Gambusia spp.] in the southeastern USA, fish of the order Characiformes in the Neotropics, killifish [Aphyosemion spp.] in Central and West Africa, as well as Australian native fish of the genera Galaxias, Melanotaenia, and Pseudomugil). Naturally occurring fish predation has been witnessed in more than a dozen spider species from the superfamily Lycosoidea , in two species of the superfamily Ctenoidea (family Ctenidae), and in one species of the superfamily Corinnoidea (family Liocranidae). The majority of reports on fish predation by spiders referred to pisaurid spiders of the genera Dolomedes and Nilus (>75% of observed incidences). There is laboratory evidence that spiders from several more families  predate fish as well. Our finding of such a large diversity of spider families being engaged in fish predation is novel. Semi-aquatic spiders captured fish whose body length exceeded the spiders’ body length . Evidence suggests that fish prey might be an occasional prey item of substantial nutritional importance.More than 80 incidences of fish predation by semi-aquatic spiders – observed at the fringes of shallow freshwater streams, rivers, lakes, ponds, swamps, and fens – are reviewed. We provide evidence that fish predation by semi-aquatic spiders is geographically widespread, occurring on all continents except Antarctica. Fish predation by spiders appears to be more common in warmer areas between 40° S and 40° N. The fish captured by spiders, usually ranging from 2–6 cm in length, are among the most common fish taxa occurring in their respective geographic area (e.g., mosquitofish [ Plectrocnemia conspersa (Polycentropodidae), has been observed preying on fish fry Cordulegaster dorsalis (Cordulegastridae) have been reported to kill fish of >2.5 cm in length A diverse array of predators feed on fish, including piscivorous fish, birds , fish-eating bats, otters, bears, snakes, certain turtles, etc. Dolomedes and Nilus (‘fishing spiders’). The notion of fish-catching spiders is rather peculiar if we consider that spiders, as a whole, are traditionally viewed as the classic example of a predator that feeds on insects, yet some spiders are well-adapted for life near, or on, the water surface Another group of predaceous arthropods known to catch and eat small fish is spiders, particularly large, semi-aquatic pisaurid spiders of the genera An extensive bibliographic search was conducted to locate information concerning fish predation by spiders. The search was based largely on the Thomson-Reuters database (Web of Science), Google Scholar, Google Books, and ProQuest Dissertations & Theses. In addition, an internet search for information on this topic was conducted; authors of photographic material and reports on fish predation by spiders were contacted to obtain detailed information on these observations. Furthermore, inquiries among biologists were undertaken for unpublished reports on this topic. A total of 89 incidences of fish predation by spiders was gathered . For theTrechalea spp.) no estimates of fish length were made. The estimates obtained in this manner were similar to those reported in the literature where the lengths of predated fish were measured in the laboratory indicating that our estimates are fairly accurate. Report numbers used in the tables refer to the respective detailed report description (see Unpublished photographs of such events gained during the study were sent to ichthyologists and spider taxonomists for identification (see Acknowledgements for details). The resolution of a small number of the images was reduced sufficiently to result in uncertain identification beyond genus level but in most cases, identification to species level was considered appropriate. This is true for fish and spiders. Nomenclature of spiders follows Platnick tion see .Fish capture by spiders has been reported from all continents with the exception of Antarctica, where semi-aquatic spiders are absent ; Table 1Fish predation by spiders has been most frequently documented in North America, with 45 incidences from the USA  from the Neotropics of large semi-aquatic spiders with a nocturnal life-style found either on the banks of rivers and streams in tropical forests in Brazil, Colombia, Costa Rica, Panama, and Peru or near shallow puddles and creeks on the lowland tropical forest floor in Ecuador . Less coThe superfamilies Lycosoidea and Ctenoidea are those documented as preying upon fish under open-field conditions and all can be loosely categorized as hunting spiders . Approximately 80% of reports of fish predation were attributable to Pisauridae (nursery web spiders), with Ctenidae , Trechaleidae , Lycosidae  and Liocranidae  comprising the remainder ; Table 1Dolomedes (Pisauridae)  was capable of catching fish in laboratory experiments whereas the two smaller species (Dolomedes aquaticus and Dolomedes minor) were not The most dominant group of fish-catching spiders are in the genus auridae) , 7-8. Thauridae) ; Table 2octurnal , these ss triton ; Table 1Nilus , it can reasonably be deduced that such species could include fish in their diet as well    occur mothe wild –2. In adTrechalea  also engage in fish predation  is limited to parts of Asia and is found in stagnant pools, rice fields and swamps where it rests on aquatic plants Pardosa pseudoannulata has further been documented in the laboratory Aside from the abovementioned spiders, with well documented though poorly understood fish-catching abilities, a number of other spiders have been reported in the literature as occasionally preying upon fish . For exaArgyroneta aquatica (Cybaeidae), the only truly aquatic spider (spending its entire life under water) known so far, which has been observed killing and devouring tiny fish of the families Cichlidae, Gasterosteidae, and Poeciliidae when kept in aquaria (Desis marina (Desidae) and the ‘swimming’ huntsman spider Heteropoda natans (Sparassidae) There is laboratory evidence that spider species of even more families  are capable of catching and eating fish Dolomedes and Nilus has been well documented Dolomedes and Nilus rely on stimuli perceived by mechanoreception The prey capture and feeding behavior of Gambusia spp.] in the southeastern USA, fish of the order Characiformes in the Neotropics, killifish [Aphyosemion spp.] in Central and West Africa, as well as Australian fishes of the genera Galaxias, Melanotaenia, and Pseudomugil). Spiders killed small-sized fish predominantly 2–6 cm in length  or the very small immatures of species which achieve larger body size . Ictalurus punctatus and Oncorhynchus mykiss can reach a body weight of >10 kg once fully grown.All 89 cases of fish predation listed in n length ; File S1In general, spiders feed predominantly on prey items – usually insects – that are smaller than themselves Dolomedes and Nilus, with a weight of ∼0.5–2 g  with an average fresh weight of ∼0.4 g required 50 minutes before death Dolomedes sulfureus into the thorax of zebrafish (Danio rerio) in the laboratory caused severe neurological disturbance resulting in disorientation, uncoordinated movement (spinning), lack of buoyancy control and ultimately death within 20 min Dolomedes spiders exhibited similar spinning behavior prior to dying.It is arguable whether all incidences reported in this paper are real predation events or whether some are just cases of scavenging. Predation requires that a prey item must have been killed and eaten by the predator A fish prey must always first be dragged by the spider to a dry place before the feeding process can begin Dolomedes spiders accepted dead sticklebacks as food, but this was observed only in hungry adult females during periods of increased food requirements between mating and oviposition Trechalea spp. did not feed on dead prey if offered in captivity In captivity Trechalea spp. and Ancylometes spp.) occur most commonly in remote areas of the tropical rainforest and are strictly nocturnal as adults The majority of incidences of spider predation upon fishes were reported from the Americas, especially the eastern part of USA, whereas few were reported from Africa, Asia, Australia or Europe. To a large extent, the pattern shown in Dolomedes occur in North America, in contrast to Europe which contains only two species Dolomedes plantarius; Dolomedes fimbriatus) appears to depend on open water to a lesser degree Dolomedes fimbriatus often occurs in wetlands such as highly acidic moorlands or seasonally intermittent marshy areas in which fish are naturally absent Dolomedes fimbriatus is perhaps less well-adapted to predating fish in the wild. An extensive observational study by Poppe & Holl Dolomedes fimbriatus very rarely exhibited a behavior of ‘fishing’ or underwater hunting while foraging for aquatic arthropod prey. Instead this species fed predominantly on terrestrial arthropods captured on plants Dolomedes are less common (or as in the case of Dolomedes fimbriatus show less affinity with water inhabited by fish) in Europe than in the eastern part of USA. This may result in a lower likelihood of encountering or observing feeding on fish prey by such spiders in Europe. Notably however, Dolomedes is particularly species rich in south-east Asia Semi-aquatic spiders may be more common in some geographic regions than in others and our reported distribution of observations may reflect this difference in abundance and diversity. Semi-aquatic spiders are very common in eastern USA, particularly in the