The genetic and biological similarity between non-human primates and humans hasensured the continued use of primates in biomedical research where other speciescannot be used. Health-monitoring programmes for non-human primates provide anapproach to monitor and control both endemic and incoming agents that may causezoonotic and anthroponotic disease or interfere with research outcomes. In 1999FELASA recommendations were published which aimed to provide a harmonizedapproach to health monitoring programmes for non-human primates. Scientific andtechnological progress, understanding of non-human primates and evolvingmicrobiology has necessitated a review and replacement of the currentrecommendations.Macaca mulatta (Rhesus macaque) andMacaca fascicularis (Cynomolgus macaque). In addition,other species including Callithrix jacchus (Common marmoset)Saimiri sciureus (Squirrel monkey) and others are included.The important and challenging aspects of non-human primate health-monitoringprogrammes are discussed, including management protocols to maintain and improvehealth status, health screening strategies and procedures, health reporting andcertification. In addition, information is provided on specific micro-organismsand the recommended frequency of testing.These new recommendations are aimed at users and breeders of the commonly usednon-human primates;  New methodologies have been developed and priorities forhealth screening non-human primates (NHPs) have changed with new assessmentsoutlined in EU directive 2010/63/EU. This has necessitated a review of the currenthealth-monitoring guidelines for NHPs.Since the publication in 1999 of recommendations for health monitoring of non-humanprimate colonies2 This use, however, should be limited to investigations where alternativemethodologies and where in-vitro models or other animal models areunavailable, for the preservation of the respective NHP species and in essentialareas of biomedical research with a high probability of achieving benefit for humanhealth.The use of NHPs in biomedical research is still necessary for the advancement of science.The source of NHPs in biomedical research is not limited to European breedingcolonies, although it is now effectively limited to purpose-bred animals. In EUmember states, only NHPs that are offspring of animals that have been bred incaptivity (F2/F2+ generation bred) will be permitted to be used after 10 November,2022. Monitoring the health and improving the welfare of these animals at allstages, in both the source breeding colonies and in the research centres through aharmonized approach to husbandry and health monitoring, will ensure the suitabilityof NHPs in quality-driven research. In addition, since many pathogens have theability to infect and cause disease in NHPs and also infect and cause disease inhumans, this harmonized approach will also assist in reducing the risk of zoonosisto animal handlers and conversely anthroponotic infections in animals.In contrast to many other commonly-used laboratory animal species NHPs poseconsiderable challenges when trying to establish and manage health status. They arecomplex and mostly large animals which must be co-housed in compatible social groupsin an enriched environment. Gestation and time to weaning is prolonged and thereproductive rate is generally slow compared with other laboratory species. Inaddition, the importance of appropriate behavioural management and socialization isbeing increasingly recognized in the maintenance of non-human primate health andwelfare, requiring the consideration of human health in addition to animalhealth.Cercopithecineherpesvirus 1  and Mycobacteriumtuberculosis.35 When supplied,they must be accompanied by a relevant lifetime veterinary history and a healthdeclaration detailing all health screening carried out including when it was carriedout, the name/details of the laboratory performing the testing and the methodologyemployed.All NHPs supplied for use in biomedical research should be of known health status,particularly with respect to major zoonotic pathogens such as Microbiological unit: the microbiological unit is considered as theframe for health monitoring. It is possible for the microbiological unit to be asingle animal but in the context of an NHP this is considered unlikely. More likelyis the group of animals occupying a room, a set of rooms or a defined area which maybe complicated by access to an external environment or by being serviced by the sameplant or staff as other groups of animals which may link the groups in amicrobiological sense. Identification of the microbiological unit is key to healthmonitoring and management.Pathogenic agent: an infectious or parasitic agent capable of causingclinical disease and possibly mortality in immunocompetent animals.Opportunistic agent: an agent which may be present within the animal’senvironment or as part of the normal commensal flora without causing clinicaldisease but may become pathogenic in certain pathological conditions. Opportunistorganisms may act synergistically with other infectious agents or in situations whenimmune status is compromised.Interfering agent: an agent which may or may not have any pathogenic oropportunistic capacity but which has the potential to interfere with scientificaims.Zoonotic agent: a pathogen which is naturally transmitted betweenvertebrate animals and man.Anthroponotic agent: a pathogen which may be transmitted from man toanimals.The health status of any group of animals is determined by various factorsinteracting to exert influence, with the most significant challenge provided byexposure to infectious microorganisms. Maintaining an established health statuswithin a colony depends on eliminating challenges from non-endemic infectious agentsentering the colony and reducing the level of challenges from endemic infectiousagents. The consequence of these challenges is determined by the immune status ofindividual animals and the exposed population as a whole. There are both direct andindirect influences exerted on the immune system associated with environmentalconditions and management practices.In order to maintain physical and mental health it is important to reduce thepotential for stress or distress as these factors are known to have a negativeeffect on immune function. These effects can be minimized by providing anappropriate and hygienic environment together with the supply of a wholesome andbalanced diet. The importance of manipulation, handling and socialization to avoidstress is also an important consideration.Minimizing the level of challenge from endemic and non-endemic infectious agentsshould include separation of clinically unwell animals from the colony. Wherepossible, sick animals should be separated from the group for treatment to allowrecovery and improve immune function.In order to improve the health status of a colony, sources of endemic infectionshould be identified and action taken to reduce or prevent the transmission of theinfectious agent to other non-infected animals. Maintaining the highest possiblestandards of hygiene and the immediate isolation of infected animals are important,but it is also important to implement appropriate health screening protocols toidentify infected animals and determine appropriate action. In such situations, itis vital that realistic goals are set, and that the limitations of the availabletechnology, including reliable animal identification and sensitivity and specificityof laboratory-testing technology are recognized and understood.6The greatest challenge from non-endemic infectious agents for any group of animals ofany species, is likely to be as a result of the introduction of additional animalsinto a colony. If this is necessary, biosecurity precautions to prevent theinadvertent introduction of infectious agents must be carefully considered andimplemented. This should include a detailed examination of the health status of thenatal group and group of origin of the animal(s) in question and a period ofquarantine. The duration of quarantine will depend on the particular pathogens ofinterest. During quarantine, clinical samples should be collected for appropriatelaboratory testing and appropriate prophylactic or preventative medication given, orvaccination carried out as appropriate.Vaccination can be an important component of disease-control programmes to minimizethe transmission of non-endemic infections in a colony, for example, some animalfacilities have chosen to immunize their macaques with measles vaccine. Thelimitations associated with vaccination should be considered. Vaccination can, forexample, reduce the prevalence or severity of a disease but may not preventinfection in animals who are unable to sero-convert. In addition, vaccination maymask an infection, resulting in the delay of treatment and promoting disseminationto unvaccinated subjects. Health-monitoring programmes can be hampered becauseserological analysis to determine presence or absence of disease is not easilyachieved in vaccinated primates for the vaccinated agent. However, to some extentthis can be overcome by using direct detection methods such as polymerase chainreaction (PCR).A significant risk factor associated with disease transmission to NHPs is presentedby wildlife, particularly rodents, insects and birds. A vector-control programmeshould be in place to reduce transmission risk. Animal handlers also present asignificant risk as many organisms associated with human disease are also able toinfect NHPs. Food may also present a risk, for example fresh fruit and vegetablescan serve as vehicles of transmission.Health screening at its most basic level starts with close observation of everyprimate by experienced staff at an appropriate frequency (at least daily). Thisshould also include periodic clinical examination by a veterinary surgeon familiarwith the species in question. Ill health often first presents as behavioural changesbefore clinical signs of disease become apparent. Behavioural changes includinginactivity, hiding away, changes in eating or drinking, crouching and scratchingexcessively can be primary indicators of ill health. For example, tuberculosis inmacacques may present as under-eating and weight loss without any clinical signs.Unexplained behavioural changes and clinical signs should be investigated further toestablish the cause, but it must be considered that NHPs often mask signs of painand it may be difficult to identify affected NHPs by behavioural changes.Post-mortem examination of animals who die unexpectedly or areeuthanized, either as a planned action or as an emergency procedure, also providevaluable information about the health status of individuals and their colony.What sample types should be collected: blood, faeces, swabs, tissues?How many animals should be sampled?Which animals should be sampled?How frequently should the animals be sampled?Which type of analysis is appropriate: PCR, serology, culture,microscopy?The answers to these questions depend on various factors including what isunderstood about the biology and epidemiology of the organism of interest.The most common understanding of health monitoring is the collection of samples ofblood or faeces. When designing a health-screening programme the following factorsshould be considered: Consideration should also be given to the aim of screening. Health screening may beused to confirm a negative colony, to determine the presence of an infectious agentor to determine the prevalence of an endemic agent. Understanding whether the host’simmune response to challenge an infection will eliminate the infectious agentwithout persistent, latent or chronic carrier status is also important –1C. TablTo establish prior challenge from an infectious agent amongst a group of animals, asingle positive antibody ELISA (enzyme-linked immunosorbent assay)-test result cando this, but the agent may no longer be present. If determining that a colony isnegative for a particular agent, then demonstrating that every animal within thegroup of interest remains seronegative even on multiple occasions may not besufficient. Seronegative latent carriers may exist in which case additional testingmay be required, for example PCR.If testing is used to determine prevalence, it may be sufficient to sample and test aproportion of the animals in the group of interest.It is important that sampling is representative, testing appropriate animals (e.g. byage or gender) and the number of animals to be tested must be determined using validstatistical methods . Table 2Understanding the epidemiology, and particularly the rate of transmission betweenindividuals, of the infectious agent under consideration is essential. Anunderstanding of epidemiology for each agent will also influence frequency ofsampling and testing. For example, understanding that organisms may beintermittently shed is particularly pertinent when screening animals for thepresence of enteric pathogens, for example, the collection of rectal swabs forculture on a single occasion or daily on three consecutive days.Consideration should be given to the possible limitations of the laboratory-testingtechnology and methods employed in health screening . SensitiStandardization of health-monitoring reports and certification is important toprevent confusion. In order for a realistic risk assessment, reports andcertificates should provide clarity about whether they relate only to the animalsidentified on the report, or if they relate to the source of those animals.Test-negative animals sourced from a colony in which the infectious agent ofinterest is endemic should be regarded as a higher risk than test-negative animalsfrom a test-negative source.The report or certificate should also provide information about the laboratoryperforming the testing with regard to their accreditation and quality assurance.Reports should provide information about the methods employed including publishedsensitivity and specificity data where possible. If reporting or certificationrelates to groups of animals, the numbers of animals sampled and tested relative tothe population of the group, the frequency of testing and how these are selectedshould also be reported, in order to assess the confidence that can be placed in theconclusions drawn from the results.All facilities that breed or house NHPs for biomedical research should implementrisk-based programmes for the detection and control of potential pathogens and otheragents of interest. Where appropriate these should be aimed at the eradication ofthe agent in question, or prevent its introduction, to ensure the health of animalsand staff and also to prevent compromise to research programmes. It must beaccepted, however, that the aim of eliminating all infectious agents from coloniesof NHPs may not be a realistic goal nor, in fact, desirable.Macaca mulatta (Rhesus macaque) and Macacafascicularis (Cynomolgus macaque). Additional comments relevant toCallithrix jacchus (Common marmoset), Saimirisciureus (Squirrel monkey), Chlorocebus aethiops(Vervet monkey) and Papio sp. (Baboons) are included where speciesspecific examples or discussion is considered necessary.This paper considers the species of NHPs most commonly used in biomedical research:The organisms of importance discussed are limited to the major pathogenic, zoonoticand interfering agents relevant to NHPs from captive bred sources. In specificcircumstances it may be important to consider additional agents depending on, forexample, where the facility includes an outdoor environment, where there areparticular requirements for the research being undertaken or in rare situationswhere wild-caught animals may be used.79 Herpes Bvirus has been mainly associated with Asian macaques.10 However, Herpes B virus has also been reported in a colony of Capuchinmonkeys that developed persistent and asymptomatic Herpes B virus infection,while housed in the proximity of Rhesus macaques without direct contact. Other,sometimes fatal, herpes virus infections have been documented in variousnon-human primate species including Cebus apella,Papio sp. and in Callithrixjacchus.12Herpes B virus is arguably the most significant zoonotic infection to considerwhen working with macaques. Human infection is rare but frequentlylethal.In macaques, infection is usually transmitted via bites, scratches, sexualcontact or contact between saliva and other bodily fluids from an infectedanimal with defects of the mucous membranes or skin. Vertical transmission canalso occur. Viremia is intermittent and does not always coincide with thepresence of clinical signs of infection. Clinical signs are predominantlyvesicular lesions along the muco-cutaneous junctions and in the oral cavity.Peak seroconversion usually occurs between two and three years of age duringadolescence and during the onset of sexual maturity.Like other herpes viruses, Herpes B virus exhibits latency, particularly withinthe trigeminal ganglion. This leads to lifelong infection which may remainquiescent for considerable periods. During these periods, antibody titres to theinitial infection may decrease to a level below the detection limits ofserological assays. Titres may rise again periodically, particularly at times of‘stress’ or where there is a possibility of immunosuppression. This suggeststhat a single negative antibody test result, particularly when only anindividual animal is being tested, cannot be relied upon to confirm the absenceof infection. Absence of this organism is more reliably detected in groupsituations following serial testing. However, it should be noted that someanimals have developed serological evidence of infection many years after theestablishment and maintenance of a closed, entirely seronegative colony. PCRcarried out on swabs collected from the buccal cavity may provide additionaluseful information. A positive result can only be obtained if the animal isviraemic and the virus is being shed at the time of sampling. Direct detectionmethods such as PCR can be useful to determine the risk of Herpes B virusinfection associated with potential exposure to animal handlers, for exampleafter bites or other potential exposure.Retroviruses are RNA viruses which are characterized by the presence of theenzyme, reverse transcriptase. Reverse transcriptase converts single strandedRNA into double stranded cDNA. In retroviruses, cDNA is integrated into thehost-cell genome to make new RNA copies or it remains latent for a period whichmay be measured in years. During this period latently-infected animals canfrequently be antibody negative, therefore sensitivity of this type of testingis limited and a negative serological result does not confirm the absence ofinfection. Direct methods such as PCR to detect the viral genome is more usefulin this regard.Although infections with these viruses appear to have minor or absent clinicalsigns in the animals they infect, the immunosuppression associated with themincreases the morbidity and mortality associated with other pathogens. Theseorganisms can also have significant adverse effects on immunological research,vaccine efficacy or research involving therapies against other retrovirusesChlorocebus aethiops and Papio spp.which generally remain as asymptomatic carriers of the infection. SIV is notnaturally present in wild populations of Asian macaques. However, theseanimals can be readily infected with SIV making SIV a useful model of HIVfor researchers in this field. The risk of transmission of SIV in macaquecolonies other than those involved in HIV research is considered low.Ongoing health screening for this pathogen is considered unnecessary exceptwhen animals are being sourced for addition to the colony.SIV is common amongst populations of African monkeys includingSIV carries the potential for zoonotic infection. However, very few cases ofseroconversion in people exposed to this virus have been reported andpathogenicity in humans has yet to be demonstrated.13STLV, a c-type member of the oncornavirus subgroup of retroviruses is endemicin Old World NHPs. Three serotypes have been reported with STLV-A being byfar the most prevalent, particularly in macaques, but more than 18 differentspecies of Old World NHPs including baboons and African green monkeys havebeen documented with STLV infections.STLV is highly T-cell specific. Transmission is primarily by the transfer ofsemen or cervical secretions during breeding. STLV can also be transmittedvia breast milk to infants. Prevalence increases as animals age and becomesexually mature.Seroconversion is slow, often taking as long as six to nine months even inimmunocompetent animals. In individuals co-infected with anotherimmunosuppressive retrovirus this may be extended to several years. Althoughthere are reports of aetiological links between STLV infection and malignantlymphomas and lymphoproliferative disease in some primate species, mostinfected animals remain apparently healthy and asymptomatic albeit withpossible deleterious effects on the immune system.STLV-1 shares between 90 and 95% genetic homology with Human T-cellLymphotrophic Virus-1 (HTLV-1) (together referred to as PTLVs – PrimateT-cell Lymphotrophic Viruses). In humans, HTLV-1 is considered theaetiological agent of adult T-cell leukaemia, lymphoma and the progressiveneurological disease Spastic Paresis. Although little has been reported,this homology indicates that there may be potential for STLV-1 to establishinfections in man.The SRV(D) are a group of closely-related viruses which have been isolatedfrom many species of Asian NHPs including macaques. Different serotypespredominate in the different NHP species. Infection can result in a widerange of clinical manifestations from a subclinical carrier state to rapidlyfatal immunosuppressive disease. Direct animal-to-animal contact is the mostcommon route of transmission.In infected animals SRV(D) can often be demonstrated in a variety of tissuesand organs. However, a significant proportion (30%) of infected macaques mayremain seronegative when tested for SRV(D) specific antibodies. This must beconsidered when designing health-screening protocols.Foamy viruses are highly prevalent in virtually all species of NHPs,approaching 100% prevalence in many populations. They appear to benon-pathogenic but can interfere with studies requiring the growth ormaintenance of cell cultures and transplant studies because of their highlycytolytic effects.Morbillivirus. Humans are the natural host for this virus,but most non-human primate species, particularly macaques, are susceptible toinfection. Infection with measles can have serious consequences including fatality.14 Measles-virus infections in marmosets can rapidly spread through a colonyresulting in high morbidity and mortality.15Measles is a highly infectious paramyxovirus of the genusMeasles infections in colonies of NHP are generally the result of transmissionfrom animal-care staff. Transmission occurs via aerosols, although directcontact and fomite transmission may also be possible. Clinical signs in NHPgenerally appear approximately a week following infection and are similar tothose seen in man. The predominant signs being a maculopapular skin rash,conjunctivitis, blepharitis and malaise. Measles is immunosuppressive causingtransient humoral and cell-mediated immune dysfunction.The value of health screening colonies of NHP with respect to measles isdebatable. The clinical signs of disease are obvious and positive antibody-testresults confirm previous exposure (or vaccination). Alternatively, the possiblebenefits of introducing a vaccination policy to protect the animals andconfirming the animal-care staff are vaccinated, should be considered.Macaca fascicularis populations.16 In some countries, Hepatitis B vaccination is routinely carried out oncaptive NHPs and may be a requirement.Historically, Hepatitis viruses including Hepatitis A and Hepatitis B, have beenconsidered an infection of humans and the great apes. However, it should beborne in mind that there is now one report which demonstrates that naturallyoccurring transmissible chronic Hepatitis B virus infections can exist amongsome wild 17 Infection is usually via the faecal–oral route, is self-limiting andasymptomatic. Control usually centres on maintaining appropriate environmentalhygiene and the use of personal protective equipment by those in contact withthe animals or their environment.A high seroprevalence to simian Hepatitis A, which may carry the possibility ofzoonotic infection, has been reported in non-human primate colonies.In closed colonies of captive-bred NHPs, rabies is not generally of concern.However, a route of transmission is plausible where animals have access tooutdoor pens allowing the possibility of interaction with local wildlife.In some European countries serological testing and/or vaccination against thiszoonotic agent is required for regulatory reasons before animals can be importedfrom countries or regions where rabies remains endemic.18 With the exception of animals sourced from areas where infection isendemic, it is not considered necessary to screen for this agent.Cases of monkeypox, which is closely related to smallpox in man, have beenreported in animals from the African continent.Historically, cases of infection with Marburg virus and strains of Ebola havebeen reported within captive colonies of NHPs. Screening for this agent is notconsidered necessary except in circumstances when animals are sourced fromlocations where infection is endemic (e.g. Africa) and should be performedduring quarantine screening.Callithrix jacchus, are well knownto have a greater susceptibility to many anthroponotic viral infections thanmany of the Old World NHPs although there is little evidence for naturaltransmission of many of these viruses within primate colonies. Outbreaks ofParainfluenza 1 (Sendai-like) virus have, for example, been reported in Commonmarmosets with a relatively high morbidity but low mortality.19New World NHPs, particularly M. avium and M. intracellulare, arefrequently diagnosed, particularly in immunocompromised non-human primatespecies. However, the Mycobacterial species of greatest concern, are M.tuberculosis and M. bovis due to their zoonoticand anthroponotic potential.21 Although largelycontrolled in captive-bred animals in Europe, these agents remain a significantthreat in animals imported from other regions of the world where there are highrates of human infection or where there is potential for the primates to havecontact with endemically infected wildlife.Opportunistic infection with various ‘atypical’ Mycobacterial species includingMycobacterial infections are characterized by a prolonged incubation period withrespiratory disease usually becoming the most common clinical manifestation ofinfection. Systemic dissemination to almost any organ can occur, as well aslatency. Treatment is prolonged and is not recommended.M. bovisPurified Protein Derivative (PPD) intra-dermally into the skin of the eyelidclose to its margin, or the hair-free skin of the abdomen or both. The injectionsite is monitored at 24, 48 and 72 hours for the development of a delayedhypersensitivity response with the degree of erythema and oedema beingcategorized on an increasing scale. MOT is generally considered the test reagentof choice due to its enhanced ability to evoke an immune response providingimproved test sensitivity. However, this can also result in an unacceptably highproportion of false positive results. PPD may be used when MOT availability inEurope is limited. Consideration must be given to the possibility of falsenegative results which may occur both very early during the onset of infectionor in the advanced stages of infection, if excessive testing leads to anergy orwhere there is concomitant infection with an immunosuppressive agent.Regular health screening of animals and personnel is essential. The frequency ofhealth screening should be determined according to risk and should be carriedout on at least an annual basis for all captive NHPs. Screening is commonlybased on the tuberculin skin test (TST). In NHPs, the test is performed byinjecting either Mammalian Old Tuberculin (MOT) or Thoracic radiography, but pulmonary lesions are not specific fortuberculosis and may not be apparent very early in the course of thedisease.2224Serological or γ-interferon testing using blood or serumsamples.M. tuberculosis orM. bovis which can be carried out on sputum,broncho-alveolar lavage or necropsy samples.Culture or PCR testing for Although Callithrix jacchus is very susceptible toexperimentally induced infections with M. tuberculosis25 natural Mycobacterial infections in this species appear rare withinfrequent reports in the literature.Given the complexity in diagnosing Mycobacterial infection, all positive TSTresults should be investigated further to confirm health status. Confirmatorytests which could be considered include: Salmonella sp.,Shigella sp., Campylobacter sp. andYersinia sp.2628 Pest control policies forinsects, rodents, birds and other wildlife are important biosecurity measures inpreventing the transmission of these organisms to NHP colonies. Biosecuritymeasures should also be in place to prevent anthroponotic transmission.NHP are frequently asymptomatic carriers of Enterobacteriacae. Enterobacteriacaehave the potential to cause disease, particularly in immunocompromised animals,and they also have the potential for zoonotic spread. The bacterial specieslikely to be of greatest interest include Salmonellae, including species such as S.typhimurium and S. enteritidis have the potentialto cause generalized systemic illness as well as gastro-intestinal disease. Insuch situations treatment may be warranted. However, in less severe situationsthis may prolong faecal shedding of the organism or even induce a carrierstatus. Salmonellosis is a reportable disease in many European countries.S.flexneri being the most common species isolated.Shigellosis is, in many respects similar to Salmonellosis in NHPs with Yersinia enterocolitica and Y.pseudotuberculosis have both been associated with disease incolonies of NHPs .Y. pseudotuberculosis in particular has been associatedwith severe infections with systemic as well as gastro-intestinal manifestations(including reproductive failure) and high mortality amongst groups of marmosets.Vaccination in such situations should be considered.Screening for the various potential Enterobacterial pathogens generally relies onmicrobiological culture. Detecting these organisms particularly when screeningapparently healthy populations, can lead to false negative results. This is dueto limitations of the currently available methods and intermittent or low-levelexcretion of these organisms. Detection of Enterobacteriacae can be improved bycareful sample selection , sampling strategy  will vastly increase sensitivity compared to collectinga single rectal swab for culture, especially when there is intermittentexcretion of the target organism. The use of specific enrichment techniques suchas Selenite F broth and Chromogenic agars will also improve the sensitivity ofculture. PCR can also be useful to confirm the identity of suspect organismsfollowing culture but may be considered overly sensitive for use directly onfaecal samples.Before embarking on any screening programme for potentially pathogenicEnterobacteria, consideration should be given to any action that may need to betaken should one of the target bacterial species be isolated. This isparticularly true if the samples are from animals where clinical signs areabsent. Treatment may be considered if prevalence is high, however, althoughthis may prevent or reduce the severity of disease or reduce bacterial shedding,it may also prolong bacterial shedding and induce a carrier state and isunlikely to ever eliminate infection. If treatment is considered necessary, anantibiotic sensitivity test should be performed to choose an effectiveantibiotic. A careful harm-benefit analysis should be performed when treating awhole population to avoid the development of antibiotic resistance.Many Campylobacter species can be isolated from the faeces of clinically healthyand diseased NHPs. The significance of Campylobacters is debatable and maydepend on the bacterial species/strain and the presenting clinical signs.Treatment is not usually recommended unless the clinical signs are severe.Various Leptospiral species can infect NHPs and cause disease, with zoonoticpotential, and even death. Screening is recommended when risk is consideredhighest, in facilities where contact with infected wild rodents and otherwildlife cannot be prevented.K. pneumoniae is associated with severe infections with highmortality in marmoset colonies.29 Infections more often present at three months of age when maternalantibodies decrease and the individual antibody production of the infant is notyet effective.B. pseudomallei is an environmental saprophyte found insub-tropical and tropical regions of mainly South-East Asia and Australia. Inthese endemic areas it can easily be isolated from samples of soil and water.Infection resulting in the disease ‘melioidosis’ (mainly cutaneous lesions)occurs via aerosol transmission or ingestion. Treatment is generally noteffective.Only animals originating from areas in which this disease is endemic areconsidered at risk and routine health screening is not required in Europeancolonies.Toxoplasma is only considered a risk where there is access by primates to outdoorenclosures allowing possible contact with infected cats. Clinical disease ismore severe in new world primates than old world primates and primary infectionmay be fatal. Toxoplasma has zoonotic potential.Entamoeba histolytica (E. coliand E. dispar are considered non-pathogenic),Balantidium coli and Giardia sp. In lownumbers these organisms can be considered part of the normal gut flora, causingno adverse effect but in higher numbers, particularly in immunocompromisedindividuals intermittent to severe diarrhoea or dysentery may be seen.31 Intestinalprotozoal parasites of NHPs carry the risk of zoonotic infection.This includes In apparently healthy animals treatment is not usually required or recommendedbut in debilitated animals treatment with metronidazole can be effective.Cryptosporidium parvum infections can occasionally occur infacilities where NHPs have access outside enclosures where puddles of standingwater may persist. This agent has zoonotic potential.Health screening for the presence of intestinal protozoal parasites is generallycarried out on pooled faecal samples using flotation, formyl-ether concentrationand microscopy examination although PCR testing is available. In most cases,antibiotic treatments are available.Strongyloides and Trichuris can affectvarious species of NHP. However, it is rare in animals internally housed and fedpelleted diets supplemented with washed fruit and vegetables. When infection isdetected, usually by microscopic examination of pooled faecal samples for thedetection of parasite eggs, it is usually without clinical signs. Variousanthelmintic treatment options are available.Parasitism involving various helminth species includingEchinococcusmultilocularis.32 Echinococcus is only considered a risk if primates have access to outdoorenclosures, allowing possible contact with infected foxes in areas where thisparasite is endemic. However, Echinococcosis can occur after a long period oftime after importation from an endemic area; this might include several changesof facilities until the illness finally develops. Serological and PCR screeningis possible but postmortem examination provides the most useful information.Special consideration should be given to 33 Coughing is a common clinical sign of Pneumonyssus infection. Diagnosisis usually made at postmortem and often coincidental. Treatment with effectiveendectocides is available.Lung mites are not considered a significant problem in European captive NHPsalthough they can be seen in macaques imported from regions of the world wherethey are endemic.As in other mammals, mites and lice are a theoretical risk in NHP. Especially inoutdoor facilities, an ectoparasiticide programme should be implemented.Trichophyton sp., resultingin areas of roughly circular alopecia with cutaneous inflammation around theborder will normally be detected during routine clinical examination. Thediagnosis can be made by collecting skin scrapings for fungal culture ormicroscopic examination. Trichophyton sp. are zoonotic andhumans may become infected by direct contact.Dermatophytosis, usually caused by It is important to consider that all NHP facilities have their own specificrequirements and that these recommendations should be adapted to suit local needs.These requirements will depend on the geographical location, regulatoryrequirements, prevalent endemic organisms and the research undertaken.This review is not exhaustive and continuous efforts to increase the knowledge ofinfectious diseases of NHPs should be undertaken. Regular monitoring of scientificdevelopments in this field is required for the optimal management of NHP colonies.We encourage other authors to update this guidance as necessary.


This study aimed to examine the scoring strategies differentiating between winning and losing teams during FIBA EuroBasket Women 2017 in relation to different game scores. Data were gathered for all games of FIBA EuroBasket Women 2017 from the official website. The investigated scoring strategies were fast break points (FBP); points in the paint (PP); points from turnover (PT); second chance points (SCP); and points from the bench (PB). Games were classified with cluster analysis based on their score difference as close, balanced, and unbalanced and the differences in the scoring strategies between winning and losing teams were assessed using magnitude-based statistics. Results revealed no substantial differences in FBP in any investigated cluster. Furthermore, winning teams showed a substantially higher number of PP and PT  and SCP  compared to losing teams. Finally, winning teams scored substantially lower and higher number of BPs in close games and unbalanced games, respectively, compared to losing teams. In conclusion, all the investigated scoring strategies discriminate between winning and losing teams in elite women’s basketball except for FBP. These results provide useful information for basketball coaches to optimize their training sessions and game strategies. Basketball is one of the most popular sports worldwide and in particular women’s basketball is increasing its popularity . In the From a technical standpoint, many studies investigated the game-related statistics differentiating between winning and losing teams in women’s basketball ,7,12. PrThe above-mentioned scoring strategies might change in relation to different game scores. Indeed, games with a low or high score difference showed different performance indicators differentiating between winning and losing teams in elite women’s basketball . TherefoThe study was approved by an institutional review board, and meets the ethical standards in sports and exercise science research . The gamhttp://www.fiba.basketball/eurobasketwomen/2017). The considered game-related statistics referring to scoring strategies were as follows: (a) fast break points (FBP), which refer to the points scored during fast break actions; (b) points in the paint (PP), which indicate the point scored in the key area; (c) points from turnover (PT), which refer to points scored after a turnover made by the opposite team; (d) second chance points (SCP), which refer to points scored after an offensive rebound; (e) points from the bench (PB), which refer to the amount of points scored by bench players.In the tournament, sixteen teams competed in four groups at the preliminary round. Only the top two teams from each group qualified for the final stages  competing for the 1st–8th place. Data were gathered from the official box score on the website of the FIBA EuroBasket Women 2017  . The difThe aim of the study was to examine the scoring strategies differentiating between winning and losing teams during FIBA EuroBasket Women 2017 according to final score differences . Results revealed that (a) no substantial differences were shown in FBP in any investigated cluster; (b) winning teams showed a substantially higher number of PP and PT  and SCP  compared to losing teams; (c) winning teams scored substantially lower and higher number of BPs in close games and unbalanced games, respectively, compared to losing teams.While the game-related statistics differentiating between winning and losing teams have been widely investigated in women’s basketball ,6,7,12, The results of our study also identified PP as one of the main indicators differentiating between winning and losing teams particularly in unbalanced and close games. This result might be explained by the possible importance of inside games in women’s basketball. The interaction between outside and inside players has been suggested to be a crucial element in European basketball and in NBA ,24. IndeA further scoring strategy adopted substantially more by winning teams regards the PT. This result might be a consequence of the fact that losing teams performed more turnovers during the games. Indeed previous investigations analyzing the game-related statistics highlighted that turnover is the main parameter differentiating between winning and losing teams in women’s basketball ,12. ThusThe analysis of SCP demonstrated that although winning teams scored a substantially higher number of points deriving from second chances in unbalanced and balanced games, an unclear difference was shown in close games. Previously, Gomez et al.  highlighThe analysis of PB highlighted contrasting results in unbalanced and close games. Winning teams scored a substantially higher number of PB compared to losing teams in unbalanced games, possibly due to the use of more bench players for winning teams during the garbage time likely to allow their best players to recover for the subsequent phases of the tournament. Conversely, winning teams showed a substantially lower number of points scored by bench players compared to losing teams in close games. A possible explanation for our result may be that losing teams were substituting more players, possibly to recover from the disadvantaged situation. This would allow more playing time for bench players, allowing them to score more. Indeed, playing time has been shown to be positively related to shooting performance in the male 1st division Spanish championship . TherefoAlthough this study provides new information regarding the scoring strategies differentiating between winning and losing teams, it presents some limitations. Indeed, it only focused on the points scored but not effectiveness of the investigated actions. Moreover, the use of different statistical procedures might provide new insights regarding the association between the investigated scoring strategies and the possibility to win. Therefore, future studies should focus on investigating the effectiveness of the fast break, inside game, actions deriving from turnovers and offensive rebounds, and of substituting players using the notational analysis technique and further statistical approaches such as binary logistic regression or the conditional inference classification tree.In conclusion, this study provides information on some of the most adopted scoring strategies differentiating between elite women’s winning and losing teams according to different game scores. Overall, FBP do not differentiate between winning and losing teams in each investigated cluster. All the other investigated scoring strategies differentiate between winning and losing teams in unbalanced and close games, except for SCP, which demonstrated an unclear difference in close games. These findings might provide useful information for basketball coaches to optimize their training sessions and game strategies.


Psychiatry has been limited by historically rooted practices centered primarily on subjective observation. Fields such as oncology have progressed toward data-driven clinical decision-making that combines subjective clinical assessment of symptoms and preferences with biological measures such as genetics, biomarkers, imaging, and integrative physiology to derive quantitative risk scores and decision support. In contrast, psychiatry has just begun to scratch the surface of measurement-based care with validated clinical questionnaires. An opportunity exists to improve modern psychiatric care with novel data streams from digital sensors combined with clinical observation and subjective self-report. The prospect of integrating this complex information with modern computational and analytical methods could advance the field, both in research and clinical practice. Here we discuss this possibility and propose some key priorities to enable these innovations toward improving clinical outcomes in the future. This is especially worrying as we have no objective yardstick for this confidence.”1– Emil Kraepelin, The Manifestations of Insanity, 19202 At best, this approach allows practice to remain patient-centered, but at worst, this approach could be maintaining biases that are preventing patients from receiving optimal care.3 Selecting medications to treat depression based on potential advantage of an anticipated side effect (such as sedation) is an example of such clinical practice–therapeutic adherence may be improved, but how will we know we are not withholding better treatments from patients as a consequence of our own biases? Here, we propose that today’s era of technological innovations in wearables and mobile devices offers a unique opportunity to redefine these limits of practice toward a new, data-driven future.5Despite modern advances in the scientific understanding of psychiatric disorders, clinical practice today remains bound to intuition-based assessments that have persisted since Kraepelin’s era. For the most part, psychiatric practice continues to rely upon heuristic-based decisions that are frequently reinforced without good comparative evidence, and often for the sake of maintaining a therapeutic relationship for lack of a better alternative.Specifically, measurement tools that integrate information over time, such as smartphone-based monitoring of circadian rhythm, physical activity, and social trends, may allow us to quantify behavior at levels of granularity never before obtained over long periods of time and at scale. Supplemented with self-reported outcomes, this approach to measurement could enable testing of clinical heuristics already in use, and create an opportunity for a data-scientific approach toward understanding the clinical significance of behavioral phenomena already encountered in daily practice. Furthermore, these tools may enable personalized care in specific clinical situations where measured constructs and interventions are appropriately matched. Activating these insights and adding a transformational data-driven dimension to the field could have a major impact on clinical care.56 One is that continuous measurements will offer useful signals over and beyond sporadic measurements obtained at clinic visits. Similar to all of medicine, limitations in recording, storing, and computing have relegated research and practice to periodic assessment influenced heavily by recall of what happened between visits. Rather than recalling the clinical course between physical visits, we can now attempt to measure them. Evidence exists in other branches of medicine that continuous measurement in ambulatory settings  may be better at predicting clinical outcomes than in-person visit measurements alone. For example, ambulatory 24 h systolic blood-pressure measurements are more strongly associated with cardiovascular and all-cause mortality than in-clinic systolic pressure.7 Interventions may also be targeted for clinical impact, just as implantable cardioverter defibrillators that continuously monitor cardiac rhythm in the real world can deliver automated shocks to reverse sudden cardiac death.Enthusiasm for the positive impact of “digital phenotyping” is built on fundamental assumptions.8 Features of heart rate variability obtained in defined continuous segments appear to be predictive of a posttraumatic stress disorder diagnosis with an area under the receiver operating curve (AUC) of 0.86 (23 diagnosed subjects and 25 control subjects).9 Emerging work with smartphone sensors raises the possibility that continuous human–computer interaction metrics may predict neuropsychological function in healthy individuals (as assessed by gold-standard psychometrics in 27 subjects),10 and even delays in on-device survey completion rates appear to be associated with subsequent self-report of negative symptoms in patients with schizophrenia (16 patients).11 These findings highlight that continuous measurements are showing early signs of promise at providing additional value beyond traditional subjective reports.Continuous objective data collected in mental health populations are already demonstrating how these measurements could augment conventional periodic, subjective assessments. For example, one study showed that sleep actigraphy measures modestly outperformed a more conventional depression symptom assessment (Beck Depression Inventory) at predicting future suicidal ideation in a cohort of 50 young adults.12 continues to inspire attempts at real-world evidence collection of clinical and genomic cancer data.13A second assumption is that integrative analysis of data from measurement tools, combined with clinical measures and assessment of outcomes, may uncover behavior-symptom-environment clusters that could inform new subtypes of disease that were previously unknown. This dimension could be akin to the transformation of oncology into treatment based on tumor genetics rather than organ of origin. A fundamental reclassification in cancer was not possible until the genome could be sequenced and tumor sequences could be matched with clinical outcomes and response to therapy. Striking examples of this impact, such as the United States Food and Drug Administration’s recent approval of pembrolizumab for the first genomic signature (anatomic site-agnostic) indication,14 as well as to self-report symptom data obtained from large clinical trial datasets of depression treatment.16 Here, analyses using data science approaches posited the existence of clinical depression subtypes with implications for differential treatment response profiles: neural connectivity biomarkers significantly outperformed clinical symptoms alone at prediction of response to transcranial magnetic stimulation therapy (in 154 depressed subjects)14 and selected baseline self-report profiles significantly outperformed chance at predicting antidepressant treatment response for symptom clusters .16 Digital measurement tools may similarly refine traditional boundaries of psychiatric diagnosis by potentially stratifying patient characteristics in a way that is clinically actionable.Similarly, behavioral and physiological measurements could define axes of clinical significance, which, when taken together, map onto different prognostic outcomes or indicated treatments. This interesting possibility in mental health has been suggested by recent studies applying machine learning methods to functional magnetic resonance imaging (fMRI) data of brain connectivity patterns obtained from depressed individuals,What are some steps that can be taken in this new world of digital phenotyping to improve clinical outcomes? We propose four areas that could help transform this early vision into meaningful impact: (1) collect data from real world individuals and conditions beyond the current constraints of clinical practice; (2) invest in data science and analytics, and the interface of quantitative methods with clinical care; (3) uphold the patient experience within appropriate bounds of self-education and self-empowerment; and (4) work with clinicians to develop effective approaches to incorporate the use of data in daily practice.17 Although for some types of questions, rarified populations are needed to evaluate a mechanistic hypothesis, these trends have understandably led to legitimate skepticism about the generalizability of many clinical trials.18 There is a need to conduct trials with research participants representing patients seen in current ambulatory contexts so that findings can be translated better into practice.20Although all fields of medicine have struggled with the portability of findings from clinical trials into the real world, psychiatry has been particularly challenged. Patients enrolled in most research studies have been carefully selected and frequently screened out for comorbidities in order to optimize response and follow-up.5 A potential synergy thus emerges from the ubiquitous availability of behavioral sensor technology and resulting data, juxtaposed with the need for real-world evidence generation, spanning the spectrum from observational cohort studies to randomized treatment or implementation trials. Digital phenotyping has the potential to become clinically useful precisely because it can be used to measure data ecologically from living populations, yet also allows a focus on a specific outcome or actionable decision in order to guide future clinical practice.Wearable and smartphone devices, in contrast to genetic tests, analyte sampling, and neuroimaging, are immediately accessible and affordable to patients and researchers today.21 Investments in scrupulous data collection, secure data management, quality control of data streams, carefully validated feature engineering of the collected data, and rigorous predictive and causal modeling22 for clinical use are prerequisites for digital phenotyping to have meaningful impact in clinical care.With streams of continuous data, investments in appropriate data science and analytics are certainly required. Measurement tools in particular often carry a temptation to confuse clinical-grade and consumer-grade analytics. As studies have shown, consumer-grade evidence may not be reliable enough to serve as the basis for algorithms to inform medical decisions, and few clinical trials have been done to validate the potential benefits for clinical populations or use cases.16, for example, suggested a focused survey of baseline interview questions that could aid prediction of remission with specific antidepressants. Using large-scale datasets, robust evidence-based modeling approaches for actionable prediction and phenotyping of outcome could bypass time-consuming trial-and-error approaches of testing particular heuristics. As an example from the study of psychiatric genetics, scaled genome-wide association studies have disproven the previous hypothesis of a large contribution of rare variants of large effect size.23 Analogously, learning whether or not decreased physical activity, for example, is of large enough clinical significance to inform treatment change  could save the field from another decade of the “deceptive yet powerful plausibility” Kraepelin warned against.The potential for data science to drive improved interpretation of clinical data holds great promise to energize the field. Machine learning algorithms in Chekroud et al.24 Specifically, data collection and management will need to be performed in a secure, confidential, and quality-controlled manner, in compliance with clinical data protections. Transparency into how digital data are de-identified, stored, and accessed, including by potential third parties, is crucial. For lasting trust to develop, users need to be empowered to “opt-in” to data collection efforts with as clear control over their data as possible.Parsimony of data collection (limiting to that which is needed), transparency to users along with control of privacy settings, and protection of data should be cornerstone values for any measurement tool that hopes to earn patients’ trust, adoption, and continued use.Recent trends in wellness apps and devices have primed users to these channels being used for health data collection, but these modalities also carry user expectations around receiving accordant value in exchange for the investment of effort and data. Such value may come from returning the data collected in a digestible format, suggesting specific actions based on the data, or surfacing relevant educational content and support resources within a compelling user experience. Developing such user-oriented features may improve adherence with measurement tools and even empower users to assume a greater sense of agency for personal health within reasonable bounds. However, it is important to maintain transparency with users regarding the ethical limits of returning health-related data, and to set appropriate expectations around the value of clinical information that is being measured and returned.25 an influx of novel data and analytics would ultimately lead to a redefinition of the role of clinician teams who will need to interpret these data in the midst of the complex subjective issues in mental health care. The availability of these tools will necessitate clinician education to evaluate the clinical utility and validity of outputs derived from algorithms: clinicians will not need a detailed understanding of computational methods per se, but rather a familiarity with statistical measures of algorithm performance  to be able to interpret and apply clinical research to use cases as easily as a number-needed-to-treat result from a clinical trial. We see this evolution akin to how advances in precision medicine have motivated medical institutions to incorporate more integrated exposure of genetics into clinical training, in anticipation of widespread genome sequencing and genetic risk assessments becoming part of clinical care.27Similar to how machine learning of clinical imaging data has begun to redefine traditional roles of radiologists and pathologists,28 digital phenotyping data and clinical judgment can meaningfully coexist without jeopardizing standard of care, as in the optimization of behavioral outcomes . In comparison with clinical endpoints based on disorder categories , clinical behaviors are immediate, quantifiable, and modifiable. Thus, the greater proximity of measurement inputs to intervention outputs for health-related behaviors may allow for data-driven heuristics to play a greater role under appropriate supervision of clinical care. Additional uses may include careful monitoring during medication titration in specific cases , relapse detection, patient self-regulation, and delivery of selected digital interventions.33 Engagement of ethical clinicians in defining the appropriate boundaries of personalized care using digital measurement tools is crucial to realize potential clinical benefits while protecting against potential harms.With respect to specific clinical practices, simple guidelines may be considered in the future as well. An example is defining the use cases where “N of 1”We believe that data-driven psychiatry is possible, and that digital measurement tools and analytics, as “objective yardsticks,” can help catalyze this future. With appropriate attention to real world clinical outcomes, data science, patient experience, and the role of clinical judgment with respect to standard of care, psychiatric practice can leapfrog into a modern era already occupied by other medical fields. For the sake of future patients, there is no better time for this investment than today.


Mentoring is a critical process for guiding the next generation of geropsychologists into career paths that fit their goals and needs. However, the context and content of mentorship in geropsychology is not well-documented. Understanding geropsychologists’ experiences may provide some insight into how mentorship is executed in academia versus clinical settings and which factors are relevant to career decision-making. We conducted a qualitative analysis of 28 transcripts from individual telephone interviews with geropsychologists and geropsychology trainees, focusing on mentorship and how it influenced their career path. Themes were differences in the focus of mentorship , frequency of career-focused mentorship, length of mentorship (years versus months), and mentors’ openness to share opinions and experiences . Subthemes and recommendations will be discussed.


Recent analyses of polygenic scores have opened new discussions concerning the genetic basis and evolutionary significance of differences among populations in distributions of phenotypes. Here, we highlight limitations in research on polygenic scores, polygenic adaptation and population differences. We show how genetic contributions to traits, as estimated by polygenic scores, combine with environmental contributions so that differences among populations in trait distributions need not reflect corresponding differences in genetic propensity. Under a null model in which phenotypes are selectively neutral, genetic propensity differences contributing to phenotypic differences among populations are predicted to be small. We illustrate this null hypothesis in relation to health disparities between African Americans and European Americans, discussing alternative hypotheses with selective and environmental effects. Close attention to the limitations of research on polygenic phenomena is important for the interpretation of their relationship to human population differences. We are currently witnessing a surge in public interest in the intersection of evolutionary genetics with such topics as cognitive phenotypes, disease, race and heritability of human traits . This atTheories involving natural selection have long been applied in the scientific literature to explain mean phenotypic differences among human populations . AlthougOver the past 15 years, genomic analyses have identified thousands of genetic variants that contribute statistically to variation in complex phenotypes, traits that have complex patterns of inheritance and that are affected by large numbers of genes in combination with environmental factors . In a tyFor many complex phenotypes, identification and analysis of contributing genomic variants—most having small phenotypic effects—has led to the formulation of polygenic scores, quantities that seek to predict a trait value associated with a specific genome-wide set of genotypes . For a qPolygenic scores have provided new tools for interpreting human genomes in the setting of complex phenotypes for which effect sizes of genetic variants are small. For example, they have contributed new approaches to risk prediction for adverse phenotypes related to heart disease . Using pThe genetic underpinnings of population differences in phenotype distributions have been of perennial interest in human genetics, and the use of polygenic scores promises to generate progress in understanding phenotypic differences among populations. However, interpretation of such differences in relation to polygenic score differences requires careful analysis. Although distributions of individual-level polygenic scores might differ among populations, differences in these distributions might have many potential causes, and might or might not reflect meaningful biological phenomena.The main novelty in analyses of polygenic score distributions among populations is that many trait-associated genetic variants that were previously unknown are now known. Earlier studies of the role of genetics in phenotypic differences among populations often relied on statistics such as heritabilities—fractions of phenotypic variance explained by genetic variation —which reFirst, population differences in environmental factors are important for interpreting population differences in a phenotype distribution. Depending on environmental contributions, a difference in mean phenotype might or might not reflect a difference in the magnitude of genetic effects among populations; population differences in phenotype distributions do not reveal which population has greater genetic propensities on average, whether the observed difference would persist if the environment were altered, or even whether a difference in genetic propensities exists at all A–C. ThatAPOE-ɛ4 in Alzheimer disease [Second, gene–gene and gene–environment interactions influence traits, meaning that associations between specific genotypes and a phenotype—and the importance of the genetic contributions—might differ among populations with different allele frequencies or distributions of environmental variables. In other words, because the contributions of genomic variants can differ among populations due to interactions with other variants and with environmental variables, the effects of a variant on a trait can have different magnitudes in different populations, and effects of multiple variants in one or more genes can combine in different ways. Large population differences in disease risk for well-known alleles such as  disease , 30 highFinally, mean differences between populations in polygenic scores might not be informative for prediction about phenotype differences between randomly chosen people from a pair of populations if polygenic score distributions have substantial overlap  population differences in environmental influences on phenotypes, and (ii) differential natural selection among populations that generates a substantial population difference in polygenic score distributions. However, only with strong directional selection on a trait in one population, or strong directional selection in opposite directions in a population pair, is a phenotypic difference between populations attributable largely to natural selection. In other words, because of environmental effects, the difference in phenotype distributions in Trait correlations can also complicate inferences of selection differences, as a scenario in which differences in polygenic score distributions among populations parallel differences for a specific phenotype might be due not only to environmental factors, but instead to natural selection on other correlated traits . SelectiFor these reasons, an observed between-population difference in phenotype distributions is not easily ascribed to divergent selection. Indeed, a challenge is to establish whether polygenic adaptation has even occurred. In within-population polygenic adaptation tests, for loci across the genome, GWAS-based locus effect sizes are considered with selection signals estimated for those loci. An aggregate signal of positive selection at loci with large effect sizes is taken to suggest that selection has inflated the frequencies of alleles contributing to the trait, so that the trait has undergone polygenic adaptation. Recent studies of height have suggested that polygenic adaptation tests are sensitive to the choice of GWAS data that provide the effect sizes: even if two sets of effect sizes produce correlated polygenic scores, effect sizes estimated from one study can generate erroneously exaggerated signatures of polygenic adaptation when assessing polygenic adaptation in a second dataset , 35. Thia priori as a general null population-genetic model of phenotypic similarity among populations. Dramatic claims about divergent selection should continue to be regarded cautiously in the absence of strong quantitative evidence.To date, strong effects of directional selection on human population differences have been verifiable primarily for traits connected to predictable categories of geographic variability, including dietary adaptations, infectious disease resistance and skin pigmentation . As specHealth disparities between African Americans and European Americans in the USA provide a useful case for examining genetic and environmental contributions to phenotypic differences among populations. In a study of African Americans and European Americans , among 36 physiologically diverse causes of death, adjusting for other factors, African Americans lost more years of life than European Americans in 28 of the 36 . In the It might be proposed that different strengths of directional selection have contributed to the population difference between African Americans and European Americans. However, a related computation of the overall influence of natural selection in human history, relying on measures of selection against deleterious variants rather than directional selection of favorable variants, does not suggest strong systematic differences in the magnitude of selection among different continental population groups ; indeed,Whereas natural selection cannot easily explain the observed population difference, systematic environmental effects that contribute to an increase in non-genetic risk factors in African Americans—current and historical racism, for instance —could, oWith ongoing discoveries in human genomics, it is becoming possible to address topics concerning the genetic and phenotypic differences among populations that have been the subject of much speculation. Recent advances are sure to lead to proliferation of widely disseminated hypotheses about polygenic scores, population differences and natural selection. Unfortunately, history suggests that multiple forms of misrepresentation of findings in human genetics can lend the authority of science to claims that the underlying research does not validate and might actively contradict.One recurring problem in the dissemination of studies of human genetic differences within and beyond the scientific community is the attribution of interpretive weight to plausibly compelling hypotheses about natural selection in spite of a lack of evidence . Other pAs developments on polygenic scores and polygenic adaptation connect closely to topics that have long been of central interest in human evolutionary genetics, the field can provide context for the emerging plethora of results relevant to interpretations of the roles of genetics and natural selection in contributing to traits; limitations of interpretations of research in new directions are not restricted to the topics emphasized here , 60. Vig


Spouses are commonly involved in supporting and regulating their partners’ diabetic diet. Older spouses also may be managing their own condition that requires changes to their diet. Little is known about the extent to which this spousal involvement is reciprocal and if there are individual differences in the provision of diet-related support and control (regulation). This study sought to understand the reciprocity of diet-related support and both positive and negative forms of control, whether personality traits predicted the provision of diet-related spousal involvement, and whether gender moderated these associations. We used data from a cross-sectional survey of 150 couples (50+ years) in which one member had type 2 diabetes . The provision and receipt of social support and two forms of social control were moderately correlated within individuals . Using Actor Partner Interdependence Models that controlled for age and responsibility for managing meals, results revealed that being more extraverted or having a partner who was more extraverted was associated with greater involvement, whereas being more neurotic or having a partner who was more neurotic or had more interpersonal problems was associated with less positive and greater negative involvement. Associations were particularly pronounced for men. Results suggest that there is moderate amount of reciprocity, as well as personality differences, in diet-related spousal involvement. These findings highlight the importance of targeting both members of the couple in diabetes intervention efforts.


Biosci. Rep. (2018), 38) study failed to validate nomograms using an independent dataset.Some doubts were generated during the reading of nomograms based on inflammatory biomarkers for preoperatively predicting tumor grade and microvascular invasion in stage I/II hepatocellular carcinoma (HCC). We would like to highlight and discuss with authors. First, neutrophil-lymphocyte ratio (NLR) and derived NLR (dNLR) should not be entered into multivariate analysis simultaneously. Second, authors should clarify how the cutoffs of these variables including lymphocyte-monocyte ratio (LMR), dNLR, age and tumor size were set. We insist that the type of variables should be consistent when we carry out the analysis and establish the nomogram. Last, we have to point out that Li et al.’s ( Dear editor,We read with great interest in the recent paper regarding nomograms based on inflammatory biomarkers for preoperatively predicting tumor grade and microvascular invasion in stage I/II hepatocellular carcinoma (HCC) . The nomFirst of all, about neutrophil-lymphocyte ratio (NLR) and derived NLR (dNLR). We note that dNLR is composed of neutrophils count divided by white cells count minus neutrophils count. The latter, mixture of monocytes and lymphocytes, is broadly similar to the lymphocytes count. Therefore, dNLR is an alternative for NLR especially when we are not able to get access to lymphocytes count because usually neutrophils and white cells counts are available in clinical database . What isSecond, about the binary variables in nomograms including lymphocyte-monocyte ratio (LMR), dNLR, age and tumor size. It is of note that these variables are analyzed as continuous variables through univariate and multivariate regression. However, these continuous variables were turned into binary variables in nomograms without explanation. Authors should clarify how the cutoffs of these variables were set. In my opinion, it is a wise choice to keep continuous variables in nomograms to avoid the massive information loss just like these papers ,12. We iLast, we have to point out that Li et al.’s  study faIn conclusion, the present study established practical nomograms for preoperatively predicting tumor grade and microvascular invasion. We hope that the authors can respond to our doubts and this will promote the predictive models.


After traumatic brain injury (TBI), motor impairment is less common than neurocognitive or behavioral problems. However, about 30% of TBI survivors have reported motor deficits limiting the activities of daily living or participation. After acute primary and secondary injuries, there are subsequent changes including increased GABA-mediated inhibition during the subacute stage and neuroplastic alterations that are adaptive or maladaptive during the chronic stage. Therefore, timely and appropriate neuromodulation by transcranial direct current stimulation (tDCS) may be beneficial to patients with TBI for neuroprotection or restoration of maladaptive changes.Technologically, combination of imaging-based modelling or simultaneous brain signal monitoring with tDCS could result in greater individualized optimal targeting allowing a more favorable neuroplasticity after TBI. Moreover, a combination of task-oriented training using virtual reality with tDCS can be considered as a potent tele-rehabilitation tool in the home setting, increasing the dose of rehabilitation and neuromodulation, resulting in better motor recovery.This review summarizes the pathophysiology and possible neuroplastic changes in TBI, as well as provides the general concepts and current evidence with respect to the applicability of tDCS in motor recovery. Through its endeavors, it aims to provide insights on further successful development and clinical application of tDCS in motor rehabilitation after TBI. Traumatic brain injury (TBI) is defined as “an alteration in brain function  or other evidence of brain pathology  caused by external force” . The incMotor impairment after TBI is caused by both focal and diffuse damages, making it difficult to determine the precise anatomo-clinical correlations , 10. AccTranscranial direct current stimulation (tDCS) – one of the noninvasive brain stimulation (NIBS) methods – can increase or decrease the cortical excitability according to polarity  and be used to modulate the synaptic plasticity to promote long-term functional recovery via long-term depression or potentiation , 13. RecIn this review, we will cover (1) the pathophysiology and possible neuroplastic changes in TBI; (2) physiology of tDCS; (3) current clinical evidence of tDCS in TBI for motor recovery; (4) general current concept of tDCS application for motor recovery; and (5) the future developments and perspectives of tDCS for motor recovery after TBI. Although the scope of motor recovery is wide, this review will focus primarily on the recovery of limb function, especially that of the upper limb. We expect that this review can provide insights on further successful development and clinical application of tDCS in motor rehabilitation after TBI.According to the mechanism of trauma, there can be various types of focal injury. Penetration can directly damage the brain tissue and blood vessels, leading to intracranial hemorrhage. Direct blow can cause coup and countercoup injury of the brain parenchyma. Cerebral contusion caused by non-contact external force or countercoup is common in the temporal or frontal lobes due to the fragile surface being vulnerable to the sharp and rough edges of the anterior and middle cranial fossa . The accSecondary injury occurs any time from immediately following the primary injury to several weeks after the primary injury and can be caused by the following possible mechanisms: excitotoxicity, cerebral edema, ischemia, and neuro-inflammation Fig. . In brieAfter acute injury, remyelination or neuroplasticity contributes to motor recovery, which is most eminent within the first 3 months after injury . In the After sustaining brain damage, neuroplastic changes could either be adaptive or maladaptive, the latter may be associated with poor functional recovery. In a previous study of patients with stroke, both contralesional and ipsilesional motor cortices were activated during voluntary movement of the paretic hand . When paAergic and glutamatergic synapses [tDCS delivers direct constant electrical currents to the cortical area of brain between two electrodes (anode and cathode), modulating the neuronal excitability by changing the resting membrane potential level . The chasynapses , 43, whesynapses .Therefore, according to various changes in different stages after TBI, different tDCS protocols can be considered . CathodaAlthough there have been studies investigating the effect of NIBS on the non-motor impairments  in patients with TBI , 46, stuIn a recent study with controlled cortical impact model, a standalone ipsilesional 30 Hz cortical stimulation demonstrated no significant behavioral improvements or lesion size difference using FDG-microPET when compared with no stimulation . This reStroke causes motor impairment as a result of cortical or subcortical damages and motor recovery is associated with neuroplastic changes, which is similar with TBI . TherefoTraditionally, the interhemispheric inhibition model was proposed to develop a strategy for neuromodulation after stroke. Although the pathophysiology could be different in patients with TBI, this concept may be applicable to those with TBI who have hemiparesis or hemiplegia due to the focal brain parenchymal lesion. In patients with stroke, the motor cortex activations in the bilateral hemispheres are counterbalanced by the interhemispheric inhibition . The intThere are several concerns regarding the use of tDCS in a real clinical setting due to the associated intra- and inter-individual variabilities with respect to electrical current, responses and optimal stimulation target. Although tDCS offers greater convenience than magnetic stimulation, its accessibility to users, clinicians or patients, remains low. Appropriate task-oriented training must be implemented to augment the effect of tDCS for motor recovery , 53. TheElectrical current induced by tDCS is variable in accordance with the individual different head anatomy –67. In aMoreover, recent advancements in the computational modeling have enabled a novel high-definition tDCS technique with manually configured array electrodes for relatively improved spatial resolution . The effIf clinicians can monitor the tDCS responses before, during, and after stimulation, these changes can be used as surrogate markers for the effect of tDCS on neuroplasticity and the stimulation parameters could be adjusted according to these results. MEP can be one of the candidate surrogate markers reflecting immediate changes in the brain function by tDCS . During Recent advancements in software-based signal processing techniques have enabled rapid or real-time analyses of functional activation of the brain –76. InteElectroencephalography (EEG) can reflect the tDCS-induced immediate changes in functional activation and networks in the brain. tDCS increased the 8-13 Hz mu event-related desynchronization, which showed a direct correlation with motor threshold . Anodal Therefore, integrating EEG or fNIRS with tDCS may help the clinician to optimize the stimulation parameters that maximize the adaptive plasticity and recovery, despite their respective advantages and disadvantages. The schematic of a personalized tDCS, optimized by the potential real-time response analysis is shown in Fig. NIBS seems to be more effective when it is combined with task-oriented motor training. In previous animal stroke studies, combination of cortical stimulation and rehabilitation training induces brain plasticity and functional improvement , 85. TheWith respect to using modern technology, virtual reality (VR)-based rehabilitation can be a promising option. Task-oriented training can be provided using VR combined with tDCS. VR-based therapies can induce the repetitive task-oriented motions and may be beneficial to encourage patient motivation by gamifications and various interesting feedbacks –92. In aAfter TBI, tDCS can modulate the neuroplasticity and has the potential to promote motor recovery. Different changes in the brain at different times after the onset of TBI reveal the need for different neuromodulation approaches in accordance with the chronicity. Although many stroke studies have provided some implications of using tDCS in TBI for motor recovery, TBI is associated with different pathophysiology and more diffuse network disruptions; hence a well-designed clinical trial is needed in the future to prove the efficacy of tDCS and define the optimal stimulation parameters.For more individualized approaches, imaging-based modelling or brain signal monitoring system can be combined with tDCS. By combining these technologies, optimal targeting may be possible, inducing a more favorable neuroplasticity. A combination of task-oriented training using a novel modern technology such as VR with tDCS can promote neuroplastic changes for motor recovery, which may lead to be a potent tele-rehabilitation tool in the home setting. Therefore, the development of a combination approach with tDCS and clinical trials to investigate the effect of this approach is required.


Obesity and atrial fibrillation have risen to epidemic levels worldwide and may continue to grow over the next decades. Emerging evidence suggests that obesity promotes atrial and ventricular arrhythmias. This has led to trials employing various strategies with the ultimate goal of decreasing the atrial arrhythmic burden in obese patients. The effectiveness of these interventions remains to be determined. Obesity is defined by the expansion of adipose mass, making adipocytes a prime candidate to mediate the pro-arrhythmogenic effects of obesity. The molecular mechanisms linking obesity and adipocytes to increased arrhythmogenicity in both the atria and ventricles remain poorly understood. In this focused review, we highlight areas of potential molecular interplay between adipocytes and cardiomyocytes. The effects of adipocytes may be direct, local or remote. Direct effect refers to adipocyte or fatty infiltration of the atrial and ventricular myocardium itself, possibly causing increased dispersion of normal myocardial electrical signals and fibrotic substrate of adipocytes that promote reentry or adipocytes serving as a direct source of aberrant signals. Local effects may originate from nearby adipose depots, specifically epicardial adipose tissue (EAT) and pericardial adipose tissue, which may play a role in the secretion of adipokines and chemokines that can incite inflammation given the direct contact and disrupt the conduction system. Adipocytes can also have a remote effect on the myocardium arising from their systemic secretion of adipokines, cytokines and metabolites. These factors may lead to mitochondrial dysfunction, oxidative stress, autophagy, mitophagy, autonomic dysfunction, and cardiomyocyte death to ultimately produce a pro-arrhythmogenic state. By better understanding the molecular mechanisms connecting dysfunctional adipocytes and arrhythmias, novel therapies may be developed to sever the link between obesity and arrhythmias. From 1980 to 2015, obesity rates at the population level have been steadily on the rise . Firstly, the presence of some adipose tissue in and around the heart is physiologic. Fat around the heart can be divided into pericardial adipose tissue and visceral EAT. Pericardial fat is defined by fat surrounding the parietal pericardium while visceral EAT is defined by fat between the myocardium and visceral pericardium , it has unique characteristics such as smaller adipocytes  and abdominal visceral adiposity. EAT thickness has been reported to be associated with severity of coronary artery disease (CAD)  superfamily, which may promote atrial fibrosis  in adipose tissue is known to be an early instigator of adipose tissue inflammation  leading to hyperpolarization and indirectly inhibition of cyclic adenosine monophosphate  has ganglionated plexi (GPs) within the heart located in the epicardial fat pads that can modulate cardiac autonomic nerve input  and is thought to constitute the nidus for re-entry ventricular arrhythmias  and lipid accumulation , increased dietary fat burden alone can lead to arrhythmia. For example, even a short period of HFD in gerbils can lead to radical inflammation and apoptosis causing cardiac remodeling  or a prolongation (ITO) of atrial myocyte action potential duration and thus play role in arrhythmogenesis  has also been studied in AF. In a study using a sheep model of HFD-induced obesity, there was infiltration of the posterior left atrium by EAT associated with reduced endocardial voltage in this region compared to lean sheep  and lifestyle modifications. In a study of 1425 consecutive patients offered weight management, those with >10% weight loss had 6 fold increased likelihood of arrhythmia free survival over 5 years compared to those with less weight loss  as well as increased autophagy activation possibly leading to atrial fibrosis..Thus, exploring how fat affects TGF- β 1 and potential mechanisms to inhibit this pathway may offer further treatment options.Another key player to target would be TGF- β 2+ from the cytoplasm into the ER  are valuable for the study of cardiac physiology given the lower maintenance cost, easier handling, cost effectiveness and possibility for genetic manipulation , who develop spontaneous AF induction .in vitro dish (Garg et al., Recently human induced pluripotent stem cell derived cardiomyocytes from disease patients have been shown to be a promising method to study cardiac arrhythmias, especially in arrhythmias related to genetic mutations (Garg et al., There has been an epidemic level rise in obesity. Emerging evidence suggests that obesity promotes atrial and ventricular arrhythmias. However, the function of adipose tissues is multifaceted and its interplay with the heart is even more complex. Future studies examining the connection between adipose tissues and arrhythmias are urgently needed. Numerous adipose tissue depots, such as intramyocardial, local and/or remote may play integral roles in the regulation of inflammation, oxidative stress, autophagy, autonomic tone, mitophagy, propagation of aberrant signals, creation of potential re-entry circuits and cardiomyocyte death. Upon elucidation of the mechanisms by which arrhythmias are incited, it may be possible to identify high value therapeutic targets.MP and KM are co-first authors. MP, KM, JC, and JL contributed and reviewed and approved the final manuscript. All co-authors contributed and reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.