Invasive salmonellosis is a common community-acquired bacteremia in persons residing in sub-Saharan Africa. However, there is a paucity of data on severe typhoid fever and its associated acute and chronic host immune response and carriage. The Severe Typhoid Fever in Africa (SETA) program, a multicountry surveillance study, aimed to address these research gaps and contribute to the control and prevention of invasive salmonellosis.Salmonella-specific antibodies and shedding patterns. Healthcare utilization surveys were performed to permit adjustment of incidence estimations. Postmortem questionnaires were conducted in medically underserved areas to assess death attributed to invasive Salmonella infections in selected sites.A prospective healthcare facility–based surveillance with active screening of enteric fever and clinically suspected severe typhoid fever with complications was performed using a standardized protocol across the study sites in Burkina Faso, the Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Defined inclusion criteria were used for screening of eligible patients for enrollment into the study. Enrolled patients with confirmed invasive salmonellosis by blood culture or patients with clinically suspected severe typhoid fever with perforation were eligible for clinical follow-up. Asymptomatic neighborhood controls and immediate household contacts of each case were enrolled as a comparison group to assess the level of Research data generated through SETA aimed to address scientific knowledge gaps concerning the severe typhoid fever and mortality, long-term host immune responses, and bacterial shedding and carriage associated with natural infection by invasive salmonellae.SETA supports public health policy on typhoid immunization strategy in Africa. Salmonella enterica subspecies enterica serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A), typically resulting in systemic typhoid fever (TF) and paratyphoid fever (PF), and nontyphoidal S. enterica (NTS) serovars causing self-limiting enterocolitis and bacteremia among children and adults in sub-Saharan Africa. Globally, TF accounts for 21.7 million cases and 217 000 deaths annually whereas invasive nontyphoidal Salmonella (iNTS) disease accounts for 3.4 million cases and >680 000 deaths [Invasive salmonellosis in humans is largely caused by fecal-oral transmission of 0 deaths . A recen0 deaths .Currently available typhoid vaccines include the parenteral unconjugated Vi polysaccharide (ViPS) and oral live attenuated Ty21a vaccines, both of which have been recommended by the World Health Organization (WHO) since 2008, and parenteral typhoid conjugate vaccine (TCV), which was prequalified by the WHO in December 2017 . InfantsHowever, there is a paucity of population-based data concerning the incidence and severity of typhoid and iNTS disease among children and adults in sub-Saharan Africa. The Severe Typhoid Fever in Africa (SETA) program primarily aimed to understand the burden of severe TF and the associated case fatalities, clinical characteristics, and potential host risk factors that may be related to the disease severity. The SETA program also aimed to investigate the host immune response and bacterial shedding patterns associated with invasive salmonellosis. Public and private cost burden and productivity loss due to the treatment of respective diseases were further studied. Generated data will be essential in developing adequate immunization strategies and typhoid and iNTS disease control and prevention policies. These SETA study results will have a direct impact, particularly in countries eligible for support from Gavi, the Vaccine Alliance, on potential uptake of TCV in the next 10 years .Salmonella infections ; (2) host immunity and acute and chronic carriage associated with natural S. Typhi/S. Paratyphi A, B, and C (hereafter S. Paratyphi)/iNTS infections over a 1-year follow-up period (prospective case-controlled and cohort study design method); (3) prevalences of S. Typhi/S. Paratyphi/NTS carriage in immediate household members of confirmed TF, PF, and iNTS disease cases (prospective active surveillance and cohort study); (4) public and private expenditures for treatment and productivity loss (cost of illness) associated with TF/PF/iNTS disease (cohort) (5) effects of invasive salmonellosis on the quality of life of patients and long-term socioeconomic study (cohort); and (6) validation of a new reverse-transcription polymerase chain reaction (rt-PCR) assay for the diagnosis of invasive Salmonella infections  the burden and severity of invasive fections . In addiBuilding on the Typhoid Fever Surveillance in Africa Program (TSAP) network , the SETSurveillance sentinel sites were established including primary, secondary, and tertiary healthcare facilities . SelectiSalmonella from clinical samples such as blood and specimens from perforation cases, which may be collected outside of the routine SETA patient screening procedure. The generic SETA study forms are available in the Supplementary Data.Patients visiting SETA sentinel healthcare facilities were actively screened at selected entry points of each healthcare facility, including triages where applicable, outpatient wards, inpatient medical and surgical wards, and emergency wards. Laboratories of the selected healthcare facilities/collaborating institutes were involved for laboratory-based detection of any invasive Streptococcus carriage.Patient screening for eligibility was based on the following inclusion criteria : historyDaily progress of clinical symptoms and treatment history were recorded for all enrolled patients with clinically suspected severe TF  until diSalmonella infection, particularly TF, was also analyzed through postmortem questionnaires  [Assessment of death attributed to invasive ires see  performe(ICD-10)  and the (ICD-10)  recommenEnrolled patients with blood culture–confirmed TF/PF/iNTS (cases) became part of the study cohort for clinical follow-up and health economics surveys during the period of 1 year . At eachSalmonella.For investigations of host immune response and carriage status of cases in the context of the local population, asymptomatic NCs matched to cases by age (±5 years), sex, and location of residency (1:4 case-control ratio) were enrolled  followinS. Typhi, S. Paratyphi, and NTS. Household contacts are individuals residing in the same house as the case, sharing the common living condition and environment. Priority for enrollment was given to individuals who prepare food for the case, who is the closest in age to the case, and who spends the most time with the case  are described in A healthcare utilization survey  was condAll eligible participants (or their responsible parents/guardians) were approached for voluntary written informed consent. The informed consent process included an explanation by study staff about the study purpose, expectations from participants, duration of participation, risks and benefits for participation, confidentiality, right to decline or withdraw from the study, and contact information of study investigators. Participants were asked to sign a statement of consent if they agreed to join the study. If the participant was an infant or child, his or her parent/guardian was asked to sign or thumbprint the statement of consent. If the participant was an adolescent, both the participant and the parent/guardian were asked to sign or thumbprint the statement of consent. If the participant was illiterate, an independent literate witness  was asked to sign or thumbprint the statement of consent. Study participants were allowed to withdraw from the study at any time without loss of clinical services or penalties of any kind. The International Vaccine Institute’s (IVI) Institutional Review Board and site-specific ethical review boards reviewed the study annually to ensure continued compliance with the ethical principles and guidelines based on the WHO (2009) , the CouSalmonella-confirmed patients or/and special cases and their NCs and HCs, postmortem questionnaires, and laboratory forms  unless the data recorded directly on our study forms were considered the source data. The surveillance study forms included the informed consent and enrollment form for all participants, case report forms for patients, follow-up forms for ry forms . ElectroSETA provides incidence rates and frequency proportions of TF. The incidence estimation is based on the formula used in TSAP , 30, usiSalmonella species during an acute phase and up to a 1-year time point, with that of NCs and HCs . Salmonella strains detected in stools of cases, HCs, and NCs will be analyzed to investigate any patterns potentially related to transmissions in respective study sites, for which the population-based healthcare utilization survey data will be cross-compared for various environmental risk factors such as the household WASH conditions and domestic animals. All bacterial isolates yielded through SETA will be sequenced for further molecular epidemiological analyses such as the emergence and spread of AMR/MDR strains as performed in TSAP [Analyses on severe TF will also include investigations on host risk factors that may be associated with the severity of disease  and site-specific characteristics. Various statistical methodologies will be used including the Spearman correlation coefficient and/or stratified logistic regressions for univariate and multivariable analyses to measure the odds ratios. Data from the longitudinal cohort study of the TF/PF/iNTS patients and their respective NCs and HCs will be analyzed by comparing the level of antibodies (IgG/IgM) of cases and their shedding of  in TSAP . FurtherThe SETA study protocol was aligned with the SEAP phase II , 33 and Challenges were faced and addressed during the study period. These included the following: (1) introducing a complex research study with multiple study components, especially in tertiary hospitals, was challenging as the clinicians were occupied with their routine patient care; (2) contamination rates of blood culture varied per site; (3) volume of blood draw was challenging, particularly from children; (4) enrolling healthy controls in the neighborhood was also challenging and some loss to follow-up was inevitable over the course of 1 year; and (5) follow-up visit schedules were difficult to strictly adhere to, owing to various unforeseen and unexpected reasons such as the absence or refusal of the study participants. The SETA monitoring and evaluation plan and tool was developed and implemented throughout the study period  to ensure and improve the quality of surveillance across all sites.The SETA program aimed to provide a comprehensive quantitative analysis of incidence, severity, complications, mortality, host immunity, and acute and long-term carriage, cost of illness, and socioeconomic burden of disease associated with invasive salmonellosis in multiple countries across the sub-Saharan African region. Upon completion of the study, data cleaning and analysis will be performed, and the results will be disseminated at academic conferences and international peer-reviewed journals. Observational descriptions of the surveillance study areas and populations including demographic and socioeconomic status, and WASH conditions and practices, will also provide a valuable dataset for the development of prevention policies for TF/PF/iNTS disease, including vaccination strategies, in the respective African countries. SETA results will further serve as baseline data for any future vaccination studies in these study sites.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciz715_suppl_Supplementary_Table_1Click here for additional data file.


The capacity for high-income countries to supply enough locally trained doctors to minimise their reliance on overseas-trained doctors (OTDs) is important for equitable global workforce distribution. However, the ability to achieve self-sufficiency of individual countries is poorly evaluated. This review draws on a decade of research evidence and applies additional stratified analyses from a unique longitudinal medical workforce research program ) to explore Australia’s rural medical workforce self-sufficiency and inform rural workforce planning. Australia is a country with a strong medical education system and extensive rural workforce policies, including a requirement that newly arrived OTDs work up to 10 years in underserved, mostly rural, communities to access reimbursement for clinical services through Australia’s universal health insurance scheme, called Medicare.Despite increases in the number of Australian-trained doctors, more than doubling since the late 1990s, recent locally trained graduates are less likely to work either as general practitioners (GPs) or in rural communities compared to local graduates of the 1970s–1980s. The proportion of OTDs among rural GPs and other medical specialists increases for each cohort of doctors entering the medical workforce since the 1970, peaking for entrants in 2005–2009.Rural self-sufficiency will be enhanced with policies of selecting rural-origin students, increasing the balance of generalist doctors, enhancing opportunities for remaining in rural areas for training, ensuring sustainable rural working conditions and using innovative service models. However, these policies need to be strongly integrated across the long medical workforce training pathway for successful rural workforce supply and distribution outcomes by locally trained doctors. Meanwhile, OTDs substantially continue to underpin Australia’s rural medical service capacity. The training pathways and social support for OTDs in rural areas is critical given their ongoing contribution to Australia’s rural medical workforce.It is essential for Australia to monitor its ongoing reliance on OTDs in rural areas and be considerate of the potential impact on global workforce distribution. The capacity for high-income countries to meet their medical workforce needs through education and training of local doctors and thus limit their reliance on overseas-trained doctors (OTDs), called self-sufficiency, remains an important topic of global health workforce policy interest , 2. EnsuAustralia is a useful case study of a high-income country that has both a high-quality medical education system and a national policy targeting newly arrived OTDs to work in underserved, mostly rural, communities. As such, exploring the targeted use of OTDs in rural areas provides a useful lens through which to explore self-sufficiency planning nationally. Also, Australia has supported and funded an internationally unique 10-year national longitudinal cohort study of its medical workforce which provides the objective data to inform such medical workforce planning. This is possible if the data area applied to this question and the published research which has been produced from this project is reviewed to make it more accessible for informing this topic.http://www.mabel.org.au). It was a competitively funded research project-driven initiative to improve the quality of information about the medical workforce dynamics in Australia and to inform national policy questions. MABEL commenced in 2008 by inviting all 54 750 clinically active doctors in Australia to participate in an annual survey. The sampling frame was an Australian Medical Publishing Company (AMPCo) population listing with updated details of doctors’ contact information for regular mailing purposes (the best available directory at the time). To facilitate response from doctors in remote communities (important for informing key policy questions), pre-paid monetary incentives, not conditional on response ($AU100), were applied. In the first year, 19.4% of Australia doctors responded in hard copy or via the secure online survey: 3906 general practitioners (GPs) and GP registrars , 4596 other (non-GP) specialists , 1072 other (non-GP) specialists , and 924 hospital non-specialists.This research program is known as the MABEL study  (n = 1 719), including 21% of GPs (n = 805), but the representativeness of these respondents was not assessed as there was no population data to base this on.Respondents were assessed as being relatively representative of all Australian doctors, although compared to the total AMPCo population, the respondents had slight over-representation of (no more than 4%) of age groups less than 60 years, females (6%) and non-GP specialists (5%) . After gEach survey comprises around 100 questions covering the doctor’s characteristics, specialty, work location and practice, workload, job satisfaction and remuneration. The annual operational costs (excluding research production) are $350 000 Australian dollars (Aus$), approximating $273 288 United States dollars (US$) (exchange rate March 2018). Now with around 80 000 responses from 20 000 different doctors, completed over 2008–2015, it comprises the most comprehensive source of national workforce evidence for informing planning for self-sufficiency in Australia because it covers doctor type, training and location as well as a range of other rich covariates. However, the evidence generated from the project has never been synthesised to explore the topic of rural self-sufficiency.Rural and remote areas, where around 30% of the Australian population and 65% of Indigenous Australians reside, have substantial and ongoing difficulties related to the recruitment, retention and overall supply of skilled doctors who work at the broad scope to cover the bulk of community needs , 10  to boost overall medical workforce capacity with the potential to have some impact on rural supply through market effects. Within enrolment numbers, medical courses were required to enrol a minimum of 25% rural-origin medical students, provide at least 1 year’s rural immersion for 25% of students, bond 25% of enrolled students to work in a district of workforce shortage  after completing the medical course for a pre-set period of time, and additionally half of all GP training was located in rural areas . FurtherThe principle of self-sufficiency was espoused by Australia’s government in a 2004 national health workforce strategy . It was Similar to the United Kingdom, United States and Canada, around one quarter of Australia’s doctors are trained in medical schools based in other countries . AustralWhile the degree of under- or over-supply of the broader medical workforce has been regularly debated and analysed in national reports –26, the This review draws on over 10 years’ evidence and applies additional stratified analyses of the MABEL longitudinal data to inform planning for self-sufficiency of the rural medical workforce in Australia. It explores the (1) patterns in rural work location by overseas- and locally trained doctors, differentiated by specialty and career stage, and (2) factors associated with rural work outcomes by locally trained doctors, and (3) discusses the implications of this evidence in light of the international literature.The MABEL data, applied as a new stratified analyses, shows the geographical distribution (by 2008–2013 work location) and specialty type of the locally trained medical workforce according to the year that they graduated from medical school and entered the medical workforce  are more than twice as likely as metropolitan-origin doctors to work in rural areas . AdditioGPs who are principals or associates of the practice are retained for longer in the current practice than contracted or salaried GPs , with thRural GPs and other medical specialists have higher average weekly working hours, more on-call responsibilities and less opportunities for continuing professional development, although they report equivalent job satisfaction as their metropolitan counterparts , 36, 37.The supply and retention of doctors in rural areas is also affected by a range of community and demographic factors. GPs stay longer in rural communities with more than 10 000 people than in smaller rural or remote communities . GP mobiAround 19% of medical specialists participate in outreach work, regularly travelling away from the main practice to service a rural community . Such ouSeveral implications for self-sufficiency planning are notable from applying the new stratified analyses of MABEL data and the review of a decade of published evidence from this project. Firstly, Australia relies heavily on OTDs for rural medical workforce capacity, both as GPs and other medical specialists, for access to medical services in large and small communities and this reliance is increasing. Recent locally trained graduates are increasingly choosing specialties other than general practice, reducing their likelihood of working in rural areas where the broader specialist and sub-specialist infrastructure is more limited. It is imperative for self-sufficiency that a higher proportion of locally trained doctors chooses general practice and other generalist specialties. Altman et al. noted defining and professionally recognising generalist medicine can help students see it as something concrete to be an expert in . AdditioSecondly, increasing self-sufficiency demands sustained investment for locally growing rural doctors. In this area, the published MABEL evidence denotes and quantifies the drivers of rural supply and distribution for doctors in Australia, which concurs with international evidence: from enrolment of rural origin students; providing consecutive rural training opportunities during undergraduate, pre-vocational and vocational training; and developing attractive advanced skills training and generalist career pathways , 48–50. There are still some important gaps in Australian rural workforce policy notable based on the rural workforce drivers identified from the review of the MABEL evidence, mainly related to improving sustainable working conditions for rural doctors . InnovatFinally, high-quality regional workforce planning is sorely needed for Australia to achieve self-sufficiency and minimise reliance on OTDs. Regional planning firstly requires a degree of societal determination to transition away from continued heavy OTD use and develop of local training pathways as the alternative. Research from the United States suggests that the transition away from OTDs at the community level is complicated and takes time . Though,A 2012 Parliamentary Inquiry identified that OTDs have poor access to orientation programs, professional registration, career opportunities and social supports . This isIt is incumbent on Australia as party to the Global Code of Practice on International Recruitment, to provide structured support for OTDs, whilst also monitoring the degree of reliance on OTDs and the potential impact on global workforce distribution . NotablyThe scope of this paper was confined to summarising available evidence from the MABEL research program, which limited the aspects of rural self-sufficiency investigated as such. It did not explore the level of reliance on OTDs to complement the range of skills across the broader workforce including in areas like psychiatry, where there are not enough locally trained psychiatrists for increasing population needs . Also, tThis report draws on evidence which identifies patterns of work by overseas- and locally trained doctors in Australia, to inform planning of self-sufficiency of the rural medical workforce in Australia. The evidence identifies that Australia relies heavily on OTDs working as GPs and other medical specialists in large and small rural communities, with new OTDs supplementing the lower proportion of recent locally trained doctors in rural areas. Increasing the locally trained generalist rural workforce requires sustained policies, enrolling rural-origin students into medicine, providing ongoing rural training opportunities, promoting generalist medical careers and building sustainable rural working conditions. Meanwhile, OTDs are essential to rural workforce capacity and their support should be incorporated as a key part of ongoing rural medical workforce planning. Australia, like all similar high-income countries, should monitor the reliance on OTDs within rural medical services and be acutely mindful of the potential impact on global workforce distribution.


In the treatment of brain tumors, surgical intervention remains a common and effective therapeutic option. Recent advances in neuroimaging have provided neurosurgeons with new tools to overcome the challenge of differentiating healthy tissue from tumor-infiltrated tissue, with the aim of increasing the likelihood of maximizing the extent of resection volume while minimizing injury to functionally important regions. Novel applications of diffusion tensor imaging (DTI), and DTI-derived tractography (DDT) have demonstrated that preoperative, non-invasive mapping of eloquent cortical regions and functionally relevant white matter tracts (WMT) is critical during surgical planning to reduce postoperative deficits, which can decrease quality of life and overall survival. In this review, we summarize the latest developments of applying DTI and tractography in the context of resective surgery and highlight its utility within each stage of the neurosurgical workflow: preoperative planning and intraoperative management to improve postoperative outcomes. Surgical resection remains the front-line treatment for many forms of intracranial tumor . EvidencSurgical planning has benefited greatly from advances in neuroimaging. Yet, there remain a number of barriers preventing accurate determination of tumor pathology using noninvasive means alone. Biopsy is typically relied upon to determine pathology and grading. However, it is subject to sampling error , 11 and Recent case series have highlighted the use of DTI to circumvent the weaknesses of both DES and biopsy. DTI measures water diffusion properties of neural tissue and can be used to approximate functionally relevant anatomical WMT in the brain. Within the context of intracranial tumor diagnosis and treatment, DTI has been used for planning neurosurgical interventions , 16, defIn this review, we will discuss applications of DTI and DDT in the context of neurosurgical tumor resection, provide an in-depth description of current developments, and consider their limitations.Treatment strategies for intracranial tumors differ considerably based on pathology and grading, and optimal prognosis is dependent on strategy , 28. NonDiffusion coefficients in neoplastic brain tissue provide additional information for detecting tissue differences in and proximal to the tumor . Water mNumerous studies have investigated the possibility of differentiating between gliomas and metastases , 41–52 aet al.  and of the SLF. The shorter language tracts, such as AF or the uncinate fascicle (UF), were visualized more effectively using the nTMS-based approach (p < 0.001); the UF was not detectable with the cubic ROIs-based protocol in either case. The fibers-to-tract ratio using nTMS-based DDT was 236 ± 73 and 286 ± 9 using the cubic ROIs-based protocol, which are comparable values and are both within the range Negwer et al. defined as ideal for a clear DDT result (fibers/tract 0–500) , DDT visualization during surgery aided in preserving speech for patients with tumors adjacent to the SLF , 81. Negt 0–500) .3 residual tumor) in 93.0% of patients and few postoperative deficits  , a crossroad of eloquent WMT difficult to preserve with a standard “anatomical” approach . In a stt cases) .Brain shift is known to affect the reliability of preoperatively generated DDT , 86. ThiThat said, intraoperative imaging requires additional time and surgical preparation . A methoDirect electrical stimulation (DES) is regarded as the gold standard for mapping brain function, though evidence suggests improvements are needed. While DES provides real-time, approximate spatial information about eloquent fibers—enhancing surgical performance and safety—it is time consuming and places the patient at risk for intraoperative seizures due to repeated direct electrical stimulation , 93. MorA collection of studies have demonstrated a direct relationship between DES current magnitude and the distance from probe to DTI-defined tracts; as the proximity to tracts increases, stimulation current decreases , 95–99. Further support for the efficacy of combining tractography and electrical stimulation (ES) was demonstrated in a study by Yamao et al.  evaluatiAlthough DTI and DTT present many advantages and have demonstrated utility in approximating the geometry of WMT in the context of neurosurgical interventions, it is limited in its ability to resolve multiple fibers and is susceptible to partial volume effects . ProgresAlternative models involve expanding the diffusion model to account for higher order diffusion features , substituting the tensor with another shape , or modeling the Fourier transform relationship between the diffusion MR signals and the underlying diffusion displacement . While models like DKI and CSD require more extensive image sets, improvements to DDT are possible by applying models other than DTI. For example, Zhang et al.  demonstrAdvanced diffusion imaging sequences include diffusion spectrum imaging (DSI), high angular resolution diffusion imaging (HARDI), DKI, and Crossing Fiber Angular Resolution Intra-voxel structure (CFARI). Tractography based on DSI has the capacity to image crossing fibers in neural tissue using probability density functions, which specify microscopic displacements of MR-visible spins using 3D Fourier encoding of displacements. Unlike DTI, DSI is able to resolve crossing fibers, accurately reconstruct confluence of pathways, and demonstrate the decussation of fibers in the optic chiasm . In contOverall, novel applications of DTI and DDT have demonstrated that preoperative, non-invasive mapping of eloquent cortical regions and functionally relevant WMT and their use with other intraoperative adjuncts like DES and nTMS help to reduce postoperative deficits, improving quality of life and overall survival in glioma patients. Future more advanced imaging sequences will continue to improve the utility of WMT depiction in neurosurgery, improving functional outcomes in glioma patients.JC devised the structure and focus of the article, wrote a significant portion of it, and managed the manuscript through its composition and publication processes. EA contributed to the publication by writing and editing portions of the intraoperative and limitations sections. SD contributed to the publication by writing and editing portions of the preoperative section. JT and DO were equally important to crafting the manuscript’s focus and editing of the article. JT and DO share senior authorship.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.


The incidence and mortality of cardiovascular diseases (CVDs) in low and middle income countries (LMICs) have been increasing, while access to CVDs medicines is suboptimal. We assessed selection of essential medicines for the prevention and treatment of CVDs on national essential medicines lists (NEMLs) of LMICs and potential determinants for selection.Only operational NEMLs were considered eligible for this study. A selection of medicines listed under “cardiovascular medicines” or “blood products and plasma substitutes” in the NEMLs were included if they were present on international guidelines for the prevention and treatment of CVDs . The number and diversity of essential medicines selected for CVDs were studied. Moreover, determinants of selection of essential medicines for CVDs at a national level were explored. Data analysis was done using univariate linear regression and non-parametric tests.p = 0.014) and across regions . When recommendations of the international guidelines were considered, over 75% of the NEMLs contained essential medicines for the majority of CVDs.All medicine groups listed by the international guidelines were selected by the majority of the 34 countries studied with the exception of adenosine diphosphate receptor inhibitors which appeared on less than half of the NEMLs studied (41% of countries). The total number of essential medicines for the prevention and treatment of cardiovascular diseases (median 24 (range 16–50)) differed significantly across income levels  contains supplementary material, which is available to authorized users. Cardiovascular diseases (CVDs) are the most common cause of death worldwide with more than 17 million deaths annually , 3.Ongoing changes in low and middle income countries (LMICs), accelerated by urbanization and socio-economic development, have increased the exposure to health related risks such as tobacco smoking, unhealthy diet and reduced physical activity . TogetheThis study will assess selection of essential medicines for the prevention and treatment of a selection of CVDs on NEMLs of LMICs. Potential determinants for this selection, namely income level and geographic region of countries, national burden of CVDs and update of NEMLs on selection will be studied. Additionally, the extent to which different CVDs can be treated according to the guidelines by the selected essential medicines will be explored.The latest available updates of NEMLs at data collection August 2015), were obtained from the “WHO database of essential medicine lists, formularies and treatment guidelines” . Of thes5, were oMedicines listed on the NEMLs were included if they were categorized under “cardiovascular medicines” or “blood products and plasma substitutes” or similar naming and classification in other languages and if they were present in international guidelines for the prevention and treatment of a selection of CVDs (see the therapeutic guidelines section below).Data on income levels and geographic regions were obtained from the World Bank and the WHO, respectively , 15. TheIn order to assess whether the medicines listed on the NEMLs were sufficient enough to provide pharmaceutical treatment for different CVDs, the latest update of international treatment guidelines for CVD management - found following a thorough search in PubMed and other available data sources  were consulted –48. UnleWe hypothesized that number of essential medicines selected for the prevention and treatment of CVDs on an NEML varied across different country income levels , geographic regions, and burden of disease . The numbers of essential medicines for CVDs according to our inclusion criteria  and across regions  (Table p = 0.080), none of the low income countries selected medicines from the subgroup of angiotensin receptor blockers (ARBs). In addition, selection of evidence based beta-blockers for heart failure (see further details below) differed significantly across income levels (p = 0.005), being less frequently selected by low income countries, and across regions (p = 0.003). Selection of medicines which were studied as single medicine from their class such as acetylsalicylic acid, nitroglycerin, lidocaine, dopamine, dobutamine, milrinone did not differ significantly across income levels and regions.The number of essential medicines selected for the prevention and treatment of cardiovascular diseases on the NEMLs differed significantly across income levels , renin-angiotensin-aldosterone system (RAAS) inhibitors , selective beta-blockers (e.g. metoprolol) and dihydropyridine calcium channel blocker (e.g. amlodipine) was selected by 32 countries (94%) Fig . From thIntravenous thrombolytic (fibrinolytic) therapy including streptokinase, urokinase or recombinant tissue plasminogen activator (rt-PA) was selected in 25 countries  and prophylactic therapy of angina pectoris  were selected in over 90% of the countries. It has been recommended that at least two of the classes of these prophylactic therapies should be available in each country , 43, 45,For the treatment of acute coronary syndrome a nitrate, a heparin-like medicine, a platelet inhibitor and a selective beta blocker were selected on all NEMLs while dual antiplatelet therapy  was found on 41% of the NEMLs. A thrombolytic agent (e.g. rt-PA or streptokinase) which is necessary when a percutaneous coronary intervention (PCI) is not possible was on 76% of the NEMLs. From heparin-like medicines, all the countries selected unfractionated heparin (UFH) but only 15 countries (44%) additionally included low molecular weight heparins (LMWH) like enoxaparin and dalteparin. For the treatment of the most important complications of the acute coronary syndrome dopamine (recommended for cardiogenic shock) was selected in 32 countries (94%) and lidocaine (recommended for ventricular fibrillation) was selected in 26 countries (74%).Medicines necessary to treat heart failure were on most NEMLs  were able to cover all recommended treatment options for atrial fibrillation in their NEMLs. While medicines for frequency control  were selected in 91% of the countries, medicines for rhythm control including pharmacological cardioversion and maintaining sinus rhythm  in the current study.Surgery is the primary intervention. After revascularization, antithrombotic therapy with platelet inhibitors is indicated which were selected by 31 of the countries (91%). However, for those patients for whom surgery is unsuitable heparin  and thrombolytic agents (selected in 76% of the NEMLs) are recommended.CVDs own a substantial share in the total burden of non-communicable diseases . TherefoThe main medicine classes for the management of CVDs were represented on NEMLs. Suboptimal selection of medicines for the prevention and treatment of CVDs was however observed for ADP receptor inhibitors, selected by less than half of the countries studied, and statins, thrombolytic agents, medicines for pharmacological cardioversion and medicines for maintaining sinus rhythm which were not selected by nearly a quarter of the countries. The total number of selected essential medicines for the prevention and treatment of cardiovascular diseases differed across income levels and regions. Over 75% of the NEMLs included adequate treatment for the primary and secondary prevention of CVDs and for the majority of acute cardiovascular events. However, management of acute coronary syndrome, especially myocardial revascularization with PCI with dual platelet therapy, could only be covered in less than half of the countries by the current selection, whereas cilostazol or naftidrofuryl for peripheral arterial disease was only found on the NEML in 1 country.In LMICs, high cholesterol is the second highest risk factor which contributes substantially to the burden of CVDs . DespiteRAAS inhibitors were selected by all the studied countries due to extensive selection of ACE inhibitors. Nevertheless, a fraction of patients (5–35%) may not be able to benefit from ACE inhibitors because of dry cough as an adverse effect . GuideliAmong non-dihydropyridine calcium channel blockers, diltiazem is the preferred treatment for stable angina pectoris, particularly in case of monotherapy . DiltiazStreptokinase was included in about 75% of the countries studied, unlike rt-PAs selected in 15% of the countries. Streptokinase, which is currently included in the complementary list of the WHO model list of essential medicines, is deemed unacceptable by some guidelines, owing to its high rate of bleeding and frequent allergic reactions (43). In addition, rt-PAs have shown to be cost-effective in both developed and developing countries –58. HoweDespite the fact that all the studied countries selected at least a selective beta blocker, the choice was dominated by atenolol . Atenolol has been replaced with bisoprolol  for angina, arrhythmia and heart failure in the WHO model list of essential medicines . As thesAntiarrhythmic medicines indicated for rhythm control in atrial and ventricular fibrillation were absent in a quarter of countries studied while this group of medicines are life saving for patients in critical conditions. Vitamin K antagonists, e.g. warfarin were available in 32 (94%) of NEMLs whereas DOACs were not included in any of the NEMLs studied. These newer anticoagulant medicines are shown to be cost effective in health care settings in developed countries compared to vitamin K antagonists, e.g. in secondary prevention of stroke in atrial fibrillation , 64 albeEssential medicines are shown to be more available compared to other medicines worldwide . This inThis study has a number of limitations. The number of low income countries was lower compared to the other income levels. Regional results should be interpreted cautiously since the African region was only represented by low income countries. Besides, treatment of comorbidities (e.g. diabetes) and special patient groups  were out of scope of this study. Guidelines vary in recommendations while we only included the essence of the treatments in this study, and in particular we excluded innovative medicines suggested by some of the guidelines (GP IIb/IIIa inhibitors) because of the scope of this study being limited to LMICs. Selection of oxygen and analgesics (e.g. morphine) was not assessed in the current study, but there are concerns about their availability and accessibility , 71. MorIn conclusion, essential medicines for the management of CVDs were widely selected in LMICs. This has been translated into inclusion in NEMLs of essential pharmacological treatment according to evidence-based guidelines for the majority of CVDs. Nevertheless, empirical evidence suggests limited access to medicines for CVDs to this end.Additional file 1:. Including country names, World Bank income level, WHO regions, Year of (latest update) Essential Medicines List. (PDF 228 kb)Overview of the countries included in the study


A scoping search and a systematic literature review were conducted to give an insight on entry and exit screening referring to travelers at points of entry, by analyzing published evidence on practices, guidelines, and experiences in the past 15 years worldwide. Grey literature, PubMed. and Scopus were searched using specific terms. Most of the available data identified through the systematic literature review concerned entry screening measures at airports. Little evidence is available about entry and exit screening measure implementation and effectiveness at ports and ground crossings. Exit screening was part of the World Health Organisation’s (WHO) temporary recommendations for implementation in certain points of entry, for specific time periods. Exit screening measures for Ebola Virus Disease (EVD) in the three most affected West African countries did not identify any cases and showed zero sensitivity and very low specificity. The percentages of confirmed cases identified out of the total numbers of travelers that passed through entry screening measures in various countries worldwide for Influenza Pandemic (H1N1) and EVD in West Africa were zero or extremely low. Entry screening measures for Severe Acute Respiratory Syndrome (SARS) did not detect any confirmed SARS cases in Australia, Canada, and Singapore. Despite the ineffectiveness of entry and exit screening measures, authors reported several important concomitant positive effects that their impact is difficult to assess, including discouraging travel of ill persons, raising awareness, and educating the traveling public and maintaining operation of flights from/to the affected areas. Exit screening measures in affected areas are important and should be applied jointly with other measures including information strategies, epidemiological investigation, contact tracing, vaccination, and quarantine to achieve a comprehensive outbreak management response. Based on review results, an algorithm about decision-making for entry/exit screening was developed. Public health events can cause serious crises and damage to the human population if effective frameworks and systems are not in place to prevent, early detect, and respond in a timely manner to health threats. In recent years, events such as the Public Health Emergencies of International Concern of Zika Virus Disease declared in 2016 and Ebola Virus Disease (EVD) outbreak declared in 2014 affected or have/had the potential to seriously affect a large amount of the population. High mobility of populations across borders of countries can contribute to the rapid spread of diseases. Screening measures on travelers at points of entry including airports, ports, and ground crossings can be implemented to prevent international transmission of disease by detecting and prohibiting travel to exposed or ill travelers from affected areas [Member States and the European Commission shall consult each other within the Health Security Committee (HSC)…That consultation shall be aimed at “…supporting the implementation of core capacity requirements for surveillance and response as referred to in Articles 5 and 13 of the IHR” [The International Health Regulations (IHR) 2005 states in articles 5, 13, 18, 19, and Annex 1B that World Health Organisation (WHO) recommendations in response to a Public Health Emergency of International Concern (PHEIC) may include screening measures at points of entry. Moreover, WHO State Parties must have the capacities to apply entry or exit controls for arriving and departing travelers [the IHR” , includiSince the entry of IHR 2005 into force, the WHO Director General has declared five PHEIC according to Article 12: in 2009 the Influenza Pandemic (H1N1), in 2014 the Poliovirus situation worldwide, in 2014 and 2019 the Ebola virus disease (EVD) outbreak in West Africa and the Democratic Republic of the Congo respectively, and in 2016 the Zika virus disease ,9,10,11.As has been described in WHO technical guidance during past public health events, entry or exit screening measures are generally conducted as a two-step process: primary screening and secondary screening ,2. With Screening measures can be implemented for long-time periods for specific diseases as part of the country’s routine measures to prevent introduction of diseases to the country, or ad hoc after emergent public health events. Moreover, screening measures could be implemented massively to all inbound or outbound travelers at a point of entry, or targeted to specific travel routes  or to specific travelers . Previous attempts to assess the effectiveness of entry and exit screening measures have demonstrated either limited public health impact of such measures ,13,14, oThis paper describes the results of a scoping search and of a systematic bibliographic review aiming at giving insight on entry and exit screening referring to travelers at points of entry worldwide, with an emphasis among EU/European Economic Area (EEA) Member States (MS). Evidence from this study was used to inform EU MS in the framework of a training course conducted in 2019 about entry/exit screening structures and processes currently in place in EU MS and worldwide, as well as the strengths, limitations and lessons learnt from applying entry/exit screening at points of entry. Decision-making issues on implementing health measures that are commensurate with the risk, avoiding unnecessary interference with international traffic and trade, and considering business continuity plans are also discussed. Finally, the review explores preparedness issues and the capacities that must be in place at points of entry to implement entry/exit screening for infectious diseases. The scoping search was conducted to answer the following research questions: “What are the practices, guidelines and experiences worldwide on entry and exit screening for infectious diseases to travelers at points of entry that have been published in the past 15 years?”(1) “What are the effects, the benefits and the limitations of entry and exit screening measures for infectious diseases to travelers at points of entry that have been published in the past 15 years?”(2) Grey literature, PubMed and Scopus were searched for relevant documents published in the past 15 years using the following search terms: (exit screening OR entry screening OR border measure) AND (patient OR ill OR sick OR infected OR affected OR exposed OR symptomatic) AND (human OR passenger OR traveler OR traveler OR crew) AND (airport OR aerodrome OR airdrome OR seaport OR port OR point of entry OR port of entry). The scoping search was conducted independently of the systematic bibliographic review, which has been presented in the last paragraph of the first chapter. Inclusion criteria were: articles or reports or other documents published in peer-reviewed journals or national and international organizations’ publications, from 2003 until May 2018 that report practices, implementation of guidelines, experiences, structures, processes, evaluation results about national routine or ad hoc entry or exit screening activities referring to travelers at ports or airports or ground crossings, worldwide, performed during serious cross-border health events.Articles that refer to (a) migrants, refugees, and asylum seekers were excluded, except when related to response to a global health emergency, (b) screening of diseases that were not part of a global health emergency response, (c) entry or exit screening measures that were part of response to a specific outbreak on board an airplane or a ship and not part of a country response to a global health threat.The bibliographic review was conducted to answer the following research questions: (1) What are the public health impact and the cost-effectiveness of implementing entry or exit screening among travelers for infectious diseases at ports, airports, and ground crossings by using different assessment methods? (2) What are the good practices for implementing entry or exit screening among travelers for infectious diseases at ports, airports, and ground crossings? The specific objectives of the bibliographic review were the following: (1) Objective 1To identify practices and experiences on entry and exit screening referring to travelers worldwide by using the evidence found in the literature and reports published by competent authorities.(2) Objective 2To identify the lessons learnt from entry and exit screening referring to travelers at points of entry worldwide by using the evidence found in the literature and reports published by competent authorities or international organizations. (3) Objective 3 To critically appraise the evidence for the public health impact and/or cost-effectiveness of entry and exit screening measures implemented on a routine basis or ad hoc basis to travelers worldwide. (1) Search topic and conceptsThe research topic concerns the public health impact, the cost-effectiveness and the practices and experiences for implementing entry or exit screening among travelers for infectious diseases at ports, airports, and ground crossings, by using different assessment methods. public health event: infectious diseases in humans, (b) type of measure: entry screening or exit screening, (c) population of interest: travelers (crew and passengers) crossing borders, (d) setting: points of entry: airport, port, ground crossing, (e) outcomes: cost-effectiveness, public health impact. The search concepts used for the above-mentioned topic are: (a) For the purposes of this bibliographic review, the following definitions have been used for “entry screening” and “exit screening” terms: (a). “Entry screening” are the public health measures implemented at points of entry  on travelers (crew and passengers) arriving to a country, with the purpose to assess the exposure to a biological agent  and/or the presence of symptoms. Entry screening is part of the international and domestic policies of competent authorities to control disease spread and to minimize impact on travel and trade, which can be severely affected by absence of adequate measures or lack of capacity to implement these measures . (b). “Exit screening” are the public health measures implemented at points of entry  on travelers (crew and passengers) departing from a country, with the purpose to assess the exposure to a biological agent  and/or the presence of symptoms. Exit screening is part of the international and domestic policies of competent authorities to control disease spread and to minimize impact on travel and trade, which can be severely affected by absence of adequate measures or lack of capacity to implement these measures .(2) Search resources and termsPubMed and Scopus were searched to identify relevant publications in peer-reviewed journals. The search terms used are presented in To identify the relevant grey literature the following websites were searched: WHO , European Center for Disease Prevention and Control (ECDC), US Centers for Disease Control and Prevention (CDC), Public Health Agencies and Surveillance Centers of EU/EEA MS and non-EU EU/EEA countries and the following organizations: International Civil Aviation Organisation (ICAO), International Air Transport Association (IATA), Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation (CAPSCA), Airport Council International (ACI), Cruise Lines International Association (CLIA), International Shipping Federation (ISF), International Union of Railways (UIC), Intergovernmental Organisation for International Carriage by Rail (OTIF), Organisation for Cooperation between Railways (OSJD), International Rail Transport Committee (CIT), European Rail Research Advisory Council (ERRAC). A detailed list of all websites searched is included in Moreover, websites of WHO and of national public health institutes were searched in order to identify publicly available surveillance data about the number of cases of the diseases targeted by the screening measures and reported during the period of entry/exit screening measure implementation in the country. These were used to make comparisons with the number of confirmed cases identified through the entry screening measures. Additionally, the WHO website was searched to identify the temporary recommendations issued by WHO in response to the four above-mentioned PHEIC and recommended measures issued after other emergent public health events. Data from the WHO relevant reports were extracted about the timeframe of recommended screening measure implementation, the methods for screening, and the areas, as well as the advice for travel restrictions.Two researchers checked the documents independently  for the eligibility criteria.(1) Inclusion and exclusion criteriaThe inclusion and exclusion criteria used for the bibliographic review are presented in (1) Quality of articles appraisal The quality of articles included in the review were assessed based on completing the inclusion criteria. (2) Data extraction Type of screening Types of infectious disease or diseases that entry and exit screening was targeting Type of points of entry: airports, ports, ground crossingsScreening carried out on a routine basis or on an ad hoc basis after a public health event has occurredMethods used in entry/exit screening Type of technology used After screening, the applied diagnosis protocol Number of cases identified and the total numbers of travelers screenedPercentage of persons positive to screening finally diagnosed Percentage of persons diagnosed with a different disease from the initially targetedThe applied protocol for diagnosis and management of cases Health measures applied to the traveler and the environment General screening or targeted screening: outbound country, travelers directly arriving from affected countries, nationality, travelers in-transit Inter-sectorial collaboration and coordination processes Involved officers: public health officers, ministry officers, regional health system, national health system, NGOs, elseConcrete example of entry/exit screening Practices, experiences, and lessons learnt reportedChallenges reported Bad practices reportedMethods used to assess the public health impact of the entry/exit screening and their result Methods used to appraise the cost-effectiveness of screening method and resultsEvaluation of method results: sensitivity, specificity, false positive/negative (of screening method), positive and negative predictive valuesDecision-making level: public health officers, ministry officers, regional, national, intersectoral collaboration, health, and border authoritiesCommunication channels Notification practices between neighboring and possibly affected countriesSpecific timeframe referred and durationSpecific questions were used by the two researchers to systematically extract the data from the articles, as shown in the questionnaire presented in This bibliographic review concerns a literature review of already published material, and therefore ethics approval was not required.The scoping search identified 82 scientific articles, six documents/reports from public health agencies of countries and 26 guidelines/reports from international organizations. (a)Assessment for imported cases notification of infectious diseases(b)Dengue entry screening at airports(c)Preparedness and response planning for Ebola Virus Disease(d)Entry/exit screening measures for Ebola Virus Disease experience(e)Studies about evolution and predictions of Ebola Virus Disease spread(f)Entry/exit screening measures for infectious diseases(g)Influenza(h)Pandemic influenza preparedness(i)International air travel and infectious diseases(j)Preparedness planning for infectious disease(k)Screening measures at ground crossing(l)Sever Acute Respiratory Syndrome(m)Zika Virus DiseaseIn total, 114 identified documents of scoping research can be categorized into the following categories:The list of documents identified through the scoping search can be found in Screening measures as reported in the published literature were decided to be applied at the specific setting and situation, and generalizing conclusions was not considered to be appropriate . DiseaseData from the scoping search were used to develop the algorithm for making evidence-based decisions in implementing entry and exit screening measures . After full-text review the eligibility criteria were fulfilled by 27 articles (24 identified through databases searched and three after checking the reference lists of full-text articles). The two researchers independently reviewed and extracted data from the 27 documents by using a standardized questionnaire . As shown in (1) Airports Australia implemented entry screening measures at airports to prevent EVD , Influen(2) Ports Entry screening measures were implemented at seaports in four countries ,23,27,29(3) Ground crossings Two articles ,29 referIn Taiwan entry screening was applied as a response to public health emergencies as well as on a routine basis. In particular, entry screening was applied for Zika virus disease for a total of 10 months (January to October 2016) . MoreoveOnly Taiwan implemented entry screening on a routine basis for Dengue and Chikungunya ,10,11,15Targeted screening of incoming travelers arriving from affected countries was implemented in five countries for Influenza Pandemic (H1N1) 2009 ,26,33,39Screening measures for SARS in Canada were decided by Health Canada  and in SAuthorities and officers involved in the implementation of screening measures were ministries of health, public health officers/inspectors or public health emergency staff, custom, and border control staff, airlines, airport, and port authorities, emergency medical service units at airports/ports, airline check-in agents, flight crews, airport ambulance services, physicians, nurses, quarantine officers, regional authorities and communities and fire brigade ,20,21,26Health Canada introduced a traveler contact information form that collected contact details and information on location of stay that all inbound passengers were asked to fill in before arrival, when implementing entry screening for SARS . Upon laDuring entry screening measures for EVD implemented in the US, contact information for inbound travelers from affected countries was entered into a database and transmitted to states through CDC’s Epidemic Information Exchange (Epi-X) that is a secure notification system . As partIn Taiwan, all data and diagnostic results of cases of Dengue fever identified through screening were reported through the web-based National Surveillance System, for later tracking and management of cases . During entry and exit screening measures applied in Canada for SARS, Health Canada monitored the spread of SARS via the WHO-Health Canada Global Public Health Intelligence Network and regular communications with other international and Canadian provincial and territorial public health agencies documenting travel and illness histories of possible SARS cases who departed Canada and whose illnesses were diagnosed and reported internationally . As part of entry screening measures in Taiwan for Influenza Pandemic (H1N1) 2009, information of suspected cases was delivered to the local health bureaus via the Internet Information System for subsequent follow-up . In China information was entered into an internet-based surveillance system; all community hospitals were authorized to access the system . Regarding the screening protocols applied, both entry and exit screening included an initial assessment of exposure through completion of a questionnaire, temperature measurement, and if needed, secondary assessment by medical staff and laboratory testing. Screening measures were conducted at the point of entry facilities. One article reported that primary screening measures were conducted on board the aircraft . Some coAs far as exit screening for EVD is concerned, visual screening, health questionnaires and temperature measurement (non-contact infrared thermometer) were applied ,16,22,28Similarly, entry screening for EVD included screening of travelers by asking questions about symptoms and potential exposure risks and temperature checks ,16,22,28For exposure and/or symptoms assessment, travelers were asked to complete a questionnaire ,38,39,40Visual screening for the presence of symptoms was also part of the screening protocols ,37,38,40In all but one article included in the literature review, entry screening to in-transit travelers has not been addressed. Those in-transit travelers were screened during entry screening measures for Influenza Pandemic (H1N1) 2009 at the airport in Japan, either at the aircraft cabin or at the quarantine station at the terminal .Temperature measuring devices used to measure body temperature of travelers were electronic handheld or fixed/stationary non-contact thermometers, and ear or oral thermometers ,35,36,39Screening protocols for SARS in Canada, Taiwan, and Singapore used thermal scanning machines as part of the primary screening, while as part of the secondary screening, Australia and Taiwan used ear temperature thermometers and Canada used oral temperature thermometers ,9,35. Screening measures implemented in response to Influenza Pandemic (H1N1) 2009 in Australia, Japan, Singapore and Taiwan were conducted using stationary infrared thermoscanners ,33,36,39Entry screening measures for SARS did not identify any confirmed cases in the studies included in this review; however, cases of SARS were notified in the countries where screening took place. Entry and exit screening measures for EVD did not identify any confirmed cases. In the two  out of the five countries that implemented entry screening , EVD disease cases were imported (one case in the UK and nine in the US), but were asymptomatic during travel ,34. The The numbers of travelers screened and identified as suspected and confirmed can be found in For SARS, six out of the 46 suspected cases identified through entry screening measures for SARS were diagnosed with atypical pneumonia or chronic obstructive pulmonary disease with secondary infection or bronchopneumonia in Taiwan . SARS waIn Australia, four hospitalized persons were ultimately given an alternative or undetermined diagnosis other than the initial targeted SARS . For Influenza Pandemic (H1N1) 2009, Among 391 travelers identified as suspect cases during entry screening measures applied for Influenza Pandemic (H1N1) 2009 in Japan, five were diagnosed as influenza type A and one as type B ; while gSimilarly, two other articles ,39 descrFor EVD, during entry screening measures applied for EVD in Australia, six out of 123 screened travelers from EVD-affected countries developed symptoms compatible with EVD, and when further assessed, were diagnosed with influenza or upper respiratory tract infection . Entry sNone of the 27 articles fulfilling the eligibility criteria systematically conducted a cost-effectiveness analysis for entry or exit screening measures. Five articles addressed issues for the cost of screening measures  9,10,1515,20,23.In respect to health measures applied to the travelers during the exit screening for EVD, the ECDC technical report refers that 77 out of 36,000 screened travelers were identified and denied boarding, although none were later diagnosed with EVD . Another ECDC report concerning entry screening for EVD, describes that in the UK persons in the low and higher risk exposure categories were monitored for 21 days after leaving the country of interest by public health emergency services . The Health Canada’s protocols for airplane passenger contact tracing had evolved during the SARS outbreak and were updated during the Influenza Pandemic (H1N1) 2009 . During the implementation of entry screening measures for Influenza Pandemic (H1N1) 2009 in Japan, patients positive for H1N1 were isolated, and close contacts were quarantined . At firsIn another article  general Regarding challenges, 11 out of 26 articles refer to limitations, failures, and mishaps of applied screening measures. Samaan et al. noted that the applied screening measures may still have been ineffective due to false declarations by travelers, denying contact with people with SARS, or taking antipyretic drugs to conceal fever . Lee et Regarding screening measures for Influenza Pandemic (H1N1) 2009 , GunaratThe authors of the 27 articles fulfilling the eligibility criteria of the current review attempted to assess the impact of screening measures or commented on the impact, as presented in In The screening methods protocol design and the robustness of application can influence the effectiveness of screening measures . The expData from the systematic bibliographic review were used to develop the algorithm for making evidence-based decisions in implementing entry and exit screening measures . Evidence from this review about prevention of international transmission of disease by detecting and prohibiting travel to exposed or ill travelers from affected countries is mainly based on the measures implemented in response to EVD in Guinea, Liberia, Sierra Leone, Nigeria, Senegal, and Mali ,16,28,49An assessment of the impact of exit screening measures at ground crossings is much more challenging than at airports and seaports. The 2014/2015 Ebola outbreak spread through the population movement in the land borders of Guinea, Liberia, and Sierra Leone and was later introduced to Senegal and Mali . As repoExit screening measures may have helped to prevent extensive travel and trade restrictions, by providing confidence to the different stakeholders that measures are in place to protect the public from exportation of cases. As stated by Rhymer and Speare, travel and trade restrictions disregarding WHO recommendations were implemented worldwide in 58 (31.0%) of 187 WHO State Parties . Exit scIt is unknown how many cases would have been exported if exit screening measures at the points of entry of the affected countries would not have been implemented. Even if no case was detected through exit screening measures, concomitant benefits from exit screening measures may be of paramount importance and should also be considered when assessing impact and making decisions for health measures. Considering that all countries should be prepared to deal with unexpected events as laid down in the IHR 2005, and lessons learnt are available from past events for which temporary recommendations for exit screening measures were issued by WHO, all countries should have the capacities to implement exit screening measures at points of entry , and this should be part of the preparedness planning ,5.entry screening may have a limited effect in reducing international spread when added to exit screening, and its advantages and disadvantages should be carefully considered… if entry screening is implemented, States should take into account the following considerations: it offers an opportunity for individual sensitization, but the resource demands may be significant, even if screening is targeted; and management systems must be in place to care for travelers and suspected cases in compliance with International Health Regulations (IHR) requirements” [Since the IHR 2005 entered into force in 2007, temporary recommendations for exit screening measures have been issued by WHO as part of a set of measures to be implemented in areas affected from outbreaks [The primary objective of entry screening measures is to prevent or to delay introduction of ill or incubating cases to a country. Evidence for achieving this primary objective is based on the measures implemented in response to the EVD epidemic in West Africa in 2014/2015, SARS, Influenza Pandemic (H1N1) 2009 and Zika virus disease, as well as entry screening measures implemented on a routine basis for Dengue fever and Chikungunya infection. None of the countries that implemented entry screening for SARS detected any case ,29,35. FSeveral attempts were made by researchers to evaluate the public health impact of entry screening measures by comparing numbers of cases identified through screenings at airports with the total number of imported cases, or with cases locally acquired in the country in the same timeframe. However, the onset of symptoms was not assessed in all cases and it is not clear if the imported cases passed through screening were symptomatic or incubating. Entry screening at airports implemented on routine basis proved to be successful in Taiwan (an island) in identifying about half of the imported cases of Dengue fever ,10. TwelAccording to the results of this review, evidence suggested that the primary objective of entry screening implemented in response to public health emergencies—which is to detect imported cases at borders—was not achieved, but several beneficial concomitant effects have been reported in several instances, including educating travelers passing through the screening points, providing contacts of public health authorities to travelers in case they develop symptoms, collecting contact details for contact tracing, maintaining confidence that air travel is safe, preserving public confidence, and helping to avoid major economic, social and international impacts which even a single imported severe disease can cause ,23,25. EThe research strategy of this bibliographic review did not reveal statistical data specifically for entry screening at ground crossings. Crossing land borders for sick, symptomatic persons may be easier than moving through air or sea means of transport. The density of populations crossing land borders can be very intense or not at all from place to place. The EVD epidemic in West Africa in 2014/2015 spread between the affected countries in West Africa through land borders . This faVery limited information is available about the cost and cost-effectiveness of screening measures. General entry screening measures at airports of Australia for Influenza Pandemic (H1N1) 2009, Canada for SARS, and Taiwan for Dengue fever cost about US$50,000 per case detected (airport clinic staffing cost), a total of 7.55 million Can$ investment for a period of four months, and US$ 43,000 for each set of instruments used at screening, respectively . InvestiAlthough the inability of entry screening measures to identify cases of SARS in the 2003 outbreak was known during the public health emergencies that occurred the following years, decision-making during the Influenza Pandemic (H1N1) 2009 and the EVD epidemic in West Africa in 2014/2015 seemed to be based on other reasons. Several authors suggest that screening measures in several cases may have been implemented mainly to relieve political and social pressure, and limit negative economic consequences from travel and trade restrictions , as wellWhen temporary recommendations from WHO for screening measures have been issued in response to a public health event, then countries should have the capacities to implement such measures. Other factors of consideration are: the disease severity, the transmissibility (and whether the transmission takes place before or after symptom onset), the mode of transmission, the incubation period, the symptomatology of disease, and how easily the disease can be detected, the proportion of febrile patients, the temporal and spatial extent and the phase of the outbreak, any available results from modeling studies, the type of country, and point of entry, the disease epidemiology in the country, the volume of travelers and connections to affected areas . All theThe scoping search identified several studies reporting results of modeling that can inform decision-makers about the potential effects of entry screening measure implementation. A study modeled the number of expected Ebola infected travelers exiting affected countries, the potential effect of air travel restrictions, and the efficiency of airport-based traveler screening at international points of entry and exit . The stuIf entry or exit screening measures are decided to be implemented, detailed planning is required, with careful execution to ensure consistent application by all staff involved and to all targeted travelers. The timing (starting and stopping of screening measures), the screening methods, the technology and tools, the human resources and training issues should be considered in the preparedness and response plans. Training of staff is an important component and should address recognizing the signs and symptoms of the disease, screening procedures and documentation, and appropriate use of personal protective equipment and technology for measuring body temperature . Interview space must be available at the facilities of the point of entry as required by the IHR 2005 . The WHOThe most suitable site of primary and secondary screening should be decided: on board the conveyance, at the terminal, or before or after checking in or collecting luggage. Gaber and colleagues suggest that exit screening at airports should take place before travelers deliver luggage at the terminal, to avoid the checking-in of suitcases from infected travelers that later may need to be traced and removed . Further essential resources include capacities for laboratory diagnosis, quarantine, isolation, and treatment of suspected exposed or affected travelers. In the US, during the EVD epidemic in West Africa in 2014/2015 customs and border protection officers conducted the primary entry screening at airports and public health officers conducted the secondary screening . As suggOther issues for consideration about entry screening are the identification of targeted travelers or itineraries at ports, airports, and ground crossings, including lists of returning workers from missions in affected countries , lists of visas granted to affected countries, disclosure policies, and expert support on legal, communication, health advisory and others issues ,38. This bibliographic review showed that most of the entry primary fever screening for SARS, Influenza Pandemic (H1N1) 2009 and vector-borne diseases was conducted using thermal scanner cameras, followed when necessary by secondary screening using NCITs or contact thermometers. An ECDC technical report reviewed evidence about the accuracy of body temperature measuring devices and concluded that there are a variety of technologies available commercially; some NCITs are approved for use as diagnostic tools as happens with the contact thermometers, but thermal scanner cameras have not been evaluated for such purpose . The repResearch questions of the bibliographic review were answered based on published information; much more unpublished evidence may exist that could not be considered. Many other countries had implemented entry screening measures in response to the 2009 Influenza Pandemic (H1N1) on the European region, but very few of them published screening results and experience . DatabasScreening measures to migrants, refugees, and asylum seekers were not under the scope of this review. In case of forced migration travelers often cross borders through unofficial points (land crossings or arriving by boats at coastlines) and not the official points of entry where authorities and structures exists. In this case, the authorities that are involved in screening and the procedures are different from what is applied at the official points of entry for regular travelers. Moreover, if migrants arrive in a country at the official points of entry, each country implements its own policy in terms of targeted diseases and examinations. This review did not analyze data from screening measures to migrants. For preparedness purposes and to be ready to respond to any unexpected public health event, all countries should have the capacities to implement entry and exit screening at designated ports, airports, and ground crossings. Exit screening measures could be prioritized compared to entry measures, based on past temporary recommendations issued during PHEIC. Evidence from this review suggests that entry screening measures alone are not effective in detecting imported cases at borders, but may allow opportunities for raising awareness and educating the traveling public. The current review further suggests that there are difficulties in assessing the impact of border screening measures. Statistical data demonstrate very low detection rates of cases in both entry and exit screening. The decision about the implementation of screening measures should be examined on a case-by-case basis, after considering the disease and outbreak characteristics, the country situation, and the available resources, which can be compared to the cost and effectiveness of other alternative measures. Screening measures have important concomitant effects when implemented in combination with health education and informative strategies for travelers, the decision-making process should take those effects into consideration. Specificities at each type of point of entry  should be considered for the implementation of screening measures, since different approaches are needed for each type of point of entry. The implementation of entry and exit screening measures require planning, allocation of resources, and careful design and application of protocols. Decision-makers should be aware and consider the limitations of screening methods, including false declarations by passengers about exposure and disease signs and symptoms, use of antipyretic drugs to conceal fever by travelers, inability to detect incubating or asymptomatic travelers, language barriers, and false positive and false negative results expected from temperature measuring devices. Based on review results, an algorithm about decision-making for entry/exit screening was developed. Guidance and advice on decision-making related to entry and exit screening measures from international organizations would be helpful to countries when developing their preparedness plans, as well as when deciding about response measures to public health events. Training of staff are among the key issues for implementing a robust screening program at points of entry.


The measurement of body composition (BC) represents a valuable tool to assess nutritional status in health and disease. The most used methods to evaluate BC in the clinical practice are based on bicompartment models and measure, directly or indirectly, fat mass (FM) and fat-free mass (FFM). Bioelectrical impedance analysis (BIA) and dual energy X-ray absorptiometry (DXA)  are extensively used in epidemiological (mainly BIA) and clinical (mainly DXA) settings to evaluate BC. DXA is primarily used for the measurements of bone mineral content (BMC) and density to assess bone health and diagnose osteoporosis in defined anatomical regions (femur and spine). However, total body DXA scans are used to derive a three-compartment BC model, including BMC, FM, and FFM. Both these methods feature some limitations: the accuracy of BIA measurements is reduced when specific predictive equations and standardized measurement protocols are not utilized whereas the limitations of DXA are the safety of repeated measurements (no more than two body scans per year are currently advised), cost, and technical expertise. This review aims to provide useful insights mostly into the use of BC methods in prevention and clinical practice (ambulatory or bedridden patients). We believe that it will stimulate a discussion on the topic and reinvigorate the crucial role of BC evaluation in diagnostic and clinical investigation protocols. A direcThe most frequently applied model to evaluate body composition (BC) in clinical practice and epidemiology splits the body into fat mass (FM) and fat-free mass (FFM), i.e., the bicompartmental model. FM indicates the water-free body component; the remaining body components  are included in the FFM. The most accurate methods to measure FM and FFM according to the bicompartment model are densitometry (underwater weighing), hydrometry (deuterium dilution), Echo-MRI, and total body potassium (TBK) counting. However, these methods are characterized by complex measurement protocols and require specialized expertise and costly equipment, making their application in clinical settings limited.Bioimpedance analysis (BIA) is a widely used method to evaluate BC for both epidemiological and clinical purposes; it measures the electrical properties of body tissue and estimates BC parameters as total body water (TBW) and FFM BC parameters (see methods).BIA is a noninvasive, low cost, and reliable method for BC assessment in clinical and nonclinical settings. The basic principle of the BIA technique is that the transit time of a low-voltage electric current through the body depends on BC characteristics . HoweverDual energy X-ray absorptiometry (DXA) is the current reference method for the assessment of BC, mainly because it provides accurate estimates of bone mineral, fat, and lean soft tissue  . DXA utiThe assessment of bone health to establish diagnosis of osteoporosis and fracture risk requires DXA for evaluating bone mineral density (BMD) in selected anatomical regions of interest . In addition, DXA is capable of providing estimates of visceral fat using validated predictive algorithms  and furnThis review aims to summarize the scientific background of BIA and DXA and to furnish a comprehensive overview of their theoretical/technical concepts and application in bedridden and ambulatory patients and the information they can provide on drug pharmacokinetics.BIA measures the electrical properties of body tissues and represents a useful approach for estimating body composition parameters such as TBW and FFM. In the bicompartment model, the human body is composed of FFM, which includes, under physiological conditions, the following components: bone mineral content ≈7%), extracellular water ≈29%), intracellular water (≈44%), and visceral protein (=20%). BIA estimation of body composition is based on body fluid volume measurement using BIA resistance value [9%, intra%, extracZ, Ω), is defined as the opposition of a conductor to the flow of an alternating electrical current applied to it. Bioimpedance varies with tissue composition as well as with the frequency of the applied current. Bioimpedance is a complex parameter derived from the vector relationship between resistance , which arises from intracellular and extracellular fluids, and reactance , which is related to the capacitance of the cell membrane [2/R (cm2/Ω 50 kHz), defined as bioimpedance index (BI) measured at 50 kHz, and the volume of TBW, approximately 73% of FFM in healthy individuals.Bioelectrical impedance, or bioimpedance (membrane . AlthougSingle-Frequency-BIA (SF-BIA), generally at 50 kHz, is passed between surface electrodes placed on hand and foot. Some BIA devices use other electrode placements, such as foot-to-foot or hand-to-hand electrode . Many studies have compared multifrequency hand-to-foot (HF-BIA) and foot-to-foot (FF-BIA) bioimpedance analysis in order to assess differences in FFM values in populations with a wide range of body mass index (BMI) , 10 and R/Xc) × (180/π)), expressed in degrees) reflects the ratio between intra- and extracellular water. It may be affected by nutritional and hydration status [The phase angle, or PA  to high (500 kHz) frequencies, allows the measurement of TBW, FFM, FM, and ICW and ECW compartments. At low frequencies (1–5 kHz), the electric current does not penetrate the cell membrane, and therefore it is assumed that the current passes through the extracellular fluid. Conversely, at higher frequencies (>50 kHz), the current passes through the cell membranes and it is associated with both intracellular and extracellular fluid compartments –25. FreqBioimpedance spectroscopy (BIS) differs in the underlying, theoretical basis from the more commonly applied single-frequency BIA, because it does not require the use of statistically derived, population-specific prediction equations. One of the main advantages of the BIS is its ability to differentiate between ECW and ICW. BIS has been found to be accurate for measuring changes in fluid volumes .R and Xc (R-Xc graph), obtained at 50 kHz, are normalized to height , and plotted as bivariate vectors  for the individual vector were previously calculated in the healthy population and specific patient populations. Bioelectrical vectors are analyzed by evaluating their position with respect to reference values (tolerance ellipses): a significant decrease in body hydration shifts the vector towards the upper pole of the ellipse major axis, whereas fluid retention moves it in the opposite direction. The vector shifts along the minor axis of the ellipse according to individual soft tissue body cell mass, shifting on the left side with more cell mass.In the BIVA approach, introduced by Piccoli et al.,  R and Xc vectors . BIVA alAmong different methods of body composition measurements, DXA provides whole body and regional estimates of three main components: FM, lean body mass (LBM), and bone mineral content (BMC). Several options are available as the first choice to investigate visceral fat, such as magnetic resonance imaging (MRI) or computer tomography (CT) scanning, because they provide a quantitative and qualitative assessment of visceral  and subcutaneous  adipose tissue ,29. HoweμSv), making the technique widely applicable. Due to DXA's advantages in terms of accuracy, simplicity, availability, and relatively low expense as compared to procedures like TBK, MRI or CT IMAGING, and low radiation exposure, DXA measurement is becoming increasingly important, emerging as reference assessment technique also in muscle mass evaluation [DXA uses a source that generates X-rays, a detector, and an interface with a computer system for imaging the scanned areas of interest. The effective radiation doses involved are small . Hence, existing equations for FFM could not be used, in as much as they do not make a distinction between the amount of intracellular and extracellular water. The development and validation of specific equations is mandatory and should be the focus of future studies.Regarding PA, it is a useful parameter in clinical practice as it allows identification and monitoring of patients at risk of impaired nutritional status and decreased survival, such as HIV/AIDS, cancer, anorexia, liver cirrhosis, hemodialysis, and pulmonary disease geriatric and surgical patients , 36–40.Few studies have also addressed the possibility to apply PA in Sport Medicine to evaluate physical performance –43. SilvDespite the close correlation between nutritional status and phase angle, however, not all studies found the phase angle a reliable indicator of disease-related malnutrition. This led to the use of BIVA approach as an alternative tool to assess and monitor patients' hydration and nutrition status in several pathologic conditions, such as hemodialysis  or ambulR-Xc graph can theoretically produce identical phase angles  of the body, and four regions  so as to obtain information on the efficacy of treatment in osteoporosis and other clinical conditions related to bone turnover.Other examples of clinical indications to DXA are the following:Body composition analysis in children provides a window into the complex changes that occur throughout childhood and gives the opportunity for understanding metabolic and physiological correlations , 51, 58.DXA total body composition with regional analysis can be used in HIV patients to assess fat distribution in those using antiretroviral agents who are at risk of lipoatrophy . DXA allDXA can be used in obese subjects undergoing bariatric surgery in order to monitor lean and fat mass changes. Repeat scans could be done at 3 months after bariatric surgery. Early detection of lean soft tissue decline during weight loss may prompt clinical recommendations for increasing physical exercise and more appropriate dietary advice , 63, 64,There are no contraindications to the use of DXA in the clinical practice with the exception of pregnancy . HoweverThere is still scant awareness on the issue that responses to drugs can be affected by changes in body composition. Even though obesity and cachexia, at the extremes, may interfere with drug pharmacokinetics and pharmacodynamics at multiple levels, the most relevant effects are on drug distribution, i.e., on the diffusion of drugs from the blood to the tissues –68. GiveConversely, higher peak concentrations and shorter persistence in plasma are expected when its distribution compartment is smaller than normal, suggesting that, in these conditions, toxicity could be higher even in the setting of a lower clinical efficacy. The pharmacokinetic consequences of the expansion of drug distribution compartments have been studied in more details in general anesthesia in obese patients , 69. MorIn addition, until recently, little attention has been paid to the effects of the decrease in fat and/or fat-free mass on the pharmacokinetics of drugs in sarcopenic conditions, with the exception of few studies performed in selected pathologic conditions such as AIDS . The intThis review highlighted the relevance of body composition assessment and monitoring by BIA and DXA in the evaluation of nutritional status in several pathological conditions. However, for a wider clinical application, some issues related to these techniques should be addressed.Improving validation of BIA equations according to age, sex, and ethnicityDeveloping specific equations for under or overhydrated patientsDeveloping PA prognostic/survival predictive values in pathological conditionsAccurate validation of MF-BIA, segmental BIA, and BIS in conditions of body fluid abnormalities Future investigations on BIA could include the following:Individuating factors that affect the accuracy of the methods, such as subject's body shape and size, calibration procedures, software version, and instrumental modelsAdvanced analysis techniques that significantly reduce the impact of motion artifacts on infant DXA scansHighly standardized and reproducible patient positioning and image analysis procedures to accurately measure axial, appendicular, and segmental regions of interestAssessing how changes in fat distribution affect the accuracy of estimates/measurements, in as much as an estimated body composition by DXA changes with age, exercise, and dietFor DXA, future developments could be the following:Finally, future studies appear mandatory to better understand the relationship between pharmacokinetics and pharmacodynamics of different drugs and BC in different nutritional states.


OBJECTIVES/SPECIFIC AIMS: Our Goal is to enroll 500 students over 10 years into the CTSI 500 Stars Initiative. Student family members and community members are essential to career achievement and success; as such, the program also engages student families, along with key community members, as part of an Advisory Group, throughout the entire student experience. Besides programmatic and planning activities, students, family, and community members participate in our CTSI Community Engagement Science Café monthly series, where students may also present on a number of research and health-related topics of interest. The Advisory Group meets every 3–4 months in ensuring continuous engagement and overall program success. METHODS/STUDY POPULATION: Our Initiative takes both direct and supportive roles in offering 2 educational and training pathways; namely, our Summer Internship Program (6–8 wk duration) and our Students Modeling a Research Topic (SMART) Year-round Education Program  for high school students only. In the SMART Teams program, we work with regional public and private school districts to train science teachers, and assist them in developing and/or enhancing their science curriculum, thus creating pathways towards careers in translational science settings. Our aim is that students who participate in the year-round program  subsequently participate in our summer program. Therefore, overall program engagement is continuous throughout the year. In Summer, 2017 we engaged with well-established regional partners and collaborators  to move the translational workforce along existing regional diversity education and training pipelines. A Kick-off event was held on June 15, 2107 and attended by students and family members. We offered 6–8 weeks of hands-on experiences working with faculty researcher mentors and their research teams conducting real-life studies, in addition to professional experiences in research “support” settings, as well as in the community. We also developed established a “Summer” SMART (Students Modeling a Research Topic) Teams Program and a Summer “Advanced” SMART Teams Program, where a number of students were placed at 2 CTSI partner and collaborator institutions. The primary goal of the SMART Teams experience is to introduce students to translational science by building upon laboratory research to better understand clinical and community impact of disease within a patient population. Overall, internship sites included research labs, protein modeling labs, numerous research support settings, clinical care settings, and community sites for those students who were interested in population health sciences. In addition, students were offered career enrichment and professional development lunch and learn sessions, career panel sessions presented by long term, expert professionals in various fields translational science, and confidence building and networking sessions. Students also participated in a community volunteer day activity, a trip to the Chicago Science Museum, and numerous CTSI engagement activities . RESULTS/ANTICIPATED RESULTS: The 2018 year-round program will initiate in the Fall. Our 2017 Summer Internship Program received 192 students/trainees applications of whom 133 were underrepresented minorities (URMs). We enrolled 109 participants, including 83 URMs (84 high school students and 25 college students). A total of 53 Wisconsin high schools and 19 colleges and universities  participated. Students engaged in all activities as outlined in the Methods section. At the end of the summer program, students created and presented posters as part of the closing ceremony. Certificates of completion were given to the students by program leadership and the Al Hurvis/ADAMM leadership (program funding agency). Students wore white lab coats to create an atmosphere of cohesion and accomplishment. Parents and other family members attended the closing ceremony, demonstrating strong support for students and the program. Our anticipated results for CTSI 500 Stars Initiative is to increase diversity in the Translational Science Workforce via education and training of 500 high school and college students over 10 years. We will also remain engaged and track student’s various venues for at least 10 years to determine the outcome of their experiences towards careers in Translational Science settings. We will continue to engage community members and community-based organizations as collaborators and advisors to participate in every stage of our activities. Moreover, we plan to broaden our reach by establishing additional relationships with additional high schools and middle schools to further enhance the 500 Stars Initiative. In addition, we will develop metrics by which to measure the validity and success of our program. DISCUSSION/SIGNIFICANCE OF IMPACT: The aim of the CTSI 500 Stars Initiative is to provide real-life, practical experiences in translational science settings as a part of our efforts to train and cultivate the translational science workforce, while also engaging patients, families and community members in every phase of the translational process. Targeting under-represented minority students contributes towards increasing diversity in the workforce. It is also our hope that by increasing URMs in the workforce, there will be positive impact on communities of color, with respect to increasing participation in their health care decision making and in clinical/translational research; thus, ultimately leading to better health outcomes in the communities we live and serve. Our overall framework is to engage, educate, enrich, empower, elevate, enable students towards careers in clinical and translational settings.