freshwater wetlands of Florida and neighboring regions 6 spp.; . Nine spDolomedes, at least, occur there Dolomedes triton . Instead the spiders were seen feeding almost exclusively on arthropods and in one instance on a small frog Dolomedes triton while spending approximately 300 man-hours as a wildlife photographer in freshwater wetlands in the Tampa Bay area in Florida.Most of the reported incidences of fish predation were from a broad latitudinal band from 40° S to 40° N, with very few reported instances of fish predation by spiders occurring north of 40° N despite the fact that members of Fish eating spiders are constrained in the size of fish they can capture and a greater reliance on fish as prey may occur in regions inhabited by more small-bodied fish, not withstanding the fact that all large-bodied fish must also be small-bodied while juvenile. Freshwater fish assemblages of North America and Europe do indeed contain fewer small-bodied species at higher latitudes Dolomedes spp. The same may be true for freshwater wetlands in the northern part of Asia where very few incidences of fish predation have been reported so far (Gambusia spp.)  and blue-eyes (Pseudomugil) both consume terrestrial insects from the water surface Dolomedes spiders may have difficulty catching other types of resident small fish, all of which are less likely to venture close to the water surface  . This seems to be in line with the observations of filmmaker Martin Dohrn , whereupon several specimens of Dolomedes fimbriatus had difficulty capturing sticklebacks (Gasterosteus aculeatus) and minnows (Phoxinus phoxinus) in a pool (staged situation). In the case of the sticklebacks, their dorsal spines makes it difficult for predators to catch them Dolomedes plantarius in a turf pond at Redgrave and Lopham Fen National Nature Reserve in East Anglia, UK  . These fia spp.)  they optAll five spider families reported in this paper as fish predators under natural conditions  are known from the literature to feed predominantly on arthropods Dolomedes sp.), that had become established next to an aquarium in the Steinhart Aquarium building (Dolomedes spp. are predators with broad diets composed of invertebrates and vertebrates Fish probably constitute a minor proportion of the diet of semi-aquatic members of the family Pisauridae Ancylometes spp.) were observed to feed heavily on fish at the edge of forest puddles or creeks. There is substantial observational evidence that subadults and adults of Ancylometes spp. feed to a large extent on small aquatic vertebrates Multiple incidences of fish predation by semi-aquatic spiders have been reported from the Cuyabeno Wildlife Reserve in Ecuador (report # 52–57). In this wildlife reserve, semi-aquatic ctenid spiders  and in this respect, the disparity in size of fish catching spiders and their prey is especially notworthy. It must be added that the caloric value of fish and insect tissue do not differ significantly . Additional research will be needed to reveal the extent and nutritional importance of fish in the diet of these spiders.It takes semi-aquatic spiders many hours to consume a fish Dolomedes spp. versus sunfish Lepomis spp. Riparian zones are widely recognised as ecotones of high productivity, diversity and ecological importance and cross boundary transfer of material from terrestrial and aquatic environments is frequently fundamental to the nature of the food webs of both Dolomedes and NilusIt has been long-known that semi-aquatic spiders of the family Pisauridae occasionally predate small fish; however, past studies focused on just two genera of a single family , Jeanette Carpenter Haegele (USGS Denver Field Station), Glen Collier (University of Tulsa), Dean Hendrickson (University of Texas), Jeffrey Hill (University of Florida), Brett Johnson (Colorado State University),www.dolomedes.org.uk), I-Min To (Tunghai University), and Jakob Walter  and of course, the many people who provided unpublished information and photographs.Frank Jordan (Loyola University New Orleans), Mark Kennard (Griffith University), Maurice Kottelat , Edith Marsh-Matthews (University of Oklahoma), Larry Page , Lynne Parenti , Andrew Simons (University of Minnesota), Rainer Sonnenberg (Zoologisches Forschungsinstitut Alexander Koenig), Donald Stewart (State University of New York), Melanie Stiassny , and Richard Vari . Antonio Brescovit (Instituto Butantan), Ansie Dippenaar-Schoeman (University of Pretoria), G.B. Edwards (Florida State Collection of Arthropods), Hubert Höfer (Staatliches Museum für Naturkunde Karlsruhe), Kelly Kissane (Blinn College), Astri Leroy (The Spider Club of Southern Africa), Robert Raven (Queensland Museum), Adalberto Santos , and Estevam L. Cruz da Silva  identified spider species in the photographs. Tadashi Miyashita (University of Tokyo) conducted a survey among spider researchers in Japan, using a mailing list of “kumo-net”. Appreciation is also expressed to the following people who helped us in various ways: David Dudgeon (University of Hong Kong), Thierry Gasnier , James Harwood (University of Kentucky), Alison King (Charles Darwin University), Mirjam Knörnschild (University of Ulm), Witold Lapinski (University of Ulm), Markus Metz (University of Ulm), Dolores Schuetz (University of Bern), Helen Smith (File S1Detailed Reports Description.(DOC)Click here for additional data file.Flow Diagram S1PRISMA 2009 Flow Diagram.(DOC)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Novel and more effective treatment strategies against multiple myeloma (MM) have significantly prolonged patients' survival and raised interest in the depth of response and its association with clinical outcome. Minimal residual disease (MRD) has emerged as one of the most relevant prognostic factors in MM and should be included in a new definition of complete response (CR). Although further standardization is still required, MRD monitoring should be applied in prospective clinical trials as a sensitive tool to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings, and implement individualized therapy-monitoring approaches. Here, we review current definition of deep response in MM, advantages and limitations of current MRD assessment assays, clinical evidences for MRD monitoring as a prognostic tool for therapeutic decisions in MM, and challenges to develop uniform criteria for MRD monitoring.  Multiple myeloma is a complex disease characterized by the presence of profound intratumoral heterogeneity that increases progressively from the stages of monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic MM to symptomatic or clinical MM –3. The iComplete response (CR), defined by negative immunofixation (IFX) and less than 5% bone marrow plasma cells, has been accepted as a relevant surrogate marker of survival . This de3  had a projected progression-free survival of 35–45 months, while patients achieving CR5 (0.001% deep complete response grade) had a projected progression-free survival of more than 80 months [As CR rates have improved, more rigorous definitions of response have been developed. In the last consensus criteria of response in MM, three new concepts have been incorporated: stringent CR (sCR), immunophenotypic CR (iCR), and molecular CR (mCR) . These d0 months , 27  provides powerful independent prognostic information , and catTherefore, a new definition of CR including different levels of MRD is needed in MM to compare different treatment strategies and develop a truly personalized approach to MM therapy. Likewise, this definition will be applied in all clinical settings and will be interchangeable between different centers.−3), intermediate (10−3 to 10−5), and low (>10−5) MRD levels showed significantly different TTP . Accordingly, 10−5 should currently be considered as the target cutoff level for definition of MRD negativity.Improving CR rates have made the measurement and monitoring of MRD in MM a relevant task. However, implementation of MRD assessment into clinical practice is a major challenge, hampered by differences in the assays and analytical methods employed between different routine laboratories. Most patients who achieve MRD-negative status eventually relapse, indicating that the sensitivity and specificity of traditional techniques for MRD assessment can be improved. Recent data by Rawstron et al.  suggestsIn this section, we will consider the various methodologies available at present for MRD detection, taking account of their relative advantages and limitations.Measurements of monoclonal protein biomarkers, which can be in the form of intact immunoglobulin, immunoglobulin fragments, or free immunoglobulin light chains (FLC), in either the serum or the urine are all widely available and noninvasive methods used for diagnosis and monitoring of disease burden in MM. One of the earliest identifıed biomarkers is Bence Jones protein, described in 1848 .During the past decade the measurement of serum kappa and lambda free light chains (sFLCs) has also become part of routine clinical testing, particularly for the diagnosis and follow-up of patients with nonsecretory and oligosecretory myeloma, light chain myeloma, and amyloidosis .The International Myeloma Working Group (IMWG) in 2006 has introduced normalization of sFLCs and absence of clonal PCs in BM biopsies by immunohistochemistry and/or immunofluorescence as additional requirements to define more stringent CR criteria . sFLC raβ regions [The US Food and Drug Administration- (FDA-) approved heavy/light chain (HLC) assay (Hevylite) measures suppression of the uninvolved HLC pair . The HLC ratio reflects the balance between monoclonal and polyclonal immunoglobulins of involved and uninvolved isotypes taking into account the polyclonal plasma cell suppression or expansion that occurs with the treatment. However, only few studies have shown the ability of the Hevylite assay to give additional prognostic information in MGUS and MM . In gene regions .Morphologic bone marrow examination is one of the most commonly used methods to measure tumor burden in MM. Two different studies demonstrate that microscopic assessment of the BM can have prognostic value , 41. HowMultiparameter flow cytometry (MFC) and Ig allele-specific oligonucleotide-based quantitative polymerase chain reaction (ASO-PCR) have emerged as the most attractive, well-suited, and sensitive approaches to detect MRD in the BM of MM patients during and after therapy . Molecul−4 and 10−5) because of simultaneous assessment of ≥8 markers in a single tube that can readily identify aberrant PC phenotypes at MRD levels if sufficient cell numbers  are evaluated [−6, with the potential to be distributed across multiple laboratories, because it relies on automated data analysis and does not involve expert interpretation by an operator. Moreover, molecular techniques are not influenced by genetic heterogeneity and clonal tiding throughout patients' treatment. However, additional validations are needed to prove and confirm the utility of this technology for patient risk stratification.In myeloma, several reports have demonstrated the ability of both MFC and quantitative PCR to stratify patient cohorts with different prognoses , 25, 45.valuated . The reqvaluated , 48. ThiUnlike other hematologic disorders such as acute leukemia, the pattern of BM infiltration in MM is not uniform. Moreover, hemodiluted BM aspirates may lead to false-negative results. These aspects, together with extramedullary disease, represent a potential challenge and pitfall common to all techniques that use BM samples for MRD assessment, as nonrepresentative samples of disease infiltration are sometimes obtained. For this reason, MRD-negative results may correspond to a false-negative case. The use of alternative methods for disease assessment such as imaging techniques , 49, monMultiple myeloma presents a high frequency of extramedullary relapses, and sensitive imaging techniques have become relevant in assessing low levels of disease outside BM. Magnetic resonance imaging (MRI) is the most sensitive noninvasive imaging technique for detection of bone involvement in the spine and also provides relevant information on the extent and nature of soft tissue disease and the pattern of marrow infiltration . However, due to treatment-induced necrosis and inflammation, focal lesions may remain hyperintense in both responding and nonresponding patients for several months after therapy, making MRI-based CR inconsistent. While MRI does not properly identify myeloma active lesions after treatment, imaging by fluorodeoxyglucose-positron emission tomography (PET) has been shown to have prognostic significance , 52 and MRD monitoring variability between different clinical laboratories is a major challenge. Because of the prognostic value of MRD in MM, a key goal of the standardization effort is to eliminate or correct the relative differences between MRD negativity assessment and response rates across laboratories.Optimal use of clinical guidelines for disease diagnosis and patient management requires first standardization and then harmonization, to maximize compatibility, interoperability, safety, repeatability, and quality as well as achieve uniformity of results , 54. ResDevelopment of reference standard and referral material to define CR grades 3 and 5.Manufacturing internal calibrators.Evaluation of current degree of measurement equivalence.MRD assessment in MM based on test results from a specific clinical laboratory measurement procedure (CLMP) without considering the possibility or likelihood of differences between various CLMPs should be flawed. When this happens, aggregation of data from different research clinical trials and development of appropriate clinical practice guidelines will be flawed by the lack of standardized or harmonized results.We here propose a roadmap for standardization of MRD assessment in MM:Previous experiences of standardization and harmonization of molecular techniques have been difficult and not very well accepted for many laboratories; furthermore the implementation of standardization and harmonization has been hard and long. However, when application in real clinical practice has started the results have been positive. In MM, standardization and harmonization of MRD assessment techniques should be considered, especially if these techniques will be considered biomarkers of response in clinical trials and in the regular clinical practice.Intra- and interpatient heterogeneity in multiple myeloma underscore the need for personalized treatment approaches. In an era of increased treatment options, there are substantial data showing the association of depth of response and clinical outcome. Achievement of CR is considered one of the strongest prognostic biomarkers in MM, both in the transplant and nontransplant settings, although the sCR criteria have failed to unequivocally demonstrate superior prognostic value compared with CR .MRD assessment is a relevant concept in myeloma and several studies using different MRD techniques have shown its value for evaluation of the efficacy of specific treatment stages and, therefore, potential treatment decisions. Overall, persistence of MRD is always an adverse prognostic feature, even among CR patients, but, so far, no clinical trial has randomized MM patients according to their MRD status and, thereby, investigated the role of MRD for individualized therapy. Achievement of MRD negativity may ultimately serve as a primary end point in clinical trials for MM and should be included in the CR criteria. However, patients achieving MRD negativity eventually relapse, and at this point we still do not know if these patients should receive the full-programmed treatment besides reaching the MRD negativity status or asymptomatic relapse. Importantly, considering the patchy pattern of BM infiltration observed in MM that leads to a degree of ambiguity regarding MRD-negative results, it would be safer to make clinical decisions based on MRD positivity rather than on MRD negativity. Several other questions on how to incorporate MRD evaluation in the treatment strategy for MM patients remain to be answered. Can we decide which patients should receive consolidation therapy based on MRD measurement? Can MRD monitoring be used to determine the need for or duration of maintenance therapy? How does maintenance therapies modify MRD levels?An important aspect to be considered is the time of MRD monitoring during the course of the treatment. Most studies have been carried out after transplantation in younger patients and after induction in elderly patients, but it is still unclear when the best time is to measure and integrate MRD measurement into therapeutic decision-making.Changing of MRD levels over time (MRD kinetics) could be relevant for a better evaluation of MM patients and needs further evaluation. For example, both the Spanish and the United Kingdom study groups have shown that MRD kinetics before and after HDT/ASCT allow the identification of chemosensitive (MRD-negative cases at 2 time points), intermediate, and chemoresistant patients (MRD-positive patients at 2 time points). A small clinical study of the Italian group showed three patterns of kinetics: high tumor burden, low tumor burden, and active disease, which could predict the relapse . These c5cells) may contribute to the design of patient-specific treatment approaches. Extensive research is still warranted to determine how to best integrate medullary and extramedullary MRD monitoring, and a process of standardization and harmonization of these methodologies is required. Harmonized MRD approaches not only will provide backwards compatibility with established assays but will also offer sufficiently high enough sensitivity as treatment strategies evolve to remain relevant for the next decade.Finally, sensitive methods of MRD detection  MRD assessment is ready for clinical application as biomarker to evaluate the response to different therapies in MM; (ii) MRD could be used to measure the efficacy of different treatments in clinical trials; (iii) MFC and NGS are both equally valid for MRD assessment in MM; (iv) standardization and harmonization are the next steps for MRD assessment in MM.Improvement in MM patient outcomes can be achieved through adaptive clinical trials involving risk models based on multiple biomarkers, but several questions are still unanswered. Different clinical trials integrating these approaches to confirm the clinical benefits of MRD monitoring are currently ongoing in myeloma and will hopefully provide the rationale for the use of MRD assessment in the evolving MM clinical paradigm. Moreover, the new generation of biomarkers, including epigenetics, novel imaging, clone burden, GEP signature, and next generation sequencing, coupled with established prognostic biomarkers holds promise for improved stratification of patients with myeloma into specific therapies and clinical trials.


As sprint swimming events can be decided by margins as small as .01 s, thus, an effective start is essential. This study reviews and discusses the ‘state of the art’ literature regarding backstroke start biomechanics from 23 documents. These included two swimming specific publications, eight peer-reviewed journal articles, three from the Biomechanics and Medicine in Swimming Congress series, eight from the International Society of Biomechanics in Sports Conference Proceedings, one from a Biomechanics Congress and one academic (PhD) thesis. The studies had diverse aims, including swimmers’ proficiency levels and data collection settings. There was no single consensus for defining phase descriptions; and kinematics, kinetics and EMG approaches were implemented in laboratory settings. However, researchers face great challenges in improving methods of quantifying valid, reliable and accurate data between laboratory and competition conditions. For example, starting time was defined from the starting signal to distances as disparate as ∼5 m to 22.86 m in several studies. Due to recent rule changes, some of the research outcomes now refer to obsolete backstroke start techniques, and only a few studies considered the actual international rules. This literature review indicated that further research is required, in both laboratory and competition settings focusing on the combined influences of the current rules and block configuration on backstroke starting performances. The total swimming race time is the sum of the starting, stroking and turning times . The staBackstroke is the only competitive swimming technique in which the swimmer starts in the water. In accordance with the backstroke start rules at the Federation Internationale de Natation (FINA) from earlier 1960s to 2005, swimmers grasped the handgrips and placed their entirely immersed feet on the wall. Gripping one’s toes on the pool gutter was not allowed. FINA backstroke start rules for feet positioning were modified by the National Collegiate Athletic Association (NCAA) from the early 1960s to 1990 to allow swimmers to curl their toes over the starting wall gutter. However, from 1991 to 2006 the feet positioning was restricted to underwater. This modification was made to prevent injuries in competitive swimming involving backstroke starts . From 2005, FINA established that swimmers must position their hands on the starting grips and their feet totally or partially immersed or entirely out of the water without using the gutter . The alleged advantages of feet placed high on the wall to generate greater horizontal take-off velocity , verticaDespite the controversies between ruling authorities, and considerable swimming and facility backstroke start rule changes recently authorized by FINA, researchers have mainly attempted to analyse the ventral start biomechanics e.g. . The greThe importance of swimming starts for enabling backstrokers to improve overall performances due to swimming rule changes and starting block modifications, makes it a valuable process to synthesise the scientific knowledge relating to backstroke starts. Literature reviews published regarding ventral start techniques were conducted by The literature search was performed using PubMed, SportDiscus™, Scopus and ISI Web of Knowledge electronic databases, only for English written documents published before March 2014. Key words including “swimming”, “backstroke” and “start” were used to locate documents. Besides the electronic databases, the identified reference lists in the articles were also used to ensure, as far as practically possible, that all appropriate studies were considered for inclusion. Searches were carried out from the Proceedings of the Scientific Conferences of Biomechanics and Medicine in Swimming (BMS), the International Society of Biomechanics in Sports (ISBS), and the International Society of Biomechanics (ISB) from 1980 to 2013.Included studies were experimental biomechanical approaches in the laboratory or during competitions with able-bodied swimmers. The documents that were available only as abstracts and duplicated studies from original investigations were excluded.Eighty-seven references were obtained from the preliminary search. Ultimately, 23 studies met the inclusion criteria: (i) two from swimming specific journals; (ii) eight peer-review journal articles; (iii) three from the proceedings of the BMS conferences; (iv) eight from proceedings of the ISBS conferences; (v) one from proceedings of an ISB Biomechanics Conference, and (vi) one doctoral thesis .The above mentioned factors, along with a limited number of existing studies, restrict quantitative assessments of the backstroke start variables. Therefore, a qualitative description was developed on relevant backstroke start evidence. This included the separate features of the starting phases, the biomechanical approaches used, and the start techniques and variations for which the main findings have been reported.The hands-off, take-off and flight are the most common aerial starting phases studied . HoweverThe beginning of the flight phase was unanimously described as the instant of take-off by the feet  Figure . HoweverThe entry and glide are the commonly studied aerial/in-water and underwater phases, respectively . As prevThe beginning of the entry phase corresponds to the final instant of the flight; and, for which, definitions differ among authors . The endAuthors have defined the glide phase as beginning at the instant entry ends until the maximum feet depth of the second downward underwater kick is reached , the hanIn previous ventral start studies, authors divided the underwater phase into two parts: the glide  and the Despite some authors using immediate feedback devices such as stopwatches  and veloMost studies used digital cameras to provide independent aerial, underwater or combined dual-media analysis. In competition settings, cameras were positioned 18 m above the swimming pool  and alonQuantitative data processing from digital cameras usually requires a coordinate scale and prevents immediate results due to the need for manual digitising . FurtherMost of the kinematics approaches mentioned in the backstroke start studies above provide biomechanical performance indicators instead of specifying how swimmers should organize body segments movements to optimise their performance. Performance indicators are less time-consuming for coaching feedback and hinder technique analysis method to be wide-used in backstroke start studies. As humans do not have rigid bodies and display combinations of rotational and linear motions , multi-sThere is a paucity of evidence concerning the parameters in the aerial/in-water and underwater phases. In fact, research usually has highlighted the importance of assessing entry  and undeDespite several studies having used kinematics, few studies of backstroke starts have included kinetic data. Kinetics requires higher costs than image based systems and presents technical difficulties when attaching the kinetic devices to the starting block and pool wall. However, The instrumentation of starting blocks for analysing backstroke starts has helped to verify how the respective movements are generated . The horDespite the understanding about the horizontal force profile generated by backstroke swimmers to propel themselves off the wall ; 2013, cThe instrumented starting blocks used in the previous research referred to the above are few and are now obsolete following the recent FINA facility rule changes approved in 2008 and 2013. The new hand and foot grips now available for backstroke starts have not been instrumented and used in research studies to date. Hence, sport biomechanists and engineers are urged to develop a 3D kinetic system in the new block configuration. Then, one could identify independently how the right and left, upper and lower, limbs contribute to propelling backstroke swimmers during the start.Beyond the linear kinetics, As for kinetics, specific EMG studies of swimming starts are few. To measure the muscle activity of backstroke swimmers during the start, a cable EMG system with surface electrodes was used by Deltoideus Anterior that had been very active fixing the body in a high set starting position. Despite this initial undertaking, Hohmann’s research group did not provide detailed descriptions of the criteria used to determine the muscles involvement along a continuum from strongly active to an inactive state. The lack of standard methodologies to define the EMG activity makes comparisons between studies difficult.The average and integrated EMGs, as amplitude signals, were calculated by Biceps Brachii, Triceps Brachii, Deltoideus Anterior, Erector Spinae Longissimus, Rectus Femoris, Gluteus Maximus and Gastrocnemius Medialis. Authors confirmed the crucial function of the lower limbs to generate the impulse during the take-off phase; however, they disagreed about the main muscle activities of the upper limbs. Studying the above-mentioned biarticular muscles (Rectus Femoris). As backstrokers are required to coordinate multiple muscles and joints to propel themselves rigorously out of the pool wall, more studies should couple EMG, kinetic and kinematic approaches to dictate how better backstroke start performance can be achieved.By studying the sequencing of muscle activation, one can focus on several factors relating to skill; including the timing and overlap of agonist and antagonist activity . The ago muscles  has highThe selected studies used a voice command , startinThe competition timing systems were used to simultaneously produce the starting signal and export a light to the video images ; and a tAlternative synchronisation methods have been implemented as the use of force instants to record the swimmer’s handgrip release ; 2013 anThe main objective of swim-start research has been to identify the most effective start technique in terms of performance . From thConsidering the backstroke start studies conducted with variations performed under the NCAA rules, both had used the 6.09 m distance to assess start time. According to Most research considered backstroke starts performed under FINA old rules and measured the starting effectiveness using distances from 5 to 15 m . Miller Backstroke starts are performed now under the current FINA rule (adopted in 2005) and only de Jesus et al. ; 2013 anThe main research findings can be summarised as follows: (1) the phase definitions used in analysing backstroke starts are inconsistent and unclear. Hence, this makes it difficult to determine how many changes over time can be attributed to a real change, or mere differences between definitions; (2) studies conducted in laboratory settings have adopted kinematics, kinetics and EMG; however, many research challenges remain in both settings to improve the methods of quantifying valid, reliable and accurate data; (3) the temporal variables, particularly the starting time, were most studied; and backstroke start movements were predominantly described using linear kinematics; (4) most of the experimental and competition research findings are now out of date since the backstroke start rules have been recently changed, and the studies were completed under swimming rules which are now obsolete.Future research would help coaches and swimmers by exploring issues not yet fully addressed in the literature. For example: (1) determination of a consistent observational model for categorisation and study of the backstroke start technique; (2) development of appropriate biomechanical measurements and research methodologies as standard tools; for scientific purposes and training support, competition preparation and analysis; (3) reinforcement of more holistic and process-oriented biomechanical approaches in laboratory procedures: involving interactions of kinematics, kinetics and EMG variables; from aerial, aerial/in-water and underwater phases; definitions for more detailed parameters which better describe the overall backstroke start in competitions, beyond the starting time; (4) focusing on studies based on the actual FINA rules and the new starting block configurations.


Although the prevalence of human immunodeficiency virus (HIV) decreased in the last decade worldwide, the number of deaths due to HIV/AIDS and communicable diseases including syphilis, hepatitis, and tuberculosis had dramatically increased in developing countries. Education and behavior are incredibly important factors to prevent these diseases' spread. This study highlights the range of differences in knowledge, attitude, and behavior of 434 sexually active medical students towards HIV/AIDS and sexually transmitted infections (STIs). Because the surveyed population constitutes the forefront of healthcare providers and was originated from different area of the world, this is the first time a study sought to investigate the behavioral attitude of this group of population irrespective of the three levels of their academic and professional knowledge. Several factors including sociodemographic characteristics, sexual behavior, HIV/AIDS, and STIs related patterns play a key role in medical student attitude and behavior towards people infected with HIV/AIDS and STIs. Our findings add consistent value in prior studies which aimed to stop new infections and also imply further investigations on the management of the studied infections by medical students. The present study arouses much interest among participants and provides evidence of reinforcing medical students' education on HIV/AIDS and STIs. Despite the great effort made by governments and international organisations to stop new HIV infection and reduce sexually transmitted infections by 2015 –7. TheseLooking at the paradigm to fight against HIV with the aim of providing the treatment to all infected people regardless of their biological and clinical stage , severalIn the last decade, China became not only more attractive in business or political affairs but also one of the main international destinations for education, especially in the field of medicine. Many foreign students studying in Chinese universities are from countries with high prevalence of communicable diseases; it is gainful and invaluable to have extensive knowledge in HIV/AIDS and STIs for practical issues when returning back home after graduation. Then, several studies revealed that barriers including lack of adequate knowledge, misconceptions, negative feeling, refusal, or even discrimination were found among healthcare professional in providing medical care and monitoring HIV/AIDS patients –19. TherThe authors designed a cross-sectional study using validated self-administered questionnaire. We focused on the rationale of this study to compare and show differences existing between foreigner and Chinese medical students' knowledge, attitude, and behavior (KAB) towards HIV/STIs infected persons. The survey tool was firstly designed in English for foreign students then translated into Chinese language. Both English and Chinese versions were discussed and pilot-studied before the final usage.This study was conducted in Tongji Medical College affiliated to Huazhong University of Science and Technology (HUST) located in Wuhan, the capital city of Hubei province known as the Chinese education city. According to the latest Chinese ranking universities, Tongji Medical College belongs to the top 1% of Chinese medical schools and is the mostly reputed for its numerous medical programs taught in English. The number of foreigners enrolled for a degree programme during the last 5 years has significantly increased to about 1500 international students annually , 21. ParTotal of 434 medical students  were randomly selected among students regularly registered and living in students' campus apartments. 157 foreign students enrolled in English medical degree programme and 277 Chinese medical students all sexually active were included in this study .student door-by-door strategy” which consisted of randomly selecting student's room from all apartments in the campus residency and inviting student to participate. To ensure the confidentiality and increase participation rate, student was asked to drop the anonymous questionnaire filled in a box placed at the entry of apartment. All students enrolled in nondegree programme and nonsexually active were excluded. Participation rate was estimated to be 65% for foreigners and 78% of surveyed local students.All students were previously informed of educational based characteristics of the survey through posters announcement and presurvey activities formed to inform and discuss with respondents publicly across the school campus. During this phase, investigators covered approximately 98% of study population. The final step consisted of using “The following variables were gathered: gender, age, education level, marital status, region of origin, sexual orientation, number of sex partners, frequency of condom use and enjoyment during sexual intercourse, history of HIV and STIs testing, and vaccination for curable infections .The variables were measured through a series of 7 yes or no questions on HIV/AIDS cause, progression, and prevention; the main sources of information included 8 items while the assessment of HIV risk factors was subdivided into the route of transmission containing right and wrong responses (16 items), high risk individuals (8 items), and risk factor increasing HIV transmission (7 items). In addition, 3 other questions were related to previous extracurricular training in HIV and STIs, student belief of sufficient knowledge about studied infections , and student willingness to know more about HIV/AIDS.Variables describing student attitude and behavior comprised 21 questions mainly on sexual behavior and condom use, HIV and STIs testing, their attitude vis-à-vis friend/classmate infected with HIV, and students' opinions related to the support of government and NGOs towards HIV/AIDS patients. We also assessed student's beliefs regarding HIV/AIDS comparing to other STIs and tuberculosis and moreover the relationship between HIV infection and ethnicity and the current development of China.Variables describing the discrimination and support of students towards HIV/AIDS patients derived from 13 items of the questionnaire which included both positively and negatively framed questions.P50 (P25–P75) was use for nonnormal continuous variables; the Mann-Whitney U test  for continuous variables was conducted to compare measurements between Chinese and foreign students. Categorical variables were compared using χ2 (for comparing proportions) tests. Where possible when assessing the knowledge, attitude, and behavior, we assigned 1 for every positive response and 0 for wrong answer. For brevity and clarity, we reported only significant factors influencing discrimination and support in multivariate logistic regression analyses. Odds ratio (OR) with 95% of confident interval (CI) was calculated to fit association levels between students' characteristics and discrimination or support of HIV/AIDS individuals. All tests were two-tailed and results were considered significant at p < 0.05.Data entry was done using Epidata version 3.5 and all analyses were conducted with SPSS version 18.0. In short, we used numbers and percentages to present most of data while  IORG S115. Moreover, all participants provided a written informed consent attached with the questionnaire at the time of the survey.Ethical clearance was previously obtained from the institutional review board of Tongji Medical College of Huazhong University of Science and Technology under authorization numberData summarized in Despite the fact that no difference was found in participants' education level, this study revealed a huge difference in HIV/AIDS knowledge between Chinese and foreign students see . OverallConfusions about route transmission and risk factors of HIV transmission were found among the two groups. Differences presented in Results given in From the multiple logistic regression analysis, results presented in Concerning the support to HIV infected individuals, several factors including students' origin , high level of knowledge about HIV transmission , and manifestations , being bisexual , and vulnerability factors such as lack of knowledge about HIV/AIDS  or poverty , condom usage , source of information , and the willingness to know more about HIV/AIDS  were associated with the support that students may provide to HIV/AIDS individuals; however, never having been tested  or vaccinated for hepatitis B  and knowing that STIs acquisition increase HIV transmission  could negatively affect students' behavior vis-à-vis HIV infected individuals.Human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) are known as a major public health concern worldwide. The constant assessment of healthcare provider knowledge and behavior would always contribute to overcoming the infection. No previous study has assessed and compared medical student's knowledge and behavior towards HIV/AIDS and associated sexually transmitted infections among local students and their foreign counterparts in China. Whether differences were found across countries in students' knowledge, attitudes, and behavior –24, mediThis study revealed high rate of homosexuals among Chinese students compared with foreigners. Despite the fact that homosexuality is contrary to Chinese values and not yet accepted, some Chinese young men and women are sexually going with the same sex partner . Of noteDespite the greater effort made by international organisations, nongovernmental organisations, and the majority of governmental institutions in developing world to inform and educate about communicable diseases, several misconceptions are persistent among students including medical students on HIV/AIDS and STIs , 26, 27.Though personal conception can significantly impact individual's behavior, medical students along their education are sufficiently trained and confronted by different illness cases that may offer opportunities to show much positive attitude vis-à-vis all patients regardless of the nature of infection. In this study, forty-five per cent of Chinese medical students compared to thirty-six per cent of foreigners preferred to avoid condom use after HIV testing. Thus, the great proportion would allow unprotected sexual intercourse among unknown HIV status person; however, this study found a lower rate of HIV testing among local students. In fact, several previous studies demonstrated the missed opportunities of medical students and healthcare providers to uptake HIV and STIs testing of populations , 27, 28;Although all participants exhibited the willingness to support HIV individuals through several actions, about twenty-nine per cent of Chinese medical students prefer to stay away from classmate or colleague infected with HIV while twenty-four per cent of foreigners though it was unwise to be close to HIV infected person. According to this finding, we suggested that medical student training time period is an opportunity to identify and correct negative attitude leading to discrimination of HIV infected individuals found within participants. More importantly, this study revealed that age, number of sexual partners, HIV testing, considering oneself as high risk individual to HIV, considering physical contact as route of transmission, poverty, and having only books and newspapers as main source of HIV/AIDS information were factors that increased discrimination of people infected with HIV by medical students; however, deeper knowledge subsequently increases medical students' support towards people living with HIV/AIDS and STIs. In accordance with previous studies , 17, 31,Several limitations appear to this cross-sectional study in nature. Although all participants were sexually active medical students, they had different background and culture that may affect the disclosure of attitude and behavior. The authors have limited the recruitment of participants to a single university out of numerous universities in China. Therefore, the extension and further clinical observational studies are warranted to assess students' knowledge, attitude, and behavior described in the current study.This study has established the overview of knowledge, attitude, and behavior on HIV/AIDS, syphilis, hepatitis B and hepatitis C, and tuberculosis among medical students in Chinese university. Chinese students scored high level of knowledge compared to foreigners while several misconceptions, confusion, and fear existed among the two groups. Students' background and sexual activity strongly affected their attitude and behavior towards people infected with HIV and STIs. The present study arouses much interest among participants and implies the need of reinforcing medical students' education on HIV/AIDS and sexually transmitted infections.


OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC Genomic technologies are increasingly being utilized in the clinical setting and are expected to transform personalized approaches to medicine over the next decade. When genomic biomarkers are coupled with clinical information, family history, lifestyle, and other environmental factors, more informed predictions about risks for rare and common disease and response to therapeutics can be provided . In addi®) is an ongoing longitudinal study, launched in December 2007, by the Coriell Institute for Medical Research to explore the core issues of utility and delivery of personalized medicine [® to investigate the impact of genomic counseling using a randomized controlled trial study design in patients with CD disease within an academic medical center environment. Patients with either a diagnosis of heart failure (HF) or hypertension (HTN) were selected because of high disease prevalence, frequent clinic visits, and long-term use of medications for disease management. All prospective CD participants were required to, (1) attend a one-hour informed consent and study education session, and (2) register on the CPMC® web portal through their home computer and complete CPMC® parent study surveys  and a baseline study specific survey. Genotyping was then performed. All participants were subsequently notified by email of the availability of an initial batch of results for eight health conditions  and one pharmacogenomic result (CYP2C19 results interpreted in the context of response to clopidogrel) through the CPMC® web portal. To determine the impact of genomic counseling on outcomes, participants were block randomized to either receive in-person genomic counseling (active arm) or no genomic counseling (control arm). Active participants were offered in-person genomic counseling after viewing of at least one test report through the CPMC® web portal. The control arm was offered in-person genomic counseling after a three-month randomization period. Follow up OSUWMC-Coriell study specific surveys are then administered to both groups through the CPMC® web portal. Additional health condition and pharmacogenomic (PGx) reports are released over the course of study, along with additional parent CPMC® study surveys.The Coriell Personalized Medicine Collaborative (CPMCmedicine . The Ohiversus those that will not (control arm) at baseline compared to follow-up. Study specific baseline and follow-up surveys measure risk perception, risk perception accuracy, general and relative risk numeracy, genetic knowledge, intention to change health behavior, acceptability of test result information, and other outcome measures related to the participant’s risk for the initial batch of results. We will measure satisfaction with genomic counseling and modifications to health behaviors over time. OSUWMC physicians were also recruited into a pilot study to explore their knowledge and test result utilization. Here we report on clinical implementation and study activities over the 28-month period, from 30 May 2011 to 31 September 2013. The study continues to collect follow-up data.The primary study outcome is to determine whether there is a change in risk perception and understanding of test results for participants who receive in-person genomic counseling (active arm) ® study was established as a prospective observational research study with ancillary randomized controlled trials seeking to determine the impact of multiplex genomic test results on health and health behavior when reported directly to study participants. It has also sought to understand best practices around the use of genomic information in medical settings and individual health management within three study cohorts: community, cancer, and CD. The community cohort participants were recruited without regard to health status or affiliation with a healthcare institution, while the cancer study group consists of participants with a personal history of either breast or prostate cancer. The CPMC® has been described in detail previously [The parent CPMCeviously .® parent study were adapted and transformed. This included customization of the CPMC® web portal to incorporate study-specific surveys, allowing access to study participant reports by the OSUWMC licensed genomic counselors, and randomization mechanisms. An encryption system allows for transfer of the DNA sample, the CPMC® test reports and phenotype/genotype data between institutions.The OSUWMC-Coriell partnership and this study focused on the CD cohort, and the randomization of this cohort to assess the impact of genomic counseling on various study outcomes. To develop the necessary study related infrastructure, the educational pieces and infrastructure currently in place as part of the CPMC® electronic medical record (EMR) system (06/2008).HF and HTN were chosen given the burden of these diseases and their prevalence  using the CPMC® web portal on their home computer. Online support was available if a participant had questions regarding access of the surveys through the CPMC® web portal, otherwise survey completion was unsupervised. Participants, however, will be prompted to review and update the data entered into the web portal periodically to provide longitudinal health data from which changes in health outcomes will be determined as part of the parent CPMC® study. Following completion of all baseline surveys, participants were block randomized to the active or control arm of the study. Each arm received the same nine personalized risk reports for their initial batch of test reports. Participants in the active arm received in-person genomic counseling, from one of two available licensed genomic counselors, within one month of viewing at least one report of the initial batch of nine reports. In contrast, subjects in the control arm were not offered genomic counseling as part of the study protocol, but were able to access in-person genomic counseling, if requested, three-months post-result viewing and post-follow up survey (study) completion  variants associated with complex diseases and drug-gene pairs deemed potentially actionable by Coriell’s advisory boards—the Informed Cohort Oversight Board (ICOB) and the Pharmacogenomic Advisory Group (PAG) [Genetic testing with Affymetrix 6.0 and DMETPlus GeneChips was performed only after participants completed the required baseline questionnaires. These GeneChip platforms were chosen to allow study of behavioral outcomes related to diseases affecting a reasonable proportion of all CPMCup (PAG) . A potenCYP2C19 report was the first drug-gene pair to be released through the CPMC®. The development of CPMC® risk reports has been described in detail previously [® web portal. This will allow for longitudinal assessment of health and health behavior through the parent CPMC® study.These eight health conditions were chosen in accordance to the Coriell Institute guiding principles for risk reporting: relative high frequency of the genetic variant used to assess risk; varied effect size of each variant on risk; and the finding that each condition has an actionable or potentially actionable component . Most ofeviously . Followi® study reports, collection of at least a three-generation pedigree, as well as evaluation of the patient’s medical history, social history, pertinent environmental risk information, and current health promotion and screening behaviors. Prior to the genomic counseling session, the patient’s medical history is extracted from the OSUWMC EMR, and the family history entered into the CPMC® web portal by the patient is extracted to develop a pedigree. As the genomic counseling sessions were designed to review results for all nine personalized reports, these are also accessed. This individual patient information is then assessed by the OSUWMC genomic counselor in conjunction with the OSUWMC medical geneticist. The design of the parent study CPMC® test reports  ,30,31,32® test reports in the EMR, and a question and answer session. In addition, the physicians were informed of the availability of the study genomic counselors and medical geneticists for consult regarding their patients’ CPMC® test reports. Interested physicians completed an informed consent document, a study survey adapted from Roederer and colleagues [OSUWMC physicians were recruited into a pilot study of their knowledge and result utilization. Two physician champions, one each from Cardiovascular Medicine (CVM), and General Internal Medicine (GIM) were identified, and internal group meetings with the respective physican teams arranged. The investigators designed an educational module consisting of an in-person lecture on genetics, genomics, pharmacogenomics, case examples, and study details including the randomization component, the makeup and availability of the CPMClleagues  related ® report was labeled with a naming standard with separate creation of a new procedure code for direct uploading to the EMR. The reports are accessible by any OSUWMC physician through hyperlinks to the report content via the EPIC/Labs tab. Patient participants seen for genomic counseling subsequently receive a risk summary research report , disease group (HF versus HTN) and relevant subgroups of interest. Histograms and box plots will be the graphical measures used to complement descriptive analyses of categorical data. Relevant continuous measures will be evaluated for normality and those differing markedly from normality will be summarized by using medians, interquartile ranges, and box-plots. In addition, response variables that violate assumptions of normality will be transformed to achieve normality or analyzed using nonparametric statistics. For statistical inference, we will employ a variety of parametric and non-parametric statistical techniques such as t-test, chi-square, Fisher’s exact test, Wilcoxon rank sum test, Person-r, Spearman-rho or point- biserial correlations, linear and non-linear regression analysis, random effects models, generalized estimating equations, factor analysis, and structural equation modeling. For analyses involving small sample sizes, exact statistical tests and bootstrap methods will be applied.The statistical analysis will proceed in several distinct phases, from generating descriptive summaries, graphical representations to identify outliers, to performing inferential analyses. Survey questions will be categorized by using summary indexes such as the genetic knowledge score, the relative risk numeracy index, and the benefits of the OSUMC-CPMC study score. In addition, factor analytic techniques will be used to categorize outcomes. Descriptive statistics, such as means, standard deviations, medians and range for continuous variables , and percentages for categorical variables  will be generated for quantitative data. These statistics will be generated for all quantitative data on the CD cohort, by genomic counseling group (active versus HTN), sex, race, education, income, occupation, number of risk reports viewed, genomic counselor, and others found to differ significantly between groups  when comparing treatment conditions (active versus control) on baseline characteristics. We will consider analyses based upon (1) all randomized subjects ; and (2) excluding those who were non-compliant. The statistical tests will be two-sided with a type-I error of 0.05.Overall differences in risk perception and other outcome measures between the active and the control groups will be assessed. The analyses will adjust for relevant covariates such as CD group (HF versus low) interaction will be evaluated. Such interactions will help us understand if between-counseling group differences in outcome measures vary by genetic risk group. Exploratory analyses will also be performed to describe the baseline knowledge of study physicians regarding genomic testing for common complex disease and the clinical utility and integration of genomic information into electronic medical records during the course of the study.In addition, exploratory analyses to evaluate the effect of counseling by genetic and non-genetic risk , provides 80% power to detect differences in changes in overall risk perception of 0.5 points  and greater. For example, if the change in overall risk perception is 0 (no change) in the group without genomic counseling (control arm), then we would be able to detect as significantly different, changes in the counseling group (active arm) of −0.5 or smaller, and of +0.5 or greater. These estimates assume a standard deviation for change score of 1.5  and two-sided tests with α = 0.05.® test reports, with equal randomization into the active (105) and control (105) arms. In the active group, 73 out of 105 participants have received genomic counseling. Nine out of 105 have received in-person genomic counseling in the control group.Of 252 patient participants accrued as of October of 2013, 210 have completed the required baseline questionnaires . Forty-ti.e., screen for coronary artery disease if the patient participant had a SNP risk variant), and perceived lack of clinical utility after the initial educational intervention. As the study design required a sufficient number of physicians to be involved in order to accrue patients, a third clinical area, the Department of Family Medicine (FM) was added in October 2012. An alternate approach was developed for patient recruitment utilizing an internal FM recruitment team. Interested FM physicians could become “physician participants”, as with the GIM/CVM group, but instead of an in-person educational module, a one-hour educational webinar accredited by OSUWMC for a maximum of 1.5 AMA PRA Category 1 Continuing Medical Education Credit(s)TM was made available. Although 16 FM physicians subsequently provided access to patients for recruitment, none completed the educational program or pre-post education knowledge assessment.Twenty General Internal Medicine (GIM) and Cardiovascular Medicine (CVM) physicians participated in the pilot study , completing pre-post education genetics knowledge assessment, attending an in-person educational module, and working with study staff to recruit patients into the study. The fifteen GIM physicians who declined participation cited lack of time, concerns with having to act on the results for their patients , and integration of genetic counselors and geneticists to establish the protocol, and processes for data return and infrastructure development. The existing CPMC® infrastructure provided key strengths, including experience with genomic based protocols and consent processes, CLIA-compliant genotyping, internal oversight boards to define actionable conditions, and an interactive web portal for direct delivery of participant results. Internal pilot funding from both organizations catalyzed project initiation. Through internal meetings, teleconferences and other interactions including travel to the partner institute, the partnership has evolved into a coordinated effort that takes advantage of the diversity and strengths of each institution. Limitations, such as privacy concerns for sharing medical records and genomic data, and the incorporation of outside genomic test reports into the EMR, were overcome by active involvement of interdisciplinary IT workgroups and legal teams. Significant infrastructure was developed that allows confidential sharing of data between institutions, specifically, direct release of the initial study results for uploading to the EMR (and prospectively for new test reports); extraction of clinical data from the EMR; and transfer of the genomic datasets. Lastly, modification of an existing comprehensive consent document addressed many of the confidentiality concerns present in prospective genomic-based research.The strengths of an academic medical center include access to patients and their clinical data, robust EMR and clinical support systems, clinician scientists, expertise with human genetics, and insightful pharmacy and pharmacogenomics support. In our view these strengths outweigh the limitations and challenges of the academic medical center environment, which include institutional inertia, fragmented expertise and the lack of appreciation and acceptance by clinicians to enact genomic guided medicine ,9,13,18.® and raised unique issues related to participant expectations [® results, and the option to view or not view each result independently. In addition, participants have been empowered, as part of the consent process, to indicate or deny their consent for sharing of data (genomic/phenotypic) with for-profit and non-profit third party researchers. The consent document, thus, provides what is now referred to as tiered-layered-staged consent [® web portal . Patient participants also signed a separate, subject information sheet which allowed investigators access to discrete phenotypic information extracted from the EMR and for that information as well as genomic data to be shared between institutions.Patient participants consented to genomic testing with the understanding that the GeneChips utilized test for over one million single SNP sites of variation, but that the study results would only be released for variants associated with actionable health conditions approved by the ICOB and PAG . This coctations . However consent . Tiered  consent . Layeredi.e., Coriell Report—Plavix) and made available to the OSUWMC physician team in the EMR. However, the length and format of the CPMC® test reports did not lend themselves well to rapid interpretation or automated clinical decision support platforms [i.e., SNPs). They will incorporate information from the patient’s EMR such as medications combined with the genomic variant data to trigger “best practice alerts” defined via conventional logical assertions. The first CDS algorithm under development is that for CYP2C19 variants, and will include, over time, additional CDS capabilities, based on the potential adverse effect, such as recommending against the use of a certain medication [Integral to the clinical genomic translation process is effective use of EMR applications to assist the physician team at the point of care. This component involved construction of IT applications for an existing EPIC-based EMR. Test results were transmitted from Coriell to OSUWMC in PDF format, in a secure manner, labeled with the appropriate disease/PGx name . More research is needed on barriers to physician participation in a study like this, especially since emerging technologies will allow more individuals access to their genomic profiles and primary care physicians, in particular, will become more involved in communicating risk information ,13,35,39® web portal. The randomization component, therefore, allows opportunity to study the utility of post-test in-person genomic counseling versus only the web-based return of results; to test our hypothesis of a significantly greater change in risk perception and understanding of test results for participants who receive in-person genomic counseling (active arm) as compared to those who do not (control arm). Our approach to development of the genomic counseling protocol was multifaceted, using literature review and feedback from the CPMC® genomic counselors, who have had extensive experience providing phone genomic counseling to CPMC® community participants. Indeed, rather than only focusing on the disease or PGx reports of interest to the participant, the in-person sessions were designed to review results for all nine personalized reports. To aid explanation, and given the amount of information discussed, we developed and incorporated a tabular visual display for all eight disease reports and the CYP2C19 report into these patient sessions, with added discussion of variants associated with an increased risk (risk variants), decreased risk (protective variants), or those with no clinical impact. The tabular display used in the in-person counseling session synthesizes each of the risk factors into a one-page document to provide an overall “quick reference” summary. There is additional counseling for the CYP2C19 result, which includes education regarding their specific haplotype , metabolizer type, and an explanation of the indications for prescription of the relevant medication(s)  [® risk reports are also accessed live via the web portal during sessions to assist participants in understanding how to navigate their results moving forward. This also presents an opportunity for “teachable moments” to enforce key concepts . How patients with chronic disease cognitively engage and react to this information; their perceived susceptibility and methods of coping given they already have a chronic condition; their approach to decision-making and on how best to utilize information for which they may have no prior experience; and what they may want and need from the process of genomic counseling are areas of address. As there is need for more scalable and streamlined delivery models for common complex disease, this collaborative effort allows for prospective comparison of the CD and community CPMC® cohorts, and to study the effects of genomic counseling on risk perception, knowledge retention and behavior change. This may also allow results from this controlled-trial to be explored for generalizability to other populations. Additional identification of risk and subsequent referral for appropriate medical services , and follow through on EMR referrals is being closely monitored, to determine whether any new referrals are dependent upon the genomic counseling assessment versus initiated independently by the patient’s physician.Genomic tests that analyze large sets of markers across the genome for multiple diseases and PGx variants continue to proliferate ,5,6,9. Aidogrel) . The CPMGenetic counseling, like other medical professions must continue to evolve and adapt to ever increasing amounts of data, and effectively translate this data to the lay person. This randomized controlled trial is among the first coordinated efforts to implement genomic information, including pharmacogenomic information, into patient care, and to investigate the impact of in-person genomic counseling in the return of actionable genomic results for common complex disease. This study will provide critical insights into the impact of genomic counseling on behavior and health, and enable the design of larger trials. It will allow for preliminary practice recommendations regarding best practices to facilitate comprehension of genomic test results, accurate risk perception, and to motivate behavior change. It will also promote further development of genomic counseling models and delivery methods. Patient response to pharmacogenomic testing, the myriad issues surrounding physician education and integrating effective clinical decision support to providers through the EMR are also areas of future research interest.


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting 36 million people worldwide and 5.2 million in the United States. The pathogenesis of AD is still elusive. Accumulations of abnormal proteins (beta amyloid and tau protein), inflammatory cascades, abnormal responses to oxidative stress and alteration in oxidative metabolism have been implicated in AD. There are few effective therapeutic options available for this disorder at present. Neuromodulation offers a novel treatment modality for patients with AD. The databases of Medline and PubMed were searched for various studies in English literature describing the deep brain stimulation (DBS) in patients with AD. Various animal and human clinical studies have shown promising initial results with bilateral DBS targeting various anatomical nodes. In this review, we attempt to highlight the pathophysiology, neural circuitry and potential neuromodulation options in patients with AD. In appropriately selected patients, DBS can potentially delay the cognitive decline, enhance memory functions and can improve the overall quality of life. However, further randomized controlled trials are required to validate the efficacy of neuromodulation and to determine the most optimal target for AD. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. This disorder was first described by Dr. Alois Alzheimer in 1901 in a 51-year-old woman with progressive memory loss , 3 (httpThe current management options for AD include medications aimed at potentiating the cholinergic pathways (acetyl cholinesterase inhibitors) and mitigating the glutaminergic pathways (N-methyl D-aspartate receptors blockers) . Anti-oxFollowing the success of deep brain stimulation (DBS) surgery in a variety of movement and psychiatric disorders , this trThe etiopathogenesis of AD is not completely elucidated. Based on animal and human studies, a variety of pathogenic mechanisms such as accumulations of abnormal proteins (beta amyloid and tau protein), inflammatory cascades, abnormal responses to oxidative stress and alteration in oxidative metabolism have been implicated in AD , 3, 5, 9These molecular alterations lead to neuronal loss and cerebral atrophy in the different regions of the brain involving frontal, temporal, parietal, hippocampus and entorhinal cortex (EC) , 5. In aThe databases of Medline and PubMed were searched for various studies in English literature describing the DBS in patients with AD. All related studies published up to December 2014 were included in this review.Various rodent models have been used to demonstrate the efficacy of DBS in modulating the memory circuits and enhancing the neurogenesis , 14. HamDBS is a well-established therapy for a variety of medical refractory movement disorders (Parkinson disease (PD), essential tremors and dystonia) with over 100,000 implants worldwide . DBS wasBased on promising results in animal models, various targets have been explored as potential DBS targets to modulate and enhance the memory functions in patients with AD. Hamani et al  reportedBased on animal studies , NBM hasSince EC/hippocampus is an integral part of Papez or memory circuits, modulation of these structures can be explored as potential therapeutic targets in patients with AD. Fell et al  conducteStefani et al  implanteVentral capsule provides a conduit for the white matter tracts originating from the basal ganglia, brain stem and hippocampus and projecting to the frontal lobe. Ventral striatum and nucleus accumbens has also been implicated in motivation and is a part of reward circuitry . ModulatAD is a complex disease with significant financial and healthcare burden. The medical therapy for AD is of modest benefit and associated with significant side effects. The use of neuromodulation in the treatment of AD is a relatively newer modality and the most optimal target is yet to be elucidated. DBS of the fornix/hypothalamus has shown promising results in terms of both delaying and reversing the cognitive deterioration in patients with AD. Other targets such as NBM, PPN, ALIC/NAc and EC have been explored with good initial results. In appropriately selected patients, DBS can potentially delay the cognitive decline, enhance memory functions and can improve the overall quality of life. However, long-term randomized controlled trials are required to validate the efficacy of neuromodulation and to determine the most optimal target for AD.