Cryptosporidium BoD models accounted only for acute episodes, while there is increasing evidence of long-term manifestations. Our objective was to update Cryptosporidium BoD and cost-of-illness (COI) models and to estimate BoD and COI for the Netherlands in years 2013–2017.Burden of disease (BoD) estimations are increasingly used to prioritize public health interventions. Previous We performed a scoping literature review and drew an outcome tree including long-term manifestations for which sufficient evidence was found, such as recurrent diarrhea and joint pain. We chose the Disability-Adjusted Life Year (DALY) metric to synthesize years of life lost due mortality (YLLs) and years lived with disability due to non-fatal outcomes (YLDs). For the costs, we adopted a societal perspective accounting for direct healthcare costs, patient costs and productivity losses. Uncertainty was managed using Latin Hypercube sampling .Cryptosporidium cases : 15,000–102,000), 7,000 GP visits, 300 hospitalizations and 3 deaths, resulting in 137 DALYs (95%UI: 54–255) and €19.2 million COI (95%UI: €7.2 million– €36.2 million). Estimates were highest for 2016 (218 DALYs and €31.1 million in COI), and lowest in 2013 (100 DALYs and €13.8 million in COI). Most of the BoD was attributable to YLD (≈80% of DALYs). The most important cost was productivity losses . Long-term manifestations, including recurring diarrhea and joint pain, accounted for 9% of the total DALYs and 7% of the total COI.In the Netherlands in 2017, we estimated 50,000 Cryptosporidium models, which contribute close to 10% of the total DALYs and costs. This may be an underestimation, as we were conservative in our assumptions. Cryptosporidium should be considered a priority organism with respect to public health surveillance, even in industrialized countries with high hygiene standards.Current evidence supports the inclusion of long-term manifestations in  During the last decades, there has been a growing interest in estimating the burden of disease (BoD) in order to prioritize healthcare, public health interventions and health research. Different metrics have been proposed for this, such as the Disability-Adjusted Life Year (DALY) or the Quality-Adjusted Life Year (QALY), among others . The DALMany of the parameters needed for DALYs estimations are not known, or are subject to great uncertainty, requiring a number of assumptions to be made based on current knowledge. Moreover, some of these parameters are context-specific and can vary between different countries or throughout the years, depending on, for example, the quality of surveillance systems, healthcare organization and accessibility, or testing and treatment policies. As new evidence becomes available, the estimates need to be updated accordingly.Cryptosporidium is a parasite that is mainly spread via the fecal-oral route from person to person or via contaminated food or water. It is more prevalent in low-resource settings, and is usually not among the health priorities for the European region [n region . Neverthn region –13. The n region , 15. Gasn region  or transn region .Cryptosporidium BoD estimations accounted only for the acute episode including death, but disregarding long-term manifestations [Cryptosporidium, increasing the number of diagnoses. More accurate estimations will better inform decisions around the appropriate scale of efforts directed to the surveillance, prevention and control of Cryptosporidium. The objective of this work is to update the models used for BoD and cost-of-illness (COI) estimation for Cryptosporidium, incorporating recently generated evidence, with an emphasis on long-term manifestations.Previous stations , 17, 18.stations  has greastations . FinallyWe performed a scoping review of published and unpublished documents  reported in the second study of infectious intestinal disease (IID2) from the UK [Cryptosporidium is not notifiable, and IID2 study excluded imported infections , we considered higher MF than the ones from IID2. Studies from the 90’s found that people with gastrointestinal symptoms were 3.4 times less likely to consult a GP in the Netherlands compared to the UK [Acute symptomatic infections were considered mild when they did not require any medical help, moderate when they motivated General Practitioner (GP) consultation, and severe when they required hospitalization. Both the number of symptomatic m the UK . This ism the UK , Cryptoso the UK . Therefoo the UK . Hospitao the UK –25, witho the UK , and coro the UK , 26, 27.o the UK . As stanCryptosporidium species up to 1 year after the acute infection [C. hominis [C. parvum [C. parvum.Regarding long-term manifestations, there was evidence of recurrent gastrointestinal symptoms for both nfection –34, 38. nfection  as companfection , 32–34, nfection , 35. Thenfection , 35. Thenfection  and ther hominis , 21, 32,Several studies have reported on dizziness , 33, 38 Cryptosporidium infection (pathogen-based approach) and assigned their effects to the infection, even if some of the outcomes occur much later in time (incidence-based approach). We calculate DALYs combining YLLs and YLDs:We considered all possible outcomes of l according to the following formula:YLD were computed for every possible outcome l, dwl is the disability weight associated to outcome l. Disability weights were taken from Haagsma et al. [Where a et al.  and wereea), accumulated for all deaths due to the infection in each age group (na), following the formula:YLLs were given by the remaining life expectancy at age of death  included costs for medical consultations, hospital stay, ambulance transport, diagnostic tests, prescribed medication, and temporary stays in nursing homes. Patient costs (PC) included cost for transport to consultations, over-the-counter medication (OCM) and extra-diapers for babies. Other sector costs (OSC) included loss of productivity  for either the sick person or a caregiver, for non-fatal cases. For fatal cases, loss of productivity was computed taking the friction time approach, i.e. the mean time needed to find a replacement worker , 41. TheAssumptions regarding consultation habits, frequency of diagnostic fecal tests, prescribed medication and over the counter medication (OCM), transportation and hours of productivity lost during an acute gastroenteritis episode were taken from Mangen et al.  and are As the base-case regarding recurrent diarrhea, we considered it did not motivate medical consultations since severity was assumed mild. OCM costs for a recurrent diarrhea episode were corrected for the shorter duration as compared to the acute episode. For joint pain, we considered that 100% of severe, 41.5% of moderate and 0% of mild cases will visit a GP  and a sith and 97.5th percentiles of the results’ distribution. Population heterogeneity in the duration of the outcomes and the disability weights were considered to be well represented by the population mean. For input parameters with model uncertainties, we ran different scenarios with varying assumptions, and varied input parameters in univariate and multivariate sensitivity analyses.The model was built in MS Excel using the add-in software Palisade @Risk 7.5. A probability distribution was chosen for most parameters to manage uncertainty, whereby using either a Pert-distribution, a uniform, or a discrete distribution. A value was drawn from such distributions iteratively using Latin Hypercube sampling with 30,000 iterations. We computed the mean and the 95% uncertainty interval (95% UI), corresponding to the 2.5Cryptosporidium, among others. For recurrent diarrhea, double incidence and duration was applied as sensitivity analysis, and also different incidence by age and severity of the acute episode. For joint pain, as scenarios we did not consider it a) for C. parvum, b) for mild cases or c) for children, and d) we assumed a higher duration of a joint pain episode. Dizziness and fatigue were included in the model in a scenario analysis, assuming similar duration as for joint pain in absence of reliable data.Cryptosporidium caused between 100 and 218 DALYs per year, with a higher burden estimated in the years 2015 and 2016, in which a higher number of cases was reported to the surveillance system. The increase was mainly due to an increase in C. hominis (160 DALYs in 2016 vs. 12 in 2014), while the BoD of C. parvum was more stable at between 58–96 DALYs .In the years between 2013 and 2017 , Cryptos96 DALYs . In the 96 DALYs . In the C. parvum. For example in year 2017, costs were €404 for C. parvum and €377 for C. hominis.The biggest share of the disease burden was due to YLD, representing 83% of the total DALYs in year 2017 , of which 8 DALYs were caused by joint pain and 5 DALYs by recurrent diarrhea . They prProductivity losses accounted for 1.5 M€ (93.8%) of the 1.6 M€ caused by long-term manifestations, in year 2017.Cryptosporidium cases similar to moderate and severe, with no differences between age groups, with similar severity as acute episodes and with twice the number of recurrent diarrhea episodes per patient and a two-fold duration of these episodes. This increased total DALYs per year from 137 to 204 (95%UI: 74–428) and total costs per year from 19 to 27 M€ (95%UI: 9–54). Using the age distribution of deceased cases from European surveillance data [The impact of key assumptions was explored in 28 different scenario and sensitivity analyses applied to estimations of the year 2017  and COI 8 M€ (95%UI: 3–15) per year. Oppositely, when applying all more liberal scenarios simultaneously, these figures went up to 395 DALYs (95%UI: 121–846) and 34 M€ (11–74) per year.Cryptosporidium infection to account for long-term manifestations. Recurrent diarrhea and joint pain together accounted for 9% of the total DALYs and 8% of the total COI. Overall, Cryptosporidium produced 137 DALYs and a cost of 19.2 M€ in the Netherlands in 2017, although this varied by year. The highest burden is observed in years 2015 and 2016, where there was an increase in sporadic cases reported to surveillance, mainly of C. hominis, resulting in 218 DALYs and 31.1 M€ in COI in 2016; no single source or prominent risk factor was found to explain this increase [This is the first estimation of burden of disease and cost of illness of increase . This prSalmonella, 92% for Campylobacter, and 151% for Shigella [Campylobacter, Guillain-Barré syndrome, accounted for around 70% of the total BoD for Campylobacter, and 60% for Salmonella [Long-term manifestations following acute cryptosporidiosis have been consistently reported in the literature and future models should consider these within the outcomes associated to infection. The proportion of the total burden of disease due to long-term manifestations was modest compared to what has been observed for other gastrointestinal diseases. For example, the inclusion of irritable bowel syndrome (IBS) as a sequelae increased the BoD by 86% for Shigella . In morelmonella .Cryptosporidium was much lower than IBS for other pathogens due to the much shorter duration and severity we accounted for. Given the mostly conservative assumptions, our results are probably an underestimation. More liberal scenarios estimated a higher burden, but were still far from the impact associated to IBS. Likewise, the lack of more detailed information on severity of the joint pain and its compatibility with a diagnosis of reactive arthritis, together with the existence of only one study addressing its duration, have probably resulted in an underestimation of its impact. Finally, because we included only sequelae with high evidence and sufficient data allowing us to parameterize the model, dizziness and fatigue were only included in a sensitivity analysis and with very conservative assumptions. Chronic fatigue syