patients in which GI with split laparotomy was fashioned, one case of infection of the surgical wound and one respiratory complication occurred . No clinically detectable leakage occurred. One death occurred for myocardial infarction. Clinical follow-up was 12 months. One hernia occurred at the site of median laparotomic scar in the GI without split laparotomy group.In Western Countries colorectal cancer is the third malignant tumor for incidence and mortality, after breast cancer in women and lung cancer in men. Colorectal cancer is rare after 40 years of age and is more frequent from 60 years of age; it reaches a peak around 80 years of age and men and women are equally affected. The number of tumors has increased whereas mortality has decreased, mostly because of more adequate information, early diagnosis and therapy improvements ; the latColorectal anastomosis leak is the most frequent complication of surgery for the treatment of rectal cancer  , preoperThe International Study Group of Rectal Cancer defines anastomotic leak as a "defect of the intestinal wall integrity at the colorectal or colo-anal anastomotic site  leading to a communication between the intra- and extraluminal compartments -16. The ® thread and fashioning the ileostomy). The two techniques does not present particular technical pitfalls, but the need of general anaesthesia in the second case should be considered especially in patients with elevated ASA score.- Exteriorization of GI under local anesthesia in ghost ileostomy with split laparotomy  vs exteriorization of GI under general anesthesia in GI fashioned without split laparotomy  is characterized by major complications related to the procedure, longer recovery time, necessity of a re-intervention under general anesthesia for stoma closure and worse quality of life ,14.The advantage of GI is that ileostomy can be performed only when there is clinical evidence of anastomotic leakage , withoutThe Authors state that none of the authors involved in the manuscript preparation has any conflicts of interest towards the manuscript itself, neither financial nor moral conflicts. Besides none of the authors received support in the form of grants, equipment, and/or pharmaceutical items.All authors contributed equally to this work, read and approved the final manuscript.


Systematic reviewers may encounter a multiplicity of outcome data in the reports of randomised controlled trials included in the review . The primary objectives of this study are to investigate in a cohort of systematic reviews of randomised controlled trials of interventions for rheumatoid arthritis, osteoarthritis, depressive disorders and anxiety disorders: (i) how often there is multiplicity of outcome data in trial reports; (ii) the association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result, and; (iii) the impact of the selection of outcome data on meta-analytic results.Forty systematic reviews  of RCTs published from January 2010 to January 2012 and indexed in the Cochrane Database of Systematic Reviews (CDSR) or PubMed will be randomly sampled. The first meta-analysis of a continuous outcome within each review will be included. From each review protocol (where available) and published review we will extract information regarding which types of outcome data were eligible for inclusion in the meta-analysis . From the trial reports we will extract all outcome data that are compatible with the meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies in the review protocol. The association between selection of trial outcome data included in a meta-analysis and the magnitude and statistical significance of the trial result will be investigated. We will also investigate the impact of the selected trial result on the magnitude of the resulting meta-analytic effect estimates.The strengths of this empirical study are that our objectives and methods are pre-specified and transparent. The results may inform methods guidance for systematic review conduct and reporting, particularly for dealing with multiplicity of randomised controlled trial outcome data. Systematic reviewers may encounter a multiplicity of outcome data in the reports of randomised controlled trials (RCTs) included in their reviews -3. For eet al. [An empirical study by Tendal et al.  suggesteet al. .et al. also recommend that systematic reviewers pre-specify a hierarchy of measurement instruments and time points when multiplicity of outcome data is anticipated  [et al. suggested that systematic reviewers have not consistently reported such detailed protocols. For example, while all of the 19 Cochrane protocols reported eligible measurement instruments, none reported a hierarchy of measurement instruments, eight (42%) reported eligible time points and only one (5%) reported a hierarchy of time points [Concerns about the potential for selective inclusion have led to initiatives to minimise its occurrence. The Cochrane Collaboration Methodological Expectations for Cochrane Intervention Reviews (MECIR) initiative and the Institute of Medicine Committee on Standards for Systematic Reviews of Comparative Effectiveness Research have recently published guidance recommending that systematic reviewers report detailed protocols that pre-specify eligible outcome measurement instruments and time points for inclusion in the review ,8. An opstudies) . Tendal e points . These pAnother initiative that may minimise potential selective inclusion of results is the development of standardised sets of outcomes (known as core outcome sets) to collect in clinical trials of a specific condition . EstabliTo our knowledge, no prior work has quantitatively assessed the evidence for potential bias in meta-analytic results, which can occur when reviewers selectively include results from the set available. Quantifying this potential for bias is important as the results of meta-analyses are used by various stakeholders to inform clinical practice and policy decisions. The aim of this study is to investigate, in a cohort of systematic reviews, the potential impact of selective inclusion of RCT results on meta-analytic effects. The primary objectives of this study are to investigate: 1) how often there is multiplicity of outcome data in RCT reports ; 2) the association between the RCT outcome data included in the meta-analysis and the magnitude and statistical significance of the RCT result, and 3) the impact of the selection of RCT outcome data on meta-analytic results.The secondary objectives are to: 1) quantify how many systematic review protocols report outcome data eligibility and hierarchies, and 2) explore how potential selective inclusion of results is modified by (i) the existence of a systematic review protocol, and (ii) a core outcome set being available for the clinical condition under review.Forty systematic reviews  of RCTs published from January 2010 to January 2012 and indexed in the Cochrane Database of Systematic Reviews (CDSR) or PubMed will be randomly sampled. The first meta-analysis of a continuous outcome within each review will be included. From each review protocol (where available) and published review we will extract information regarding which types of outcome data were eligible for inclusion in the meta-analysis . From the RCT reports we will extract all outcome data that are compatible with the meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies in the review protocol. The association between selection of RCT outcome data included in a meta-analysis and the magnitude and statistical significance of the RCT result will be investigated. We will also investigate the impact of the selected trial result on the magnitude of the resulting meta-analytic effect estimates.et al.: …‘the authors’ stated objective was to summarize evidence from multiple studies, and the article described explicit methods, regardless of the details provided’ [A systematic review was defined using the definition by Moher rovided’ . The elirovided’ , and 5) We have selected these clinical areas to explore whether the existence of a core outcome set being available for the clinical condition of the review  impacts on selective inclusion of results. We will focus on continuous outcomes since there is greater scope for multiplicity of continuous outcomes in these clinical areas  compared with dichotomous outcomes. Both Cochrane and non-Cochrane reviews will be eligible regardless of whether a published protocol for the review is available. Unpublished protocols will be requested from authors. Both new and updated reviews will be eligible. For updated reviews, the protocol drafted closest to the latest update will be included in this study.The exclusion criteria are: 1) no meta-analyses of continuous outcomes are reported in the review; 2) results from non-randomised studies are included in each of the meta-analyses of continuous outcomes, and 3) non-standard meta-analytical methods are used .We will identify systematic reviews by performing an electronic search of the CDSR and PubMed. We will use RA and OA search terms recommended by The Cochrane Collaboration Musculoskeletal Review Group , and depThe citations retrieved from the CDSR and PubMed databases will be exported to Microsoft Excel and randomly sorted using the random number generator (citations of Cochrane reviews retrieved in the PubMed search will be deleted). One investigator (MJP) will read down the list of randomly sorted citations and screen the titles and abstracts, marking them as potentially eligible or ineligible. The full text of each potentially eligible systematic review will be retrieved and assessed against the inclusion criteria. This process will continue until 10 Cochrane RA or OA reviews, 10 non-Cochrane RA or OA reviews, 10 Cochrane depressive or anxiety disorders reviews, and 10 non-Cochrane depressive or anxiety disorders reviews, are included. Within both clinical categories , we will not constrain the selection by the particular clinical condition . Any difficulties with determining whether a systematic review meets inclusion criteria will be resolved by discussion with a second researcher (JEM).We will select from each systematic review the first meta-analysis of a continuous outcome that meets the inclusion criteria . The index meta-analysis may be selected from the abstract, summary of findings table, or results section of the review, depending on where the result is first reported in the publication. We will not constrain the selection based on the outcome label of the review , because we anticipate that in some reviews the primary outcome(s) may be dichotomous or the primary continuous outcome may not have been meta-analysed. We will not constrain the selection based on the domain measured . Meta-analyses will be eligible regardless of meta-analytic effect measure , meta-analytical model , and number of RCTs included (as long as at least two RCTs are included).We will retrieve reports of systematic reviews, review protocols, and RCTs using library services. Reports of RCTs may comprise journal articles, conference abstracts, unpublished dissertations, or regulatory agency or pharmaceutical company reports. For RCTs included in Cochrane reviews with reports written in languages other than English, we will request a copy of the translation, if available, from the Cochrane Review Groups, or will use Google Translate. We will retrieve reports of RCTs included in the index meta-analysis and those reported by the systematic reviewers as investigating the same pairwise comparison but which were excluded from the meta-analyses . If more than one reference for an RCT was reported by the systematic reviewers , we will retrieve all references reported. This will enable investigation of potential selective inclusion resulting from differences in results reported across different sources -33.One investigator (MJP) will extract data from all reviews and RCTs into a standardised form created in Microsoft Excel. This form will be pilot-tested on one review from each of the four categories , and refined accordingly. A second investigator will independently extract data from a random sample of 10 reviews and their included RCTs. If many data extraction discrepancies are identified, we will consider undertaking double data extraction for the remaining reviews. Any discrepancies between the data extracted will be resolved through discussion or adjudication by a third investigator if necessary. The list of data we will extract from the systematic review protocols, published systematic reviews, and RCTs is reported in Additional file From the systematic review protocol (where available) we will extract: 1) general characteristics of the review, including date of publication, and participants, interventions, comparisons, and outcomes of interest to the review; 2) reported outcome data eligibility criteria , and 3) reported outcome data hierarchies .From the published systematic review, we will extract the same information as from the protocols. In addition, we will extract information on any other outcome data reported in the review that are related measures of the index meta-analysis outcome under the same comparison. For example, if the index meta-analysis outcome is global pain at 4 to 6 weeks, we will record whether any outcome data for different pain scales at different time points were included in the review, either in a subsequent meta-analysis or in separate tables; these additional analyses also include sensitivity analyses related to the index meta-analysis. For the index meta-analysis, we will extract the following information: 1) the measurement instrument, time point of measurement, and intervention and comparison group for each RCT; 2) summary statistics for both groups in each RCT; 3) the MD or SMD, measures of variability, the statistical significance, and direction of the effect estimate for each RCT and for the meta-analytic effect; 4) heterogeneity statistics, and 5) which outcome data were obtained from the trialists because it was not reported in the RCT publication, involved algebraic manipulation of statistics , came from a report translated into English, or required a method of imputation (such as imputing a missing SD).From the RCT reports we will extract all outcome data that are compatible with the index meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies reported in the review protocol. This could include data from multiple measurement instruments measuring the same outcome, multiple time points, multiple intervention or control groups, final and change from baseline values, intention-to-treat and per-protocol analyses, adjusted and unadjusted effect estimates, and other analyses. For example, if the index meta-analysis is an MD meta-analysis of depression scores and the systematic reviewers report in the protocol that only HRSD outcome data will be included in a meta-analysis of depression, and specify no other outcome data eligibility criteria, we will extract all data for the HRSD , but no data for any other depression measurement instrument reported in the RCTs. Alternatively, if the index meta-analysis is an SMD meta-analysis of pain intensity at 12 weeks, and the systematic reviewers have not pre-specified any outcome data eligibility criteria or hierarchies, we will extract all pain intensity data  from each RCT at 12 weeks only. For systematic reviews without a protocol, we will request the unpublished protocol from the systematic reviewers. If one does not exist or is not provided, we will assume that no outcome data eligibility criteria or hierarchies were pre-specified, and will extract all outcome data from the RCTs, as long as they are compatible with the index meta-analysis outcome as it is defined in the review (as per the second example above). Final and change from baseline values are a special case in that systematic reviewers performing an SMD meta-analysis of different measurement instruments should include only final values or change from baseline values, not a mixture . For sysFor each type of RCT outcome data deemed eligible for inclusion in the meta-analysis, we will extract: 1) the measurement instrument, time point of measurement, and intervention and comparison groups; 2) sample sizes, measures of central tendency, and measures of variability per group; 3) the effect estimate (MD or SMD) and measures of variability, the statistical significance, and direction of the effect estimate; 4) the baseline SD of the outcome per group, and 5) whether outcome data were fully reported in the RCT report . We wilCochrane Database of Systematic Reviews[A study of the characteristics of meta-analyses (with at least two studies) contained in the January 2008 issue of the c Reviews found thWe will use descriptive statistics to summarise the characteristics of the systematic reviews included in the study. These characteristics include, for example, the clinical condition, intervention and comparison type, number of primary and secondary outcomes (reported in the review protocol and published review), number of RCTs included in the review overall, and characteristics of the index meta-analysis outcome .We will calculate the proportion of systematic review protocols and published reviews reporting at least one outcome data eligibility criterion and the proportion reporting at least one outcome data hierarchy. We will also separately calculate the proportion of protocols and reviews reporting eligibility criteria and hierarchies in relation to each of the following types of outcome data multiplicity: 1) multiple measurement instruments; 2) multiple time points; 3) multiple intervention or control groups; 4) final and change from baseline values; 5) sets of participants contributing to the analysis ; 6) unadjusted and adjusted effect estimates; 7) period results in crossover RCTs, and 8) other. Further, we will calculate the proportion of systematic reviews with at least one discrepancy in outcome data eligibility criteria and hierarchies between the protocol and published review .We will calculate the proportion of RCTs with at least one type of outcome data multiplicity that is compatible with the index meta-analysis outcome as it is defined in the review and with the outcome data eligibility criteria and hierarchies reported in the review protocol. We will also calculate the proportion of RCTs with the following types of outcome data multiplicity: 1) multiple measurement instruments; 2) multiple time points; 3) multiple intervention or control groups; 4) final and change from baseline values; 5) sets of participants contributing to the analysis ; 6) unadjusted and adjusted effect estimates; 7) period results in crossover RCTs, and 8) other. In addition, for each RCT we will quantify the number of effect estimates that were eligible for inclusion in the index meta-analysis, and will quantify the median (interquartile range) of eligible effect estimates per RCT. We will also quantify the number of eligible effect estimates that were not included in the index meta-analysis but were included in other meta-analyses or elsewhere in the review .When multiple effect estimates are available for inclusion in a meta-analysis, without pre-specified selection rules, several different methods may be acceptable (in terms of not introducing bias) for selecting an effect estimate from the set available. These mechanisms may include: 1) selecting data for the most commonly reported instrument, time point, or analysis across RCTs; 2) random selection of an effect estimate; 3) selection of the median effect estimate, and 4) selection of the outcome data based on clinical criteria. The commonality of these selection methods is that the selection of the effect estimate is not based on choosing systematically higher or lower effect estimates. If across the RCTs, selection methods 1) to 4) are employed, we would expect that the distribution of selected effect estimates would be consistent with what we would observe under purely random selection, although this does not necessarily mean that the process used to select the effect estimates was indeed random selection.We have developed an index, which we call the Potential Bias Index (PBI), to assess whether the estimates selected for inclusion in the index meta-analysis are systematically higher or lower than what would be expected by purely random selection. This index is based on the ordered effect estimates for each trial and the positioning  of the effect estimate selected within that order. A rank of 1 is assigned to the smallest effect estimate and a rank equal to the number of effect estimates is assigned to the largest effect estimate. Since the number of effect estimates varies across trials we rescale the ranks of the effect estimates to reflect their relative positioning (in ranking units) between the smallest and largest effect estimates. This is obtained by subtracting one from the rank of the selected effect estimate and dividing by the number of effect estimates minus one. The smallest effect estimate in a trial then has a location of zero and the largest effect estimate has a location of 1. So for a trial with three effect estimates and the rank of the chosen effect estimate of 2, its location is (2–1)/(3–1) = 0.5 - halfway between the lowest and highest rank. The Potential Bias Index (PBI) is defined as the weighted average of the locations of the selected estimates for each trial, with the weights being the number of effect estimates in each trial. With this weighting, greater priority is given to the locations of effect estimates the larger the number of effect estimates there were to choose from. The expression for PBI is:k trials, ni is the number of effect estimates in trial i, and Xi is the rank of the selected effect estimate in trial i. Derivation of this index and a worked example is provided in Additional files P-values of the effect estimates are chosen for inclusion.where there are The PBI described above will also be used to compare the index meta-analytic effect estimates with all possible meta-analytic effects. For each meta-analysis, all possible meta-analytic effects will be calculated from all combinations of available RCT effect estimates. The meta-analysis model used to combine the estimates (either fixed or random effects) will be the model that was used in the systematic review. However, sensitivity analyses will be undertaken to examine whether the type of meta-analysis model affects the PBI.We will also investigate the impact of the selected RCT effects on the magnitude of the resulting meta-analytic effect estimates. For each meta-analysis, the difference between the index meta-analytic effect estimate and the median of all possible meta-analytic effect estimates will be calculated. These differences will be standardised (by dividing by the pooled baseline SD of the outcome) and meta-analysed using a random-effects model across reviews. The meta-analytic weights will be based on the standardised standard error of the median meta-analytic estimates, and between RCT variability estimated using DerSimonian and Laird’s method of moments estimator . Note thWe will examine whether the existence of 1) a systematic review protocol and 2) a core outcome set being available for the clinical condition of the review affects a) the specificity of outcome data eligibility criteria and hierarchies reported in systematic review protocols and published reviews; b) the proportion of RCTs with multiplicity and the proportion of systematic reviews with at least one RCT with multiplicity; c) the PBI of the RCT effect estimates selected for inclusion in the index meta-analysis, and d) the PBI of the resulting index meta-analytic effect estimates.For systematic reviews without protocols, it is not known whether the outcome eligibility criteria reported in the methods section of the review were specified prior, or subsequent to undertaking the review. Therefore, for our primary analyses, we have chosen to include the set of RCT effect estimates that are compatible with the assumption of no pre-specified outcome data eligibility criteria. However, through sensitivity analyses, we plan to investigate if the PBIs  are modified when the set of RCT effect estimates are restricted to those that are compatible with the outcome data eligibility criteria and hierarchies specified in the methods section of the review.To our knowledge, this is the first empirical study designed to investigate the association between selection of RCT outcome data included in a meta-analysis and the magnitude and statistical significance of the RCT result. In publishing this protocol we are following the lead of others who have encouraged the pre-specification and transparent reporting of the objectives and design of methodological studies -43.There are several strengths of our study. We will use systematic review methods to identify eligible reviews, including use of explicit inclusion criteria, sensitive search strategies, duplicate selection of reviews, and standardised and pilot-tested data extraction forms. We will perform double data-extraction on a random sample of reviews and their included RCTs, and will consider performing this on the complete sample if the data extraction discrepancy rate is high. In addition to exploring whether there is evidence of selective inclusion of RCT results in systematic reviews, we will examine what the potential impact of this is on meta-analytic estimates.There are also several limitations to our study. We are focusing only on meta-analyses of continuous outcomes, and so will not investigate potential selective inclusion arising from types of multiplicity unique to dichotomous outcomes . Our study is also limited to systematic reviews of RA, OA, depressive disorders and anxiety disorders. Some of the continuous outcomes likely to be included in our study  exist in systematic reviews of other conditions (such as low-back pain), but our findings may have limited generalisability to other clinical areas. However, our focus on continuous outcomes and these clinical areas enables us to examine the impact of core outcome sets on selective inclusion of results. Finally, our study will only investigate the existence of potential bias in meta-analytic effect estimates that can result from systematic reviewers’ selective inclusion of results reported by trialists. It is possible that the effect estimate(s) available in an RCT publication may have been selectively reported by the trialists . Therefore, both selective reporting by trialists and selective inclusion by systematic reviewers may in combination bias the results of a meta-analysis ; howeverMeta-analysis results are of interest to various stakeholders and are used to inform clinical practice and policy decisions. If the results of meta-analyses are biased by selective inclusion of results, additional methods guidance for systematic review conduct and reporting will be necessary. Systematic review organisations have only recently recommended that systematic reviewers pre-specify eligible measurement instruments and time points in their protocols ,8. This BDI: Beck depression inventory; CDSR: Cochrane Database of Systematic reviews; HRSD: Hamilton rating scale for depression; IOM: Institute of Medicine; MD: Mean difference; MECIR: Methodological Expectations for Cochrane Intervention Reviews; OA: Osteoarthritis; PBI: Potential Bias Index; RA: Rheumatoid arthritis; RCT: Randomised controlled trial; SMD: Standardised mean difference.MJP has roles within The Cochrane Collaboration including systematic review trainer for the Australasian Cochrane Centre, member of the Bias Methods Group, Statistical Methods Group, and Trainer’s Network, and author of Cochrane systematic reviews. JEM has roles within The Cochrane Collaboration including Co-convenor of the Statistical Methods Group, member of the Methods Board and the Bias Methods Group, Statistical Editor of the Consumers and Communication Review Group, and author of Cochrane systematic reviews. SEG has roles within The Cochrane Collaboration including Co-Director of the Australasian Cochrane Centre, past editor of the Cochrane Handbook of Systematic Reviews of Interventions, and author of Cochrane systematic reviews managed by the Cochrane Collaboration Musculoskeletal Review Group (though not rheumatoid arthritis or osteoarthritis reviews). ABF has no competing interests to declare.MJP and JEM conceived the study design. MJP wrote the first draft, with contributions from JEM. SEG and ABF provided input on the study design. ABF developed the Potential Bias Index, test statistics, and simulations. All authors contributed to revisions of the manuscript and take public responsibility for its content.Search strategies.Click here for fileData to be collected from systematic review protocols, published systematic reviews, and randomised controlled trial (RCT) reports.Click here for fileMathematical details of the construction of the Potential Bias Index (PBI) and associated statistical test.Click here for fileWorked example of the Potential Bias Index.Click here for file


Purpose. To validate the use of a computer program for the automatic calculation of the sequential organ failure assessment (SOFA) score, as compared to the gold standard of manual chart review. Materials and Methods. Adult admissions (age > 18 years) to the medical ICU with a length of stay greater than 24 hours were studied in the setting of an academic tertiary referral center. A retrospective cross-sectional analysis was performed using a derivation cohort to compare automatic calculation of the SOFA score to the gold standard of manual chart review. After critical appraisal of sources of disagreement, another analysis was performed using an independent validation cohort. Then, a prospective observational analysis was performed using an implementation of this computer program in AWARE Dashboard, which is an existing real-time patient EMR system for use in the ICU. Results. Good agreement between the manual and automatic SOFA calculations was observed for both the derivation (N=94) and validation (N=268) cohorts: 0.02 ± 2.33 and 0.29 ± 1.75 points, respectively. These results were validated in AWARE (N=60). Conclusion. This EMR-based automatic tool accurately calculates SOFA scores and can facilitate ICU decisions without the need for manual data collection. This tool can also be employed in a real-time electronic environment. Interest in assessment of organ dysfunction and severity of illness in the intensive care unit (ICU) setting has increased in recent years. The acute physiology and chronic health evaluation (APACHE) is one of the earliest scoring systems developed for this purpose and is currently in its fourth iteration , 2. OtheSeveral automatic SOFA calculation tools have been developed. One of the earliest such tools was created and validated by Junger et al. . HoweverRetrospective cross-sectional analysis of consecutive adult admissions (age > 18 years) to the medical ICU with a length of stay greater than 24 hours was performed. For the derivation cohort, these admissions were from January 2007 through January 2009. For the validation cohort, these admissions were from February 2011 through March 2011. For both cohorts, automatic calculation of the SOFA score was compared to the gold standard of manual chart review and followed by critical appraisal of sources of disagreement. For the prospective observational analysis, we studied all admissions to medical ICU during six days. Patients who denied research authorization were excluded. The Institutional Review Board approved the study protocol and waived the need for informed consent.The Critical Care Independent Multidisciplinary Program (IMP) of the study hospital has an established near-real-time relational database, the Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Data Mart. Details of METRIC Data Mart and the EMR are previously published . METRIC 2/FiO2 and respiratory support, platelets, bilirubin, mean arterial pressure and adrenergic agent administration, Glasgow coma score, and creatinine and urine output. When multiple values of SOFA elements were present within a single day for a patient record, the highest value was recorded.SOFA is a scoring system based on six organ components: respiration, coagulation, liver, cardiovascular, central nervous system, and renal. Each component is assigned a severity score from 0 to 4, with 24 being the maximum possible severity score total . The resThe gold standard of manual chart review for the derivation and validation cohorts was performed by evaluation of EMR-based patient records over the first 24 hours of admission by a trained coinvestigator (AMH).The derivation analysis was performed with a cohort of 94 patients. The validation of the analysis was performed with a cohort of 268 patients.Critical appraisal of sources of disagreement between these scores was performed to allow for subsequent adjustment of the automatic tool for use on the validation dataset. To perform this analysis, records for which the disagreement between automatic and manual calculation was greater than two were selected. The automatic and manual calculations for these records were then reviewed manually by organ system to determine the source of error. The results of this analysis were used to identify common sources of error for modification of subsequent dataset calculations.AWARE  Dashboard is an ICU rule-based patient viewer and electronic-environment enhancement program, which extracts and presents patient information that is relevant to the ICU setting from the standard EMR . This inThe primary outcome measured in this study was agreement between SOFA scores calculated using the gold standard of manual chart review and the automatic tool. Agreement was determined using Bland-Altman analysis. Critical appraisal of sources of disagreement for individual SOFA components was also performed.P value less than 0.05 considered significant. All the data analyses were performed using JMP  statistical software. The results of this analysis have been reviewed by a Mayo Clinic statistician.The agreement in calculated SOFA between automatic and gold standard calculation is reported using correlation coefficient, and the difference is reported with SD. Comparison and analysis of these calculations were performed using Bland-Altman plots . This meThere was no statistically significant difference in the derivation and validation cohorts with respect to sex or frequency of low SOFA scores . HoweverP = 0.85) or validation (P = 0.22) dataset. Thus, it was necessary to perform critical assessment of outliers to assess sources of significant discrepancy.Bland-Altman plotting can obscure cases of disagreement where large deviations in both directions result in averages close to zero. To better represent these cases, calculation of the sum of the absolute value of the difference between the automatic and manual SOFA component scores was performed. For the derivation dataset, the median for the sum of absolute value of this difference was 1 . The meaTo better understand the deviation between the automatic and manual scores in both datasets, critical appraisal of differences was performed. In the case of the derivation dataset, 20% of the total SOFA scores were found to disagree by more than 2 points . With reLikely sources of disagreement were first sought in the respiratory and renal components. This investigation revealed failure of the automatic tool to recognize patient ventilator status as one likely source of error. Another likely source of error was in the failure of the automatic tool to accurately factor scenarios of decreased urine output.In the case of the validation dataset, 12% of the total SOFA scores were found to disagree by more than 2 points . It was For the derivation dataset, the difference between the total automatic and manual SOFA scores for any sample did not disagree by more than seven points . For theWe found good overall agreement between automatic calculation of the SOFA score in AWARE versus the gold standard of manual chart review for 60 patients . Good agThe primary purpose of this study was to validate the use of a computer program for the automatic calculation of the SOFA score. For the retrospective cross-sectional analysis, good agreement between the automatic and manual scores with respect to mean difference and standard deviation was observed for both the derivation and validation cohorts. Agreement of the automatic tool with the gold standard of manual chart was increased in the validation cohort after critical appraisal of sources of disagreement and modification of the original algorithm. The success of this approach is supported by the observation that there is a decrease in the standard deviation of the mean SOFA score in the larger validation cohort as compared to the smaller derivation cohort. Similarly, the rate of disagreement between the manual and automatic SOFA calculations is decreased in the validation cohort as compared to the derivation cohort. For the prospective observational analysis, this SOFA automatic calculator was validated within AWARE.The literature reports several attempts to develop and implement automatic SOFA tools. One of the earliest studies to do this used a modified SOFA scoring system to retrospectively examine patients in the operative ICU . Using aOther groups have independently developed and implemented additional automatic SOFA tools toward similar goals. One such example is a recent, large retrospective study of several thousand cancer patients in the medical and surgical ICU of a single institution over the course of one year . As withSeveral studies exist which have attempted to develop and validate automatic SOFA tools against the gold standard of manual chart review. One such example is a recent, large prospective study by another independent group . The purThe current study has the limitation of calculation of the gold standard of manual chart review by a single reviewer in the setting of a single ICU. However, our study is strengthened by the completeness of the data supported by electronic infrastructure. Further validation of this automatic tool will require multiple-ICU studies. An important long-term consideration in designing these studies is compatibility between EMR systems across multiple institutions . The chaAnother limitation of this study is the accuracy of the automatic tool. Cases of missing automatic hepatic scores were identified when this data was available in the EMR. There were also failures of the automatic tool to recognize correct ventilator status, calculate correct urine output, and extract CNS scores at the correct time. Critical appraisal of the source of these errors in the derivation dataset was demonstrated to result in improved calculation in the validation dataset. However, some errors still persisted. Additionally, similar errors were observed in the prospective observational analysis using the real-time AWARE patient monitoring system.This study validates the use of a computer program for the automatic calculation of the SOFA score as compared to the gold standard of manual chart review. This automatic tool has the potential to be further developed and improved. However, the present study validates the use of this automatic calculator in the EMR-viewer AWARE for visualization and real-time SOFA calculation in the ICU. As demonstrated using AWARE, this program allows automatic and rapid calculation of SOFA scores in hospitalized patients. Fully implemented, this tool may be useful when utilizing the SOFA score to assess the presence and extent of organ dysfunction. However, testing this hypothesis will require an investigation of its prognostic value in a cohort of ICU patients.


Chylotorax is a relatively uncommon and difficult to treat complication after esophagectomy for cancer. We report a case of a young adult male who underwent neoadjuvant chemoradiationtherapy followed by Ivor-Lewis esophagectomy for a squamous-cell carcinoma of the distal esophagus. During the postoperative course the patient presented recurrent episodes of hemodynamic instability mimicking cardiac tamponade, secondary to compression of the left pulmonary vein and the left atrium by a mediastinal chylocele. Mediastinal drainage and ligation of the cisterna chyli and the thoracic duct was successfully performed through a transhiatal approach. Chylotorax is a rare but potentially life-threatening complication of esophagectomy . It occuen bloc with the azyos vein above the diaphragm. Pathological examination of the surgical specimen showed yT2-N1 disease and no evidence of margin infiltration.A 48 year old man was referred to our center with a 5 month history of dysphagia to solid food and weight loss. There was no significant comorbidity. The esophagogastroduodenoscopy showed an infiltrating tumor of the lower esophagus located between 33 and 38 cm from the incisors. Histopathologic examination revealed a poorly differentiated squamous cell carcinoma. Chest and abdominal computed tomography scan confirmed the presence of the esophageal lesion with enlarged mediastinal nodes and no evidence of distant metastases. The patient underwent neoadjuvant chemotherapy with carboplatin, paclitaxel, 5-fluorouracil, and 46 Gy radiotherapy. The re-staging after neoadjuvant treatment showed a partial response. The patient underwent a Ivor-Lewis esophagectomy with 2-field lymphadenectomy via laparoscopy and right thoracotomy. As usual, the thoracic duct was ligated A high-volume serous fluid output (1100-1700 ml/day) from the right chest drain was noted since postoperative day 1. On postoperatively day 3 a left pleural effusion was detected on the chest x-ray and about 2 liters of serous fluid were drained. Biochemical analysis of triglyceride contents from both drains confirmed the diagnosis of chylothorax. The subsequent hospital course was characterized by recurrent episodes of dyspnea with supraventricular tachycardia and systolic hypertension refractory to pharmacological therapy. A gastrographin swallow study was performed on postoperative day 10 and was normal. The patient was then allowed a semiliquid medium-chain triglyceride diet, but the drain output changed from yellowish to milky and the chyle drainage continued despite treatment with continuous intravenous infusion of etilefrine and subcutaneous octreotide. On postoperative day 22 another major episode of acute respiratory distress with hemodynamic instability occurred. A CT scan demostrated the presence of a retrocardiac fluid collection, extending from the level of the esophagogastric anastomosis to the diaphragm and causing compression of the left pulmonary vein and the left atrium (FIGURE Boston Scientific) was delivered under fluoroscopic control. An upper midline laparotomy was then performed. After gentle displacement of the gastric tube, a loculated collection containing milky fluid was digitally ruptured and drained. In addition, transhiatal multiple ligations of the cisterna chyli and the thoracic duct were performed on the right side of the aorta. A feeding jejunostomy was also performed. Drainage of chyle was no longer observed in the mediastinal and chest tubes, and all signs of hemodynamic instability disappeared after the reoperation.The patient was then taken to the operating room. An esophagogastroduodenoscopy performed under general anesthesia showed a 1 cm defect on the left lateral wall of the stapled esophagogastric anastomosis without evidence of ischemia of the gastric conduit. Therefore, a 28 mm covered Ultraflex stent (Pseudomonas Aeruginosa and Acinetobacter Baumanii requiring antibiotic therapy with Gentamicin and Piperacillin-Tazobactam for 15 days until complete resolution of fever and bacteremia. The patient was discharged in good general conditions and eating a regular diet on the 54th postoperative day.The postoperative course was complicated by thrombosis of the left brachiocephalic vein requiring continuous heparin vein infusion that was mantained until the 32nd postoperative day, when complete resolution of the thrombosis was demostrated by CT scan and ultrasonography. The subsequent hospital course was further complicated by sepsis from The diagnosis of chylothorax complicating a Ivor Lewis esophagectomy was made early in the postoperative course of this patient. Conservative treatment with etilefrine and octreotide was unsuccessful, and despite the presence of bilateral chest drains, a posterior mediastinal collection containing chyle developed that caused an atypical clinical picture with recurrent episodes of hemodynamic instability. Supraventricular tachycardia and systolic hypertension mimicking cardiac tamponade were likely to be caused by extrinsic compression of the left pulmonary vein and atrium as documented by CT scan and echocardiogram, and were refractory to pharmacologic therapy. Similarly, Barbetakis et al reported on a young female who was admitted with a true cardiac tamponade due to a large chylous pericardial effusion and, after the periocardiocentesis, was successfully treated by a pericardial window and ligation of the thoracic duct through a right minithoracotomy .The standard of care in patients with post-esophagectomy chylothorax is the trans-thoracic supradiahragmatic ligation of the thoracic duct. The operation can be carried out through a right thoracotomy or a thoracoscopic approach . In our Written informed consent was obtained from the patient for publication of this Case report and the accompanying image. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.MR: conception and design, analysis and interpretation of data, drafting of the manuscript, critical revision, final approval; ISR: data collection, design, analysis of data, drafting of the manuscript, final approval; DB: data collection, design, analysis of data, drafting of the manuscript, final approval; LB: conception and design, interpretation of data, drafting of the manuscript, critical revision, final approval.