Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis.All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup ; and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients.The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences. Though involvement of the extracranial branches of the carotid artery can be identified in the classic cranial GCA, GCA may also involve aorta and its major branches, predominantly branches of the proximal aorta, that is, subclavian, axillary proximal brachial arteries, representing a subset of patients with large-vessel GCA (LV-GCA).,5 Vasculitis, if untreated, can result in ischemic complications, such as ischemic optic neuropathy, which is responsible for vision loss in 10% to 15% of patients. Whereas the etiology of PMR/GCA is still unknown, genetic and environmental factors may play roles in the development of PMR/GCA. GCA and PMR share many pathogenetic and epidemiological features, and are frequently thought to represent different spectrums of the same clinical entity. Despite the high association between PMR and GCA, it is essential to differentiate these 2 conditions due to different steroid treatment regimes. Corticosteroids are considered the treatment of choice for PMR/GCA, with higher doses required for GCA.–3 PMR/GCA is generally not associated with reduced longevity; however, patients with aortic aneurysm/dissection have higher rates of mortality. Additionally, patients are at risk of different comorbidities, both due to the disease characteristic itself and also due to treatment side effects.Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease that affects individuals over the age of 50 years. The typical symptoms of PMR are bilateral aching and stiffness in selected muscle groups, predominantly in the neck, shoulders, upper arms, and pelvic girdle that are most pronounced in the morning and improve with physical activity.–3 In cases of suspected GCA, temporal artery biopsy (TAB) should be performed to confirm the diagnosis. However, it is invasive, it can be false-negative in a proportion of patients, and it does not delineate the extracranial component of the disease.,8 Laboratory findings are nonspecific in PMR/GCA. Marked elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently seen in PMR/GCA. Thrombocytosis, anemia, and increased alkaline phosphatase may also be presented.,3 Different imaging modalities, for example, ultrasonography (US), magnetic resonance imaging, and angiography, are helpful in the diagnosis of PMR/GCA; however, use of these modalities may be limited due to long assessment time for wide vascular assessment, interobserver variation, invasiveness, diminished sensitivity, specificity, and so on.–11 There have been several proposed diagnostic criteria for PMR.–15 The core components included in these diagnostic criteria were as follows: an age cut-off point, bilateral shoulder or hip pain, morning stiffness, elevated ESR, elevated CRP, rapid steroid response, and disease duration. In 2012, the provisional classification criteria for PMR has been published by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR). However, it is worth mentioning that these are classification criteria and are designed to differentiate PMR from other diseases that mimic PMR and are not useful to make the diagnosis. Furthermore, the specificity of the 2012 provisional classification criteria for PMR seems to be not sufficient, despite high sensitivity.Accurate diagnosis of PMR/GCA can be challenging since various diseases mimic these conditions and there are no specific diagnostic tests. PMR is a clinical diagnosis. Careful clinical evaluation and exclusion of several mimics of PMR/GCA can support the diagnosis.,18 The most versatile and widely used tracer, 18F-fluorodeoxyglucose (FDG), is a glucose analog depicting local hypermetabolism . In the clinic, it has mainly been used to detect focal hypermetabolism due to cancer, and the impact in the oncologic domain has been huge as PET/CT appears to cause a change in management in as many as every third patient. However, FDG is nonspecific for cancer as inflammatory lesions also show increased FDG uptake. This was until recently seen as a downside resulting in “false-positive” findings in oncology, but is now considered a great asset, since this allows for detection and characterization of inflammatory processes in many settings. 18F-FDG PET/CT is being investigated clinically in a multitude of inflammatory disorders. High sensitivity, high target-to-background contrast, accurate anatomical localization of sites of inflammation, and an absolute quantification potential may all lead to early assessment of disease processes and their extent.Positron emission tomography/computed tomography (PET/CT) is a whole-body scan combining molecular and structural imaging in a single examination. The principle is tomographic detection of radiation from intravenously administered radio-labeled tracers targeting disease processes on a cellular or molecular level. Due to its high sensitivity and an inborn ability for quantification, PET can detect diseases at their very early stage and grade their degree of activity. Besides locating focal disease, 18F-FDG PET/CT may also assess disease activity more globally, which may be especially interesting in systemic inflammatory diseases. Thus, this research protocol will also incorporate assessment of global disease assessment , a novel approach to quantifying disease. By way of novel software-based quantitative methods, the radioactivity throughout the body can be quantified, summed, and presented as 1 single number, the systemic inflammatory activity or “global disease burden.” The method is new and not yet firmly established, but it holds significant promise, especially for response assessment in systemic inflammatory diseases.,23With regard to vasculitis, recent literature emphasizes the ability of 18F-FDG PET/CT to assess inflammation in the vessel walls, whereas FDG uptake patterns in PMR are not yet firmly established. It may locate disease at an earlier stage than conventional imaging and assess response to therapy. Response assessment is based on changes in glucose metabolism from baseline to post-treatment follow-up, and the rates of change are different in responders and nonresponders.Therefore, we plan to conduct a prospective study to explore the role of 18F-FDG PET/CT scan in the management of PMR/GCA. In addition, 3 significant areas of concern in the management of PMR/GCA including: osteoporosis due to steroid treatment or disease characteristics itself, malignancy, and vasculitis/vascular stiffness will be investigated during the project. This research protocol consists of four separate studies designed to achieve below mentioned objectives that are discussed individually later in the text  and the clinical picture of PMR/GCA.2.21.To investigate the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy.2.To compare the efficacy of nationally recommended conventional diagnostic workup to detect occult malignancies in the setting of PMR/GCA  with 18F-FDG PET/CT at diagnosis and during the first year after diagnosis.3.To evaluate the influence of inflammation on regional and total bone mineral density (BMD) and body composition, and also vasculitis/arterial stiffness of aorta at diagnosis of PMR and within a year after treatment initiation with prednisolone.2.3 This research protocol will also adhere to the EULAR recommendation. Thus, 2 PRPs (co-authors Hanne Andersen and Rudolf Olsen) were invited to help us design the study. The involvement of PRPs with respect to 8 significant aspects of EULAR recommendation is depicted in Table Active collaboration between patients and researchers is relatively a new concept in the research field which is a useful tool to capture the patient perspective. By means of this, better representation of patients’ needs and uncertainties can be secured. It additionally avoids potential mismatch between patients’ preferences and researchers objectives. EULAR has introduced the recommendation for the inclusion of patient representatives in scientific projects.33.1The current study will be performed at the Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Svendborg, Denmark. The Rheumatology Department of Svendborg Hospital has the capacity of enrolling PMR/GCA patients that are required for this study, since all patients from all over Funen County with suspicious PMR/GCA will be referred to the Diagnostic Center for primary investigation at Svendborg Hospital. After confirmed PMR/GCA condition the patients will be referred to the local Rheumatology department for study inclusion. The CT-part is a low-dose CT without contrast enhancement.All parts of the project will take place at Svendborg Hospital, except the 18F-FDG PET/CT scans and bone densitometry, which will be undertaken at the Department of Nuclear Medicine and Department of Endocrinology, respectively, Odense University Hospital, Odense, Denmark. The 18F-FDG PET/CT will be performed as routine whole-body scan (from vertex of the skull to the knees) 60 minutes after injection of a weight-adjusted dose of FDG according to the guidelines from the European Association of Nuclear Medicine.3.2The study was conducted till 1 year after the enrollment of last patient.3.3 For GCA, the following criteria must be considered: age >50 years, ESR/CRP >50, and also at least 2 symptoms related to vasculitis  if patients do not simultaneously have PMR. If the patient is suspected for PMR, 1 cranial symptom is enough to suspect GCA. Besides, clinical suspicion of LV-GCA, that is, upper-extremity claudication, upper-extremity blood pressure discrepancies, and abnormal radial pulse, will be registered.All new patients with clinical suspicion of PMR/GCA will be offered to be included in the study. At least 5 (A–E) components of the PMR diagnostic criteria, including: age ≥50 years, bilateral shoulder or hip pain, morning stiffness lasting >45 minutes, elevated ESR, elevated CRP, disease duration >2 weeks, should be met to suspect PMR.1.Patients with dementia or inability to communicate in Danish2.Infections or malignancy when prednisolone is permanently unsuitable3.Contraindication to imaging studies (pregnancy and blood sugar [BS] >8 mmol/L after 6 hours fasting)4.Initiation of steroid treatment before the 18F-FDG PET/CT scan5.Inability to provide informed consentThe exclusion criteria (study I–IV) are as follows:3.43.4.1,26–28 However, the small sample size was a major limitation. On the contrary, some reports failed to show this correlation.,29,30The current study is a 1-year prospective, blinded, and explorative study. This is the first study of its kind, to our knowledge, to evaluate the association between the clinical picture of PMR/GCA and 18F-FDG PET/CT findings in a prospective setting. Previous study revealed the correlation between serological markers of inflammation and FDG accumulation in PMR.All included patients initially will undergo an 18F-FDG PET/CT scan. The results of the 18F-FDG PET/CT scans will not be made accessible to the treating physician in daily clinical routine, but unexpected findings or findings requiring further diagnostic tests or intervention will be relayed to the chief physicians responsible for inclusion. The results of 18F-FDG PET/CT scan will be blinded for both the clinicians and patients. During the year after the initial 18F-FDG PET/CT scan, the following clinical data will be monitored: cumulated prednisolone doses (using patient diaries), well-being of the patients , ESR, CRP, fibrinogen, and the eventual number of relapses. Definition of remission and relapse is based on expert opinion considering the following parameters: patient's assessment of pain, morning stiffness, ESR, CRP, clinical examination findings , and steroid dose which is required to control symptoms. which is based on more elaborate, and therefore technically cumbersome, computations involving segmentation, quantification, and summing of all FDG-avid lesions with pathologic activity defined by predetermined threshold. These metabolically active volumes (MAVs) will be summed to yield a global disease score, a metabolic volume product (MVP) of all PET-positive lesions throughout the body. This seems to be a very robust method, but also somewhat cumbersome to implement in daily clinical practice.After 1 year, the 18F-FDG PET/CT results will be unveiled and these parameters will be compared in the succeeding groups of patients: patients with vasculitis in the large vessels (PET-positive); patients without vasculitis in the large vessels (PET-negative); patients with findings compatible with PMR (PET-positive); and patients with vasculitis in the large vessels together with findings compatible with PMR (PET-positive). The classification of 18F-FDG PET/CT results (PET +/−) is based on visual assessment in a descriptive manner, and also quantitative methods. The visual assessment is based on simple visual assessment of FDG uptake patterns in a descriptive manner (PMR) and a 4-point scale of FDG uptake in the vessels (GCA). The visual assessment will be compared with simple semiquantitative analyses, that is, so-called maximum standard uptake value (SUVmax), a simple delineation of the single voxels with the highest tracer uptake. This is a simple procedure available with the generic software indigenous to the scanners and provided by the vendors, for example, in our case, GE Advantage Server 2.0 . It is easily applicable in clinic, but highly variable and prone to both technical and patient related pitfalls. Thus, a third method of quantification will be employed and compared with the visual assessment and SUVmax, that is, global disease burden,3.4.1.1,27–29 will be used for every arterial segment as follows:0: No uptake1: Slight uptake but not negligible, lower than liver uptake2: Intermediate uptake, similar to liver uptake3: High-grade intense uptake, higher than liver uptakeImages will be reviewed by 2 nuclear medicine specialists at the Department of Nuclear Medicine at Odense University Hospital who are blinded to clinical and laboratory data. FDG uptake patterns will be recorded in a descriptive manner with regard to nonarterial uptake and recorded in 6 arterial compartments for each individual patient including thoracic and abdominal aorta, carotid, subclavian, femoral, and iliac arteries. A visual 4-point scale, as described by earlier studies,A score of ≥2 and <2 will be considered PET-positive and PET-negative, respectively. SUVs will be measured for quantitative analysis for each arterial segment and calculated as follows: Global disease burden will be expressed as follows:cMVP = ∑ (MAV∗cSUVmean), wherecMVP = partial volume corrected metabolic volume product,MAV = metabolic active volumes, andcSUVmean = partial volume corrected mean standard uptake value3.4.2 However, the superiority of 18F-FDG PET/CT scan in comparison with TAB is still arguable. This study will compare 18F-FDG PET/CT scan to TAB. As mentioned in the study I, all included patients will undergo an 18F-FDG PET/CT scan. In addition to 18F-FDG PET/CT scan, TAB will be performed before or within 1 week of steroid treatment initiation. TAB will be taken by experienced otolaryngologist at Department of Ear, Nose and Throat, Svendborg Hospital. The results of biopsy will be compared with the 18F-FDG PET/CT findings after 1 year, when the 18F-FDG PET/CT results are revealed and compared with regards to the degree of agreement between the 2 modalities.,34Recent literature is in favor of the ability of 18F-FDG PET/CT scan to detect vasculitis at an early stage, which is important to decide on treatment plan.3.4.2.1In patients with lateralizing symptoms, the biopsy will be taken from the symptomatic side. The superficial temporal artery will be palpated and marked with a surgical marker. The site will be shaved if is necessary. Local anesthetic will be injected into the skin and subcutaneous tissue corresponding to planned incision using lidocaine 1% with or without adrenalin. Under sterile condition the incision will be made at the previously marked skin site. The incision should be large enough to uncover 2 to 3 cm of the vessel. The dissection will be carried through the subcutaneous fat and the artery will be identified just beneath the temporoparietal fascia. The artery will be ligated proximally and distally, and so the intervening segment will be cut out and fixated in formaldehyde. The in vivo specimen should be minimum 1.5 cm in length. At last, skin will be sutured using non-absorbable suture material.3.4.2.2The biopsy will be fixed in formalin for 24 hours, divided in sections of 3 to 4 mm, embedded in paraffin, cut in step sections, and stained with Weigert elastin and hematoxylin and eosin (H&E), respectively. Additional sections will be cut for later analysis. Some of the additional sections will include deeper sections in the block to further evaluate the extent of the lesion. The additional analysis will include immunohistochemistry for inflammatory cells, proliferation markers and markers of fibrosis.3.4.3 Another study utilized the UK General Practice Research Database and evaluated cancer risk in 2877 patients with PMR, without pre-existing cancer or vascular disease and treated with corticosteroids, who were matched with up to 5 age, sex, and general practice patients without PMR. Over a median follow-up of 7.8 years, 23.2% of patients with PMR developed cancer compared with 19.5% of controls. The risk of malignancy was increased in patients with PMR during the first 6 months after diagnosis . However, the risk of misclassification/misdiagnosis in database studies is notable, which also points out the need for studies with prospective design. Danish Rheumatology Association recommends the screening for malignant diseases in PMR/GCA patients. Various malignancies can cause PMR-like symptoms; therefore detailed assessment to exclude occult malignancies seems to be rational, especially in patients with atypical manifestations.,38 Patients with malignant disease may also present with remitting seronegative symmetrical synovitis with pitting edema, which is a closely related condition to PMR.,40The relationship between PMR/GCA and malignancies remains controversial. There are several reports regarding the association of PMR and malignancies. In a database study from Sweden, where 35,918 patients after hospitalization for GCA and PMR were included, there was a marginally increased incidence of cancer in patients with GCA compared with the general population . However, when evaluating malignancy risk in the first year after diagnosis of PMR or GCA, the standardized incidence ratio was 2.26 (95% CI 2.10–2.42).This study is a blinded prospective investigation. At diagnosis all patients undergo a CXR and abdominal US, as recommended by the Danish Rheumatology Association. The 18F-FDG PET/CT scan in every included patient (as described in study I) will be assessed with regards to malignancies before results are blinded to the clinicians for 1 year. This assessment will be blinded to other clinical and imaging results and findings on 18F-FDG PET/CT scan will be compared with CXR/abdominal US results to establish the relative diagnostic accuracy of these 2 strategies for malignant and infectious diseases in PMR/GCA patients. In case of detecting or developing any kinds of malignant disease during the study, the patients will be referred to the relevant department for further work-up and treatment. This will not be a reason for exclusion, but depends on individual assessment of the patient. 18F-FDG PET/CT scan may also be repeated for individual patient if necessary.3.4.4–43 Patients with PMR/GCA are also exposed to different changes in body compositions mainly due to inflammatory process; however, this has not been evaluated before.Patients who are diagnosed with PMR/GCA are at high risk of osteoporosis due to both disease inflammatory process and corticosteroid treatment. Nonspecific bone protection (lifestyle intervention) should be initiated at the time of steroid therapy, and specific antiosteoporotic therapy soon thereafter in patients with low BMD. The gold standard for the diagnosis of osteoporosis is regional dual energy X-ray absorptiometry (DXA) of the hip and spine. Whole-body DXA can estimate 3 body compartments consisting of fat mass (FM), lean body mass (LBM), and bone mass. DXA is currently considered the gold standard for body composition assessment. Changes in whole body bone mineral content (BMC) is a biological meaningful measure of overall calcium balance over a time period, whereas changes in regional BMD are probably more predictive for fracture risk. Changes in body composition due to inflammatory process have previously been reported in rheumatoid arthritis. The extent of large artery involvement of GCA is uncertain, but clinically apparent large-vessel disease comprises an estimated 9% to 14% of cases. ,45 LV-GCA patients have symptoms and signs of vascular insufficiency and are usually diagnosed with delays due to atypical manifestations, and also inadequacy of GCA criteria for classifying these patients.The vasculitis process in patients with classic cranial GCA preferentially involves the extracranial branches of the carotid artery; however, large vessel involvement of the aorta and its primary and secondary branches may be involved in patients with LV-GCA.,47 Pulse wave velocity (PWV) measurement is a simple, noninvasive, and reproducible method to evaluate aortic stiffness, and can be measured from different arterial sites. Common carotid artery and the femoral artery are 2 common sites to obtain pressure waveforms transcutaneously. The distance covered by the waves is corrected to the surface distance between the 2 recording sites and base of aorta , and the time delay (or transit time) is measured using the feet of the 2 waveforms . PWV is subsequently measured as the ratio of the distance to the time delay (PWV [m/s] = distance [m]/transit time [seconds]). Previous study was in favor of that PMR is associated with increased aortic stiffness which may improve upon reduction of systemic inflammation induced by treatment with glucocorticoids.Arterial distensibility has been defined as a measure of the artery's ability to expand and contract with cardiac pulsation and relaxation. Vasculitis and other risk factors  may cause alteration in the structural and functional properties of the arterial wall, which results in diminished arterial distensibility. When evaluating arterial stiffness, the aorta is a main vessel of interest, because of substantial contribution of abdominal and thoracic aorta to the arterial buffering function.1.PWV measurement of aorta at baseline and then every 3 months to assess large vessels involvement (aorta). The results of PWV assessment, which will be automatically calculated from measurements of pulse transit time and distance between the 2 sites, will be compared with vasculitis found in the 18F-FDG PET/CT (study I). The results of PWV of aorta will also be assessed regarding the actual cumulated prednisolone dose to find out the effects of steroid treatment on the arterial stiffness.2.Whole-body DXA scan at baseline and after 1 year from the initiation of study to evaluate BMD and body compositions. The degree of the difference in the T score and body composition  will be compared with the cumulated prednisolone dose and the total global disease burden of the 18F-FDG PET/CT scan at baseline (study I).This study is a 1-year prospective investigation which assesses 2 different areas of concern in PMR/GCA patients, namely BMD plus body composition and vasculitis/vascular stiffness of large vessels (aorta). The following procedures will be performed in all included patients:3.4.4.12. Individuals with BMI values <18.5 kg/m2 are considered underweight, 18.5 ≤ BMI < 25 as normal, 25≤ to <30 as overweight. BMI values ≥30 indicates obesity. LBM, FM, BMD, BMC, and fat-free mass (FFM = LBM + BMC). FM and FFM will be expressed as absolute kg and FM as percentage of total mass as well. The reference value for FM% is 12% to 20% for men and 20% to 30% for women. FFM and fat mass indices (FFMI and FMI) will also be calculated. An aged and sexed matched European reference from Switzerland will be used for cut-off values for being under lean and obese.Body mass index (BMI) of patients will be calculated from weight/heightBone mineral density values will be presented as Z scores  and T scores . T score ≤−2.5 will be considered as osteoporosis and T score <−1 as osteopenia.3.4.4.2After measuring blood pressure (BP), aortic  and upper limb  PWV will be measured using SphygmoCor device. Aortic PWV will be calculated from measurements of bulbus aorta and femoral artery, and upper limb PWV will be calculated from measurements of bulbus aorta and radial artery waveform. Aortic augmentation index  with a standardization to a heart rate of 75 beats per minute will also be assessed, which is a predictor of adverse cardiovascular events.3.5Blood pressure, pulse, weight, and also BMI of all patients will be collected at the first visit. The following laboratory tests will be recorded: hemoglobin, white blood cells and thrombocytes, erythrocyte sedimentation rate, C-reactive protein, sodium, potassium, lipid profile, thyroid-stimulating hormone (TSH), hemoglobin A1c (HbA1C), blood sugar, creatinine, liver function test (LFT), alkaline phosphatase, calcium, vitamin D, creatine kinase, immunoglobulin A, immunoglobulin M, immunoglobulin G, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), IgM rheumatoid factor (IgM RF), anticyclic citrullinated peptide (anti-CCP), S-fibrinogen, prostate-specific antigen (PSA), M component (blood and urine), serum-free light chains (sFLC), urine protein, urine analysis, and electrocardiogram.3.63.6.1Steroid treatment is based on a modification of the Danish Rheumatology Association Guidelines. Dose reduction or dose increase is also according to this guideline. Prednisolone will be initiated after performing 18F-FDG PET/CT scan Table .3.6.2Calcium (1200 mg/d) plus vitamin D (800 U/d) and 70 mg alendronate weekly (if Tscore <−1) will be prescribed to reduce risk of fracture.3.7Detailed follow-up plan is summarized in Table In addition to the mentioned investigations, patients will be invited in a coming investigation to perform a magnetic resonance of aortae, and also heart CT scan after completion of the study, to evaluate the risk of aneurisms, especially in the patients with PET positivity of the large vessels. Furthermore, a PWV measurement will also be done at that time.3.81.To evaluate the cumulated prednisolone doses, VAS, patients’ assessment of pain, morning stiffness, VAS for physician evaluation, biochemistry results, that is, ESR, CRP, and fibrinogen, and the eventual number of relapses at baseline and during the first year after treatment initiation  in patients with PET-positive and PET-negative as described above.The primary outcome measure are as follows:1.To elucidate the degree of agreement between PET positivity  and TAB positivity.2.To elucidate the degree of agreement between PET negativity (no signs of vasculitis in the large vessels) and TAB negativity.3.To reveal the prevalence of malignancies in the patients detected by the aim of 18F-FDG PET/CT scan and subsequently compare to the prevalence of malignancies detected by the aim of CXR plus abdominal US.4.To reveal the prevalence of malignancies in the patients detected by the aim of CXR plus abdominal US and subsequently compare to the prevalence of malignancies detected by the aim of 18F-FDG PET/CT scan.5.To evaluate BMI, T score, Z score, LBM, FM, BMD, BMC, FFM, FFMI, and FMI at baseline and after 1 year of treatment initiation.6.To evaluate aortic PWV, upper limb PWV, and aortic augmentation index of included patients at baseline and during treatment .The secondary outcome measures are as follows:3.9This study is, to the best of our knowledge, the first of its kind; hence, formal power calculations were impossible to conduct due to missing information from previous literature or local clinical daily routine. In this exploratory study, the number of patients to be included was set to 80, which enables the assessment of the primary objective, that is, the difference in the cumulated prednisolone dose within the first year after diagnosis between groups including a respective 95% CI, with sufficient precision. Moreover, 80 patients are deemed appropriate to assess the secondary objectives for hypothesis generating purposes.3.10All patients with the suspicion of PMR/GCR are referred to the Diagnostic Center, Svendborg Hospital. After primary investigation and evaluation, the eligible patients will be referred to the Rheumatology Department of Svendborg Hospital for formal enrolment in the study. Patients will be informed orally and written about the voluntary nature of the participation and project objectives, content, risks, and benefits. A deliberation time of 24 hours will be considered from submission of the oral and written information to obtain informed consent. Consent statement will be reviewed, signed, and dated by the patient and handed over to the department. The patient receives a signed copy of the consent form and be informed of that he/she can withdraw from the study at any time without any reason nor consequences. A scanned copy of patient consent will be added to the patient electronic hospital record, and one additional copy will be stored in a locked room at the department.3.11A PhD student will be responsible for collecting data elements from patient medical records, including: demographic data, vital signs , weight, BMI, results of laboratory tests, ECG, and diagnostic tests , and also cumulative prednisolone dose. Data will be entered into the University of Southern Denmark Research Electronic Data Capture (REDcap) database twice to minimize data entry errors.3.12P value <0.05. Statistical analysis has been discussed below with respect to each individual study.It is anticipated that 80 participants are likely to be included during a period of 1 year. The results will be considered as significant if U test or Student t test, depending on whether or not the distribution is normal. When comparing 2 binary variables, the chi-square test will be performed. Correlation analysis will be performed with Pearson correlation test.In study I, data will be descriptive (mean ± standard deviation). Comparisons of the data, between the PET-positive and PET-negative patients, will be made with the Mann–Whitney Study II consists of descriptive statistics and proportions of agreement.Study III consists of descriptive statistics. Comparisons between groups will be made with McNemar test. The sample size of 80 patients is sufficient to indicate a difference of 15% in detection rate of malignancies with 18F-FDG PET-CT scan as opposed to CXR plus abdominal UL (with a significance level of 5% (1-sided), power of 80%, and assuming discordant proportions of 15% and 0%).U test or Student t test, depending on whether or not the distribution is normal. When comparing 2 binary variables, the chi-square test will be performed. Analysis of repeated measurements over time will be done by means of mixed linear models, using standard errors that allow for intragroup correlation, relaxing the usual requirement that the observations be independent. Comparison of the above mentioned baseline data, matched by age and sex, will be made, to the extent that these data are available.Study IV consists of descriptive statistics. Univariate comparisons between groups will be made with the Mann–Whitney 3.13Initial and control blood samples will be taken regarding the routine management of PMR/GCA patients. There is no further risk, for example, pain or infection for included patients compared with other patients not participating in this study. The outpatient visit may take longer time due to systematic history taking and physical examination, PWV assessment, and so on, which is a disadvantage for a busy patient.An 18F-FDG PET/CT scan exposes a patient to about 8 mSv radiation. The average per capita background radiation is 4 mSv per year in Denmark. The average lifetime risk of cancer is approximately 25% for a 25-year-old person in Denmark. The radiation dose from one 18F-FDG PET/CT scan increases this risk to approximately 25.01%. In persons above 50 years of age, the increased risk is even less.Due to increased rate of malignancy in PMR/GCA, patients may benefit from 18F-FDG PET/CT scan, which detects possible concurrent malignancies.Whole-body DXA scan will be performed at baseline and a year after which is appropriate for patients receiving steroids. Evaluating fat mass takes place during the same session and extends the study by about 5 minutes which is acceptable. The radiation dose of whole-body DXA is negligible.Vascular stiffness will be measured by SphygmoCor in conjunction with routine outpatient controls. This method is completely noninvasive and takes about 15 to 30 minutes.Although performing 18F-FDG PET/CT scan together with TAB is a disadvantage of this study, patients are hopefully not required to do TAB in future. TAB may still be required in small number of patients.3.14The present study protocol is approved by the Regional Ethics committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). This study is also registered at clinicaltrials.gov .3.15Any modifications to the protocol which have substantial effects on the conduct of the study, potential benefits to the patient or impact on patient safety, including changes to eligibility criteria, patient population, sample size, study objectives, study design, study procedures, and treatment plan will require a formal amendment to the protocol. Such amendment will be sent to the Ethics committee for further approval before implementation. Administrative changes of the protocol defined as minor corrections having no effect on the way the study is to be conducted will be documented and the Ethics committee may also be notified of them.3.16The PhD student is responsible for obtaining informed consent from potential participants or authorized surrogates. All participants will be informed about the voluntary nature of the participation in the study and will be received detailed information about diagnostic and treatment modalities.3.17The PhD student will give a unique code to each participant which will be used to identify them during the study. Any kinds of paper reports, laboratory specimens, administrative form, and so on will be identified by theses codes. All data collection sheets, patients consent forms, daily registration chart, and so on will be secured in an office with limited access. All digital files will be saved in our local databases which are password protected.3.181.The clinical picture in PMR/GCA patients with and without PET detected vasculitis.2.Validity of 18FDG PET-CT scan for diagnosis of PMR/GCA compared with TAB: An agreement study.3.Prevalence of newly diagnosed malignancies in PMR/GCA patients with the aim of 18F-FDG PET/CT scan and CXR/Abdominal US: A blinded prospective study.4.Effects of steroid treatment on Bone mineral density and body composition in PMR/GCA patients: A prospective study.5.Effects of steroid treatment on vasculitis/vascular stiffness of PMR/GCA patients with the aim of PWV measurement: A prospective study.The current study is a large-scale study and will form the basis of a PhD thesis. The hard copy of our work will be available at the University of Southern Denmark library once completed. The results of the study are intended for the following potential papers (preliminary titles) that will be sought published in international peer reviewed journals, or presented at International or national congresses orally.After the completion of data collection, no later than 3 years, we will deliver a deidentified dataset to a suitable data archive for sharing purposes.4 Patients with positive 18F-FDG PET/CT findings will be classified as having GCA and not isolated PMR, which is of great importance in the clinic due to different steroid treatment regimes. Besides, GCA patients with aortic involvement are at increased risk of aneurysm formation, who seek close monitoring. It is our hope that our results elucidate the 3 main areas of concern regarding the management of PMR/GCA including: malignancy, osteoporosis/changes in body composition, the vasculitis process, and the interaction between them, and ultimately elucidate factors predictive of the disease outcome.The proposed study will explore the potential role of 18F-FDG PET/CT scan in the early diagnosis and management of PMR/GCA before initiation of steroid treatment, and also the association between 18F-FDG PET/CT findings and the clinical picture of the patients. Though 18F-FDG PET/CT is not yet capable of evaluating temporal artery due to inadequate resolution, the extracranial involvement of large vessels, mainly thoracic aorta, carotid, and subclavian, can be delineated.We thank Professor Kim Hørslev-Petersen, DMSci, for his insightful comments.


Mucormycosis is a rare but devastating fungal infection primarily affecting immunocompromised patients such as those with hematological malignancy, bone marrow and solid organ transplantation, and patients with diabetes, and, even more rarely, immunocompetent patients. The objective of this study was to assess the prevalence and burden, both clinical and economic, of mucormycosis among hospitalized patients in the U.S.TM Comparative Database, with more than 560 participating hospitals covering 104 million patients (January 2005-June 2014). All hospitalizations in the database were evaluated for the presence of mucormycosis using either an ICD-9 code of 117.7 or a positive laboratory result for Mucorales. Hospitalizations were further required to have prescriptions of amphotericin B or posaconazole to be considered as mucormycosis-related hospitalizations. The prevalence of mucormycosis-related hospitalizations among all hospital discharges was estimated. Mortality rate at discharge, length of hospital stay, and readmission rates at 1 and 3 months were evaluated among mucormycosis-related hospitalizations. Cost per hospital stay and average per diem cost (inflated to 2014 USD) were reported.This is a retrospective study using the Premier PerspectiveThe prevalence of mucormycosis-related hospitalizations was estimated as 0.12 per 10,000 discharges during January 2005-June 2014. It increased to 0.16 per 10,000 discharges if the definition of mucormycosis was relaxed to not require the use of amphotericin B or posaconazole. The median length of stay was 17 days, with 23% dead at discharge; readmission rates were high, with 30 and 37% of patients readmitted within one and three months of discharge, respectively. The average cost per hospital stay was $112,419, and the average per diem cost was $4,096.The study provides a recent estimate of the prevalence and burden of mucormycosis among hospitalized patients. The high clinical and economic burden associated with mucormycosis highlights the importance of establishing active surveillance and optimizing prophylactic and active treatment in susceptible patients.The online version of this article (doi:10.1186/s12879-016-2023-z) contains supplementary material, which is available to authorized users. Mucormycosis (formerly known as zygomycosis) is an uncommon, opportunistic fungal infection primarily caused by Mucorales, a filamentous fungus of the Mucormycetes class. This particular fungal infection typically shows a rapid progression and primarily affects patients with diabetes mellitus or compromised immune systems, such as those with hematologic malignancies, stem cell and solid organ transplants , 2. InfoAmphotericin B , posaconazole and the recently approved triazole, isavuconazole, in conjunction with surgery, are the only active agents against mucormycosis, and are recommended by treatment guidelines –13. EvenIn addition to the high mortality rate, mucormycosis is also associated with long hospital stays and substantial costs. Based on a study published in 2012, the average direct cost per episode of mucormycosis was estimated to be $113,511 (2004 USD), which was higher than more common invasive infections such as aspergillosis  and candidiasis  .To provide an up-to-date overview on the epidemiology and burden of mucormycosis in the general population of hospitalized patients in U.S., we sought to estimate the prevalence of mucormycosis and to assess the clinical and economic burden associated with mucormycosis-related hospitalizations using data from recent years.The study used the Premier’s Perspective™ Comparative Database (Premier), spanning from January 2005 to June 2014. Premier is a large, U.S. hospital-based database covering more than 560 participating hospitals and 104 million patients. Participating hospitals represent all regions of the U.S., are mainly non-teaching facilities, and mostly serve urban patient population. Information collected includes patient demographics , principal and secondary diagnoses, principal and secondary procedures, length of stay, drug utilization , and cost of care. Laboratory results are available from the SafetySurveillor™ product from 2009 and on for about 37% of the hospitals.Mucormycosis-related hospitalizations were identified as hospitalizations with an International Classification of Diseases 9th Edition (ICD-9) code of 117.7 (either primary or secondary) or a positive laboratory microbiology result for Mucorales, the organisms that cause mucormycosis . To decrPrevalence of mucormycosis was estimated annually by dividing the number of mucormycosis-related hospitalizations by the total number of all hospital discharges observed in the same year. An alternative calculation of the prevalence was conducted by relaxing the definition of mucormycosis-related hospitalizations to require only the ICD-9 code or a positive laboratory microbiology test, without the antifungal drug use restriction.Characteristics of hospitals and patients with mucormycosis-related hospitalizations were summarized. Hospital characteristics included region, bed size, teaching facilities, and urban/rural setting. Patient characteristics included age, gender, race, and underlying conditions, and were summarized based on disease history present in the data within 12 months preceding the admission with mucormycosis.The clinical and economic outcomes assessed included death at discharge, length of stay, and readmission rates at 1 and 3 months. Death at discharge was identified using discharge status ‘expired’. The cost for hospitalization included all supplies, labor, depreciation of equipment, etc. All costs were inflated to 2014 USD using the medical care component of the Consumer Price Index. Continuous variables were summarized by mean, standard deviation, median, and range; proportions were reported for categorical variables. All analyses were conducted using SAS 9.3.A total of 555 mucormycosis-related hospitalizations were identified among 47,131,360 total inpatient encounters in the Premier data during January 2005 to June 2014.  with a bed size > 300, and 42% of the hospitals were affiliated with teaching facilities. Our sample was predominantly from urban hospitals, accounting for more than 90% of the inpatient mucormycosis encounters included in this study , followed by hematological malignancies (40%) (Table N = 775).  patients were admitted to intensive care units (ICUs) during the mucormycosis-related hospitalizations. The death rate at discharge was high, with 23% of the patients dead at discharge. The rate was somewhat higher among patients with hematological malignancies than those with diabetes (23 vs. 19%). Nearly one third of the patients (30%) were readmitted into hospitals within a month after the discharge, and 37% were readmitted within 3 months of the discharge  with a range of $1,912 to $1,395,163. The mean per diem cost during hospitalization was $4,096, with a range of $768 to $19,728  [In our study, the economic burden associated with a mucormycosis-related hospitalization was substantial, with average cost per stay at $112,419, which was comparable to the cost of mucormycosis reported in the literature , and higher than the average cost reported for both aspergillosis-related hospitalizations and candidiasis-related hospitalizations , reflecting the significant morbidity and mortality of mucormycosis . SpecifiAmphotericin B lipid complex (52%) was the most commonly used treatment, followed by liposomal amphotericin B (45%) and posaconazole (45%) among patients with mucormycosis-related hospitalizations observed in the present study. Although Mucorales have been shown to be resistant to drugs such as fluconazole and voriconazole, they were used in 21% and 23% of the mucormycosis-related hospitalizations. Due to lack of time stamps of the drug prescriptions, it was not clear if these fluconazole and voriconazole prescriptions were intended to treat mucormycosis or were intended to serve as prophylaxis treatment for patients with high risk of various invasive fungal infections, such as patients with leukemia and recipients of stem cell transplantation , 23. GivOur study has several limitations that should be taken into consideration when interpreting the results. First, only a subset of hospitals in Premier submitted laboratory microbiology results, and laboratory microbiology results were not available before 2009. In addition, it is possible that some of the hospitalizations without use of amphotericin B or posaconazole were true mucormycosis cases, or that some mucormycosis cases were identified post-mortem, which might not have been completely captured by the data , 25. DueThe low prevalence of mucormycosis, its high clinical and economic burden, and the fact that commonly used antifungal therapies such as fluconazole and voriconazole are not effective against mucormycosis, indicate a need to increase the awareness of mucormycosis among physicians who routinely treat patients at high risk mucormycosis for the infection, and the necessity of active surveillance and optimized prophylactic treatment in susceptible individuals.


Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection in hematology. Although occasionally reported, the role of interhuman transmission of P. jirovecii in PCP, compared to that of reactivation, remains an unresolved question; the recommendation to isolate PCP patients in the hematology ward are not well evidence-based. Following an unexpected increase in the number of febrile pneumonia patients with P. jirovecii DNA detected in respiratory samples in our hematology ward, we explored 12 consecutive patients from November 2015 to May 2016. Genotyping of P jirovecii was performed using microsatellite markers. The frequency of simultaneous occupancy of these 12 patients in the same unit on the same day from 4 months prior to the first diagnosis was recorded. In three patients, the P. jirovecii genotype could not be determined because DNA was insufficient. One rare single genotype (Gt2) was found in four of the other nine, all allogeneic stem cell transplant recipients. The transmission map showed that these 4 patients had multiple opportunities to meet on the same day  at the daycare center. It was much less among the eight non-Gt2 patients . This study, based on modern molecular technics, strongly suggests that interhuman transmission of P. jirovecii between allogeneic stem cell transplant recipients is possible. P. jirovecii DNA detected in respiratory specimens supports that isolation and respiratory precautions be recommended in such cases in the hematology ward. Pneumocystis jirovecii pneumonia (PCP) is a life-threatening fungal complication in hematology patients, particularly recipients of allogeneic hematopoietic stem cell transplantation (HSCT), where mortality is greater than 50%  instead of microscopy and immunofluorescence staining  without air filtration that has eight beds, two units with laminar air-flow filtration that have six (Unit 2) and 12 (Unit 3) beds, and a daycare clinic, which cares for 30–50 patients daily on the upper floor. When the patients are at the daycare center, they all arrive between 8 and 9 a.m. and may stay several hours on site, sharing a unic waiting room. The department mainly recruits patients with acute leukemia, myelodysplastic syndrome, myeloproliferative disorders, and aplastic anemia. Around 40 allogeneic HSCTs are performed annually. Patients, hospital stays, and daycare center stays numbered 255, 505, and 2,450, respectively, and the median hospital stay was 20 days. These values have not appreciably varied since 2013.P.jirovecii by May-Grünwald Giemsa (MGG) staining  and an indirect immunofluorescence assay  as previously described   thrice weekly, but if not tolerated, the second-line is atovaquone  or pentamidine aerosol monthly. Patients with pneumonia, except those in palliative care, are investigated by fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) with a systematic search for P. jirovecii between January 2013 and May 2016. It was 4 to 5 cases per year before the fall of 2015, but 4 cases were observed from November 6 to 14, 2015. Eight additional cases were observed from December 2015 to May 2016. This unexpected high incidence led to a search for evidence of transmission using P. jirovecii genotyping and an analysis of patient presence in the ward. According to French Health Public Law (CSP Art L1121-1.1), such an investigation does not require specific informed consent or ethics committee approval.Figure P. jirovecii was performed on DNA extracted from respiratory specimen (BAL or/and sputum) that were frozen at −20°C. Microsatellite analysis was performed according to previously published methods  or for AML (n = 3) and one because of deep neutropenia after HSCT. In the other two, prophylaxis was stopped several months prior, after withdrawing immunosuppressive drugs. As a result, none of the 12 patients received TMP-SMX prophylactically.Twelve consecutive PCP patients hospitalized from November 2015 to May 2016 were included, and their characteristics are summarized in Table P. jirovecii genotype could not be determined because insufficient amounts of DNA were obtained. In Patient 1, only one marker (#022) was amplified, but with a different allele from other patients, allowing the assumption that this patient had a specific genotype (Gt5). In the eight remaining patients, the six markers were correctly amplified. One genotype (Gt2) was found pure in four patients , all of whom were diagnosed within a timeframe of 4 months . Of note, Gt2 had not been found in our collection of genotyped P. jirovecii sspecimens from France and Europe  , the Patients 4 and 9 shared Gt3 genotype, in addition to other alleles in Patient 4, and in addition to Gt4 in Patient 9. Of note, Gt3 has been very rarely observed in our experience .P = 0.048). Additionally, non-Gt2 to non-Gt2 patient contact was zero for five patients, one for one of them, and three for two of them. Figure Gt2 was first observed on November 9, 2015 in the BAL of Patient 2 , who transmitted the disease to Patients 5 and 10, either of whom could have contaminated Patient 7. Alternatively, because Patient 5 was retrospectively identified as a Gt2 carrier, she could have been the first transmitter.We report here the documentation of interhuman transmission of r Figure  where thThis transmission likely occurred because of the absence of effective PCP prophylaxis. Indeed, out of 30 PCP outbreaks reviewed by Yiannakis et al., in 2016, 25 (83%) were reported in kidney transplant recipients, and most were not receiving PCP prophylaxis  was found in four patients, a recent acquisition in these patients is suggested. Whether the transmission of Gt2 was direct, interhuman, the result of close contact, or was indirect through the environment can also not be determined. Healthcare workers could be the culprits, as suggested in other studies  to improve test sensitivity  TMP-SMX, the optimal PCP prophylaxis  nosocomial transmission of CR, AA, and CC conceived and designed the study. CR, AA, MG, GL, FS, ML, FlB, RR, CP, AT, and SM provided study materials or patients. CR, AA, GL, FrB, and CA collected and assembled data. CR, AA, CC, and SB analyzed and interpreted data. CR, AA, SB, and CC drafted the manuscript. All authors approved the final version.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.


After a series of clinical relevant examinations. The patient was dignosed as pancreatic tomor in the pancreatic tail accompanied with the symptom of anenmia and dizziness.Until now surgery is the best treatment strategy for pancreatic tumors.So we take a joint multiple organ removal surgery.Before surgery, the main concerns of patient is whether the operation can relieve the anemia-related symptoms and improve the quality of life.The patient was dignosed as nonfunctional pancreatic neuroendocrine tumor.A joint multiple organ removal surgery including pancreaticbody and tail, spleen, part of the stomach wall, left adrenal gland,and portal splenic vein thrombosis and lymphadenectomy were performed on this patient.After surgery, the concentration of hemoglobin gradually increased and remained stable (88 g/L) on the postoperative day7. Furthermore, complete resolution of the symptom of anemia was achieved on postoperative day 30. There was no recurrence of the tumor or the symptom of anemia during the 3-month follow-up.We conclude that NF-PNETs can manifest as anemia at the time of diagnosis, and if the tumor is resectable, surgical resection is a safe and curative form of therapy not only for the anemia but also for the original tumor. The overall 5-year survival rate is in the range of 5% to 6%.–6 For patients with pancreatic neuroendocrine tumors that have metastasized, prognosis is poor, with a survival of only 1–3 years. PNETs are classified clinically as nonfunctional or functional, based on the properties of the hormones they secrete and their ability to produce a clinical syndrome. In addition, nonfunctional PNETs (NF-PNETs) are more common when campared with functional PNETs (F-PNETs). NF-PNETs can secrete multiple peptides and lead to present a wide variety of clinical manifestations. Herein, we describe an unusual case of pancreatic neuroendocrine tumor, which is primarily manifested as anemia.Neuroendocrine tumors (NETs) are considered rare neoplasms with an annual incidence of 2.5–5 per 100.000. NETs are distributed in the gastrointestinal system and approximately 1/10 develop in pancreas.2A 36-year-old man was admitted to our hospital presenting anemia, dizziness, and fatigue for the previous 3 weeks along with weight loss of 5 kg. He had suffered a magnetic resonance imaging and gastroscopy at the local hospital. The MRI indicated a mass in the pancreatic tail and splenomegaly. The gastroscopy reported esophageal and gastric varices. A detailed physical examination revealed abdominal pain, the pale nail, and conjunctiva but no sign of jaundice. Besides the patient had a history of smoking for 20 years, consuming 10 cigarettes per day averagely and a history of drinking for 15 years, consuming 2 bottles of beer per day averagely.9/L,PLT: 90 × 109/L). In addition, urinalysis, routine stool, and occult blood test were negative. Transaminase and jaundice index were normal. Tumor markers  were negative. Abdominal ultrasonography indicated fatty liver, intrahepatic bile duct calcification, splenomegaly, a hypoechoic mass in the pancreatic tail. A computed tomography scan demonstrated splenomegaly, a tumor (9.6 cm × 7.6 cm) in the pancreatic tail closely related to the stomach and spleen, multiple enlarged lymph nodes, and portal vein thrombosis . The white blood cell count and the platelet count was reduced . The concentration of hemoglobin gradually increased and remained stable (88 g/L) on the postoperative day 7. Furthermore, complete resolution of the symptom of anemia was achieved on postoperative day 30. There was no recurrence of the tumor or the symptom of anemia during the 3-month follow-up.3Pancreatic neuroendocrine tumors are different from exocrine tumors of the pancreas (pancreatic adenocarcinoma) not only in their clinical feature but also in their pathology. They are fairly rare and account for approximately 3% of all pancreatic tumors. However, their incidence is increasing, due in part to heightened awareness of the disease, improved diagnostic techniques, and imaging studies.,8 F-PNETs are much less common and account for about 20% of pancreatic neuroendocrine tumors. Historically, the 9 commonly recognized F-PNETs include insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma, GRFoma, ACTHoma, PTHrp-oma, and PNET causing carcinoid syndrome.,10 They present with specific clinical syndromes related to their hormonal secretions so the clinical diagnosis of F-PNETs are easier than NF-PNETs. Table  erythropoietin, renin, and pancreatic polypeptide.Pancreatic neuroendocrine tumors are divided into 2 major categories: nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) and functional neuroendocrine tumors (F-PNETs). NF-PNETs account for more than 75% of pancreatic neuroendocrine tumors and can synthesize more than 1 peptide to produce all kinds of clinical features. These symptoms may include abdominal pain, weight loss, anorexia, nausea, and jaundice. For this reason, most of NF-PNETs are accidentally discovered, with 70% being greater than 5 cm and more than 60% presenting with synchronous liver metastases. More than 30% of cancer patients have cancer-related anemia (CRA) at the time of diagnosis. Till now, CRA has been described in ovarian cancer, breast cancer, and colorectal cancer.,17 Here, we describe an unusual case of nonfunctional pancreatic neuroendocrine tumor masked as anemia.According to the World Health Organization (WHO), anemia is defined as hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men. In terms of development rate, anemia is categorized into 2 classes: acute anemia and chronic anemia. During clinical work, a variety of reasons can lead to anemia, one of the most important reasons is the diseases related to blood system. But underlying causes of anemia also include some chronic diseases, such as infections, cancer, autoimmune, chronic rejection after solid-organ transplantation, and chronic kidney disease. The etiopathogenesis mechanism of CRA remains uncertain. One theory is that CRA may be a consequence of chronic inflammation. Pro-inflammatory cytokines including (IL)-6, (TNF)-αinduce changes in the proliferation of erythroid progenitors, erythropoietin production, and survival of circulating erythrocytes. Plasma CRP levels reflect the levels of (IL)-6, which also modulates the concentration and biological activity of hepcidin. Hepcidin strongly induced by IL-6, inhibits duodenal absorption of iron and blocks iron release from macrophages which eventually lead to CRA. Besides, nutrition and metabolic components also induce cancer-related anemia. However, the laboratory assays revealed no evidence of immune response and nutritional change in our patient.Anemia is one of the most frequently reported in patients with cancer.,22 So the patient eventually manifest anemia and gastroesophageal varices.Anemia, esophageal and gastric varices, and splenomegaly are more common in patients with hepatocrirrhosis. But, these syndromes presented in pancreatic neuroendocrine tumors are seldom mentioned. Until now the symptom of anemia is encountered in F-PNETs, usually in glucagonoma and somatostatinoma. Here, we describe an annual case of nonfunctional pancreatic neuroendocrine tumor presenting as anemia. In our case, pancreatic neuroendocrine tumor invaded splenic vein and formed a huge splenic vein thrombosis to obstruct splenic vein reflux, resulting in hypersplenism. This may be the main cause of anemia in the patient. Regional portal hypertension (RPH) is a pathological condition resulting from outflow obstruction of the splenic vein, which creates a high pressure system in the left side of the portal venous system with formation of collaterals and gastroesophageal varices.Nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) have an aggressive ability, compared with pancreatic carcinoma and functional pancreatic neuroendocrine tumors (F-PNETs). Therefore, they usually invade the surrounding organs and blood vessels to produce a series of clinical presentation. What's more, the NF-PNETs are a progressive disease and most of patients are discovered with liver metastases. Due to the low sensitivity of chemotherapy and targeted drugs, surgery is often as the preferred therapy for pancreatic neuroendocrine tumor.4Finally, we conclude that NF-PNETs can manifest as anemia at the time of diagnosis, and if the tumor is resectable, surgical resection is a safe and curative form of therapy not only for the anemia but also for the original tumor. However, considering some limitations in the case report, a further multicenter study is necessary.


Supplemental Digital Content is available in the text The primary aim of this study was to evaluate metabolically healthy status (MHS) among participants in obesity, overweight, and normal weight groups and characteristics associated with this phenotype using baseline data of Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The secondary aim was to investigate agreement among 4 different MHS criteria. This cross-sectional study included 14,545 participants aged 35 to 74 years with a small majority (54.1%) being women. Of all participants, 22.7% (n = 3298) were obese, 40.8% (n = 5934) were overweight, and 37.5% (n = 5313) were of normal weight.Socio-demographic, behavioral, and anthropometric factors related to MHS were ascertained. Logistic regression models estimated the odds of associations. We used 4 different criteria separately and in combination to define MHS: the National Health and Nutrition Examination Survey (NHANES), the National Cholesterol Education Program (NCEP-ATPIII), the International Diabetes Federation (IDF) and comorbidities, and the agreement between them were evaluated by Cohen-kappa coefficient.P < 0.001). In final logistic models, MHS was associated with lower age, female sex, lower body mass index (BMI), and weight change from age 20 within all BMI categories.MHS was present among 12.0% (n = 396) of obese, 25.5% (n = 1514) of overweight, and 48.6% (n = 2582) of normal weight participants according to the combination of the 4 criteria. The agreement between all the 4 MHS criteria was strong (kappa 0.73 This study showed that, despite differences in prevalence among the 4 criteria, MHS was associated with common characteristics at every BMI category. Following the last 3 decades of socioeconomic and nutritional transition, approximately 70% of Brazilian adults are obese or overweight. Being obese or overweight contributes to the increasing public health burden of noncommunicable conditions such as cardiovascular diseases, type 2 diabetes, and cancer. In addition, the risk of mortality attributable to obesity is substantial, although a high BMI, which is widely used as a marker of obesity in population-based studies, does not necessarily reflect an increased fat mass.–6 Clinical and epidemiological studies have demonstrated that obesity and being overweight are neither necessarily linked to an adverse cardiometabolic profile nor to higher chronic disease prevalence and mortality.,7 Concerning this, the term metabolically healthy obesity (MHO) has been proposed to characterize a phenotype that is not accompanied by cardiometabolic dysfunction.–10According to the 2013 Global Burden of Disease Study, almost 2.1 billion adults in the world were obese , premature birth , self-rated health  were self-reported. Social class  was categorized according to per capita household income. According to job activities performed, occupation was classified as routine manual , routine nonmanual (as administrative activities), or nonroutine and nonmanual (as teaching).2.32] was calculated. We used World Health Organization (WHO) criteria to stratify BMI into 3 categories . Relative weight change from the age of 20 years old was calculated as (current weight: 20 years old weight/20 years old weight)∗ 100.Anthropometric parameters were measured using standardized and calibrated instruments, according to the study protocol. Weight (kg) and height (cm) were measured with the participant barefoot, wearing light clothes, and standing straight with the head level, using Toledo scales (to the nearest 100 g) and a stadiometer (accuracy of 0.1 cm), respectively. Waist (mid-point between lowest rib and iliac crest) and hip  circumference were measured by inelastic tapes (cm). The average of 2 measures was used for analyses. BMI .All laboratory analyses were performed at a single research center (University of São Paulo).2.6Arterial hypertension was defined by a self-reported medical diagnosis of hypertension, use of anti-hypertensive agents, or blood pressure ≥140/90 mm Hg at the moment of evaluation. Diabetes mellitus was defined by abnormal laboratory findings of FPG ≥ 126 mg/dL (≥7.0 mmol/L), or plasma glucose levels 2 hours after a 75 g load of anhydrous glucose ≥200 mg/dL (≥11.1 mmol/L), or hemoglobin A1c ≥6.5%, or by the use of insulin or oral/subcutaneous hypoglycemic drugs, or if there was a previous medical diagnosis of the disease (self-reported). Dyslipidemia was defined by TG ≥150 mg/dL (≥1.7 mmol/L) or HDL-C <40 mg/dL (<1.04 mmol/L in men) or <50 mg/dL (<1.30 mmol/L in women), or the use of lipid-lowering agents.2.7; the metabolic syndrome criteria of the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF); and a comorbidities criteria. The last uses the presence of arterial hypertension, diabetes mellitus, or dyslipidemia, as defined above, as a proxy of unhealthy status (Table S1). Individuals were considered metabolically unhealthy if so classified by any of the 4 criteria, and as metabolically healthy if so considered by all 4 criteria. Three variables were created on the basis of the combination of individuals’ metabolic status and BMI (yes/no): metabolically healthy obese, metabolically healthy overweight, or metabolically healthy normal weight.Healthy or unhealthy metabolic status was classified according to 4 commonly used criteria: those used in analyses by the National Health and Nutrition Examination Survey (NHANES)2.8t test) were used to compare socio-demographic, current lifestyle habits, self-rated, and mental health between metabolic status groups, across BMI  categories. To assess the agreement between the 4 sets of MHS criteria, we used the Cohen-Kappa coefficient.Normality of the data distribution was assessed by histograms and Shapiro–Wilk tests. Descriptive and univariate analyses  or poor relevant clinical/laboratorial, socio-demographic, current lifestyle, habits, self-rated, and mental health covariates on univariate analysis; Model III—significant variables on Model II along with BMI and relative weight change. Similar adjustments were performed for multiple logistic regression models with metabolic health status defined by NHANES, NCEP, IDF, and comorbidities criteria separately as dependent variables. As waist circumference is part of NCEP and IDF criteria, and the correlation between waist and BMI was strong (0.85), we decided to adjust either for BMI or WC. All the P values given are 2-sided with the level of significance set to P < 0.05, except for multiple comparisons when it was set to 0.05 divided by the number of comparisons.For each BMI category, logistic regression models were performed to determine associations between metabolic status  and the following covariates: Model I—sex and age; Model II—Model I and significant , 40.8% (n = 5934), and 37.5% (n = 5313) were classified as obese, overweight, and normal weight), respectively. Sixty-six percent (9656) were married, and 52.3% (7516) were white. Frequency of arterial hypertension, diabetes, and dyslipidemia was 35.9%, 19.6%, and 47.5%, respectively. Characteristics of the study population are depicted in Table P < 0.001). The agreement of MHO, overweight, and normal weight across the 4 different criteria is presented in Figure S1. Characteristics of each category are demonstrated in supplemental content .MHS was present in 12.0% (n = 396) of the obese, 25.5% (n = 1514) of overweight, and 48.6% (n = 2582) of normal weight study participants, respectively (Table 3.2P = 0.74), overweight (P = 0.44), and normal weight (P = 0.66) groups. There was a strong correlation between educational level and social class (p < .001). When we analyzed the variables associated with MHS according to the 4 different criteria , results were quite similar .In the univariate analysis of each of the 3 groups , a healthy metabolic status was associated with younger age, female sex, higher educational level and social class, higher self-rated health; and healthy behaviors  Table . AlthougIn adjusted logistic models, lower age was related to MHS, so that the risk of being unhealthy increased by 6% to 7% for each additional year of life. Female sex, good self-rated health, lower BMI, and % relative weight change were associated with being metabolically healthy in each BMI category.2 of BMI, within the same BMI category, and 1% to 2% for each 1% weight increment from age 20 to the study baseline . The proportion of MHS within the normal weight subgroup was lower in comparison to results in the Netherlands (97.3%), the United States (76.5%), and Spain (93.5%), but higher than in Finland (20.4–23.8%) and China (16.0%). This might be due not only to the more strict approach we undertook to define metabolic health but also to age and behavioral differences among these populations.In this large sample of predominantly overweight and obese participants from the ELSA-Brasil cohort study, only one-third of the individuals were metabolically healthy according to all 4 MHS criteria. Systematic reviews and meta-analyses of population-based studies have identified a large variability in the prevalence of MHS among those who are obese and those of . All this points out that it is difficult to compare different classifications, as stressed by other authors,,26 and that defining metabolic health remains challenging. The term “metabolically equipoised” might be more appropriate, as the absence of cardiometabolic dysfunction can be transitory.,20 Criteria that include biomarkers of insulin resistance  and inflammation (CRP), though theoretically more accurate, have the downside of being based on subjective cut-offs, so that each population sample will exhibit diverse values. In addition, in clinical and epidemiological settings, classifications that do not demand expensive examinations are preferable as long as they correlate well with the clinical ones. In our study, the NHANES criteria, which applied more complex biomarkers, had good agreement with the comorbidities criteria across all BMI categories .The proportion of having MHS across BMI categories varied according to the criterion applied, although good agreement was found in the obese category, differently from what was demonstrated by Phillips et al.,19,27 However, Yoo et al studying a younger sample (median age 37.2 years) and Martínez-Larrad et al, with a Spanish-Caucasian sample of adults could not confirm that. After full adjustment, female sex was associated with MHS within the BMI subgroups, as demonstrated by similar findings.,29 The fact that women are more likely to use health services than men and, therefore, can have more opportunities for receiving preventive counseling, is one possible explanation.MHS was associated with younger age in all BMI subgroups, as demonstrated by others.Higher educational level was associated with MHO in the present study. Educational level, which is a proxy for socioeconomic and cultural status, influences living conditions and opportunities for having a healthy lifestyle. Interestingly, social class, which is strongly related to educational level, was associated with MHS only within the overweight and normal weight subgroups. A low education level and low household income link cardiovascular disease with risk factors such as smoking, hypertension, impaired glucose tolerance, diabetes mellitus, physical inactivity, and being overweight with associated metabolic disturbances. It is hypothesized that self-rated health reflects health problems, general physical and mental functioning, and educational levels that might be in the pathway between lifestyle behaviors and metabolic abnormalities.Another interesting point is that higher levels of self-assessed health, a valid measure of health status, increased the odds of being metabolically healthy in all BMI categories. Self-rated health has been associated with glycemic abnormalities, incident diabetes, and diabetes-related mortality in longitudinal studies. Differently from ELSA-Brasil, a study that also used the IPAQ instrument could not demonstrate any association among MHS and physical activity in obese participants, whereas in NHANES and in the International Population Study on Macro/Micronutrients and Blood Pressure (INTERMAP), MHS was related to higher physical activity levels.,33 Another cross-sectional study that used the IPAQ questionnaire could not demonstrate any association between moderate/higher activity levels and the lipid profile of the overweight and obese participants. Questionnaires of physical activity cannot provide the same precision in measurement that one would achieve with objective devices. It is also noteworthy that only 5.4% of the obese participants in our population had high levels of physical activity. Despite that, as higher physical activity levels are inversely related to manual occupation, it seems that our results are really related to leisure time and transportation. We also tested physical activity according to WHO criteria, but this adjustment variable was not applied to the final logistic models. It was interesting to note that only 3495 (24.4%) of ELSA-Brasil participants are physically active according to WHO criteria. This is much lower than the Brazilian telephone-based survey, which estimates that 39.9% residents adults of 27 capitals are active, according to the same criteria.Regarding the association between MHS and lifestyle habits, we found that higher physical activity levels determined MHS in the BMI subgroups. Regular physical activity has been associated with a better profile among the components of metabolic syndrome, such as arterial pressure, lipids, and glycemia. Moreover, physical inactivity is an important risk factor for cardiovascular disease. or in participants in other BMI categories in other populations. Conversely, MHS was demonstrated to be inversely related to smoking by some authors.,21 In the present study, higher alcohol consumption was associated with a metabolically unhealthy profile only in the normal weight group. On the contrary, moderate (not excessive) use of alcohol was not associated with MHS in normal weight participants, contrary to what Wildman et al demonstrated.Interestingly, although tobacco is related to a higher risk of diabetes and hyperglycemia, as well as arterial hypertension and detrimental effects on lipids, such as lower HDL-C levels, smoking was related to a poorer metabolic profile in the present study only for the overweight and normal weight participants. Similarly, no significant relationship was found between MHS and smoking in obese individuals,–36 In cross-sectional studies, it is not possible to assess the influence of prior dietary counseling with previous diagnosis of obesity or comorbidities, which could explain these findings.Contrary to our hypothesis, regular daily consumption of fruits and vegetables, which are surrogates of a healthy diet, was not associated with MHS. Paradoxically, regular daily consumption of fruits was associated with unhealthy metabolically status among the obese group. Similar to our findings, although having used different analyses of dietary patterns, other cross-sectional studies have not demonstrated any association between diet and MHS in cohorts. and in the Korean National Health and Nutrition Examination Survey, we found that lower waist circumference was also associated with MHS (data not shown). However, we decided to adjust only for BMI in the final logistic model, due to the easy applicability of this measure in both clinical and epidemiologic settings. Another interesting finding was the association between lower relative weight gain and MHS within each BMI category. Even in normal weight participants, the lower the weight gain during adult life, the higher the risk of being metabolically healthy. In the Nurses Health Study, women and men who gained 5.0 to 9.9 kg from 18 to 20 years had a 1.5 to 3.0 higher risk of coronary heart disease, arterial hypertension, and diabetes in comparison with who maintained their weight.MHS was also associated with lower BMI levels within each BMI category. Like in the NHANESThe large sample of adults living in a middle-income country, where the impact of socio-demographic and nutritional transition as well as the burden of chronic noncommunicable diseases are not completely understood are major strengths of this study. However, our results may not be generalizable, as our population is different from the adult populations of higher income countries. The methodological rigor in data collection, the centralized analysis of the laboratory tests, the quality assurance control, and the large set of covariables are other strengths of the ELSA-Brasil cohort study. In view of the lack of a standard definition, we decided to use the combination of 4 different criteria to define metabolic status, which increased specificity. Therefore, MHS is very well-defined. Regarding study limitations, we point out the cross-sectional nature of the study and that final sample of this study excluded 3.7% (n = 560) of the original cohort, but that was necessary to better standardize the MHS criteria. Another limitation of the study is the unavailability of data on nonmetabolic chronic conditions, such as chronic obstructive respiratory disease or cancer, which might have introduced some residual confounding to the analyses. As well, ELSA-Brasil used a relatively simple method of estimating leisure time and transportation-related physical activity, assessed by the IPAQ questionnaire. However, IPAQ is a validated method according to World Health Organization. In addition, the lack of data on body composition at the baseline in ELSA-Brasil does not allow us to better assess the impact of lean or fat mass on MHS.Baseline data of this large cohort showed that, despite differences in prevalence, MHS was associated with common characteristics at every BMI category. A follow-up of this cohort with repeated measures of socio-demographic, anthropometric, behavioral, and laboratorial characteristics may help to further improve our understanding of the determinants associated with maintaining a MHS.


Enterovirus 71 (EV71) infections have a major public health impact in the Asia-Pacific region. We reviewed the epidemiology, pathogenesis, and molecular epidemiology of EV71 infection as well as EV71 vaccine development. Previous studies were found using the search terms “enterovirus 71” and “epidemiology” or “pathogenesis” or “molecular epidemiology” or “vaccine” in Medline and PubMed. Articles that were not published in the English language, manuscripts without an abstract, and opinion articles were excluded from the review. The reported epidemiology of cases caused by EV71 infection varied from country to country; seasonal variations in incidence were observed. Most cases of EV71 infection that resulted in hospitalization for complications occurred in children less than five years old. The brainstem was the most likely major target of EV71 infection. The emergence of the EV71 epidemic in the Asia-Pacific region has been associated with the circulation of different genetic lineages  that appear to be undergoing rapid evolutionary changes. The relationship between the gene structure of the EV71 virus and the factors that ensure its survival, circulation, and evasion of immunity is still unknown. EV71 infection has emerged as an important global public health problem. Vaccine development, including the development of inactivated whole-virus live attenuated, subviral particles, and DNA vaccines, has been progressing. Picornaviridae [Hand, foot, and mouth disease (HFMD) is a common childhood disease caused by enteroviruses. A proportion of HFMD patients develop severe neurological complications and die . Enterovaviridae . Initialaviridae . Human eaviridae ,2. Enterovirus 71 (EV71) is one of the major etiologic agents of HFMD and herpangina . EV71 waAll papers published from January 1965 through August 2016 describing patients affected by enterovirus 71 were obtained by searching Medline  using the keyword “enterovirus 71” and “epidemiology” or “pathogenesis” or “molecular epidemiology” or “vaccine”. Articles not published in the English language were excluded from the review. Updated information on enterovirus 71 infection in Taiwan was obtained from the Taiwan Centers for Disease Control (Taiwan CDC) .The articles were reviewed, and only reports of original studies were retained; manuscripts without an abstract , review articles, opinion articles, etc., were excluded. After selecting the articles, relevant information was extracted and classified with respect to the basic science , the clinical indicators , the information source , the year of publication, and the study design. Searches were performed in July and August 2016. A total of 1235 documents were retrieved from Medline. After screening the articles, 195 were considered to be relevant. Eighty-five percent of the studies were retrospective studies, 10% were perspective studies, and 5% used other study designs.The EV71 epidemic was reported in the 1970s by various countries in America, Europe, Australia, and Asia ,19,20,21After the EV71 epidemics occurred in Australia and Japan in the 1970s , furtherOutside the Asia-Pacific region, EV71 circulates at a low level in the regions of Canada, the USA, Europe, and Africa and causes sporadic cases or small outbreaks  6,50,51,60,61,62A higher incidence was observed during the summer months in Asia ,64,65, at < 15 °C and 15 °C ≤ t < 20 °C, and peaked at 20 °C ≤ t < 25 °C. The distribution of pathogens’ serotypes and the level of sunshine could be risk factors for the outbreak of HFMD in China. Current hypotheses explaining the seasonal pattern of EV71 infection include host immune competence fluctuations mediated by seasonal factors, such as melatonin or vitamin D levels ; seasonaHFMD is spread from person to person by contact with saliva, respiratory secretions, fluid in vesicles, and feces. Transmission of HFMD can be reduced by isolation of confirmed cases of patients with viral shedding, and maintaining good hygiene, including hand-washing and disinfection of surfaces in child care settings .Taken together, EV71 infection has emerged as an important public health problem in the world, especially in the Asia-Pacific region. The morbidity and mortality of EV71 infection are influenced by geographic, host, and environmental factors. Understanding the epidemiology and transmission dynamics of EV71 is helpful for leading to the control and elimination EV71 infection. EV71 infection that causes brainstem encephalitis, especially affecting the medulla and associated with cardiopulmonary dysfunction, has become a notable feature in EV71 epidemics in Asia and is associated with high mortality. The most common manifestation of enteroviral infection is a non-specific febrile illness lasting three days, followed by recovery. However, some cases progress to severe or fatal illness. Brainstem encephalitis, especially affecting the medulla and associated with cardiopulmonary dysfunction, has been noted as a clinical feature in EV71 epidemics in Asia and is an important cause of death ,69,74,75Viremia occurred more frequently in children under the age of one year ,77. HoweEV71 is a highly neurotropic virus, and the brain stem is the most common target of EV71 infection ,79,80,81The strong neurotropism of EV71 and retrograde axonal transport in neurons might represent the major transmission route of EV71 in mice ,87. In aNeurological virulence is one of the most severe complications responsible for death . The mecWhat is the mechanism of pulmonary edema among severe cases with EV71 infection? It may be due to the destruction of the medial, ventral, and caudal medullas, which may lead to sympathetic overactivation, causing a blood shift to the lungs ,93. SimiIn summary, some EV71 strains are often related with neurological manifestations but EV71 also causes aseptic meningitis and fever without a source with good outcomes in very young infants. Some of the epidemiologic studies include cases of children with non-severe manifestations ,97. MoreThe phylogenetic origins of the EV71 strains recently circulating in the Asia-Pacific region have been studied  3,9,10,,47,48,49In South Korea, an EV71 outbreak was reported during 2009 . The preThe phylogenetic origins of the EV71 strains circulating outside the Asia-Pacific region have been studied  6,50,51,60,61,62EV71 has a high mutability and is in constant evolution, similar to poliovirus . HoweverTaken together, the dynamics of the genetic and antigenic evolution of EV71 in the past decade showed a genotype shift with an antigenic property change and genome recombination. Almost all HFMD outbreaks were correlated with genetic variations caused by EV71 switches. Recombination of EV71 in the region encoding the nonstructural proteins is frequently observed, and numerous recombination crossover breakpoints have been identified within the non-structural genes, particularly of the more recent EV71 subgenotypes ,110,111.EV71 is most commonly transmitted via close person-to-person contact; however, the majority of EV71 infections are asymptomatic or result in mild disease, which limits the effectiveness of public health interventions such as hand washing. The development of an effective vaccine may be the best way to control EV71 infection . Many EVInactivated whole-virus EV71 vaccines are the most advanced candidates among the current EV71 vaccines. Inspired by previous experiences in developing inactivated vaccines, the development of inactivated whole-virus EV71 vaccines is progressing rapidly . The forThe development of virus-like particles (VLPs) vaccines is a different approach from the inactivated whole-virus EV71 vaccines. VLPs vaccines provide the advantage of presenting all surface epitopes of the EV71 capsid proteins in their native conformations at once ,130. AltIn summary, the formalin-inactivated EV71 vaccines have reported to have high efficacy for preventing EV71 infection. EV71-related HFMD could become a vaccine-preventable disease in the world. However, no formalin-inactivated EV71 vaccines protect against CAV16, which is predominantly responsible for annual HFMD outbreaks. The development of vaccines that cover multiple species of enterovirus is a prospective option. Live attenuated vaccines, subunits vaccine, synthetic peptides, and DNA vaccines have been approached by researchers, but these approaches are in the early stage of vaccine development.EV71 has emerged as a significant infection in the Asia-Pacific region. It is a potentially fatal neurotropic virus that may be considered the new polio. Several factors have been indicated to regulate EV71 replication. However, specific factors that contribute to neural pathogenesis remain unclear. Further study on the mechanism of EV71 infection is still needed. Although inactivated EV71 vaccines have been rapidly developed in the last few years, these vaccines have some limitations. Other types of vaccines are being developed to prevent EV71 infection. A global EV71 infection surveillance network should be established, and continuous epidemiological surveillance is important for identifying and detecting the potential emergence of new EV71 variants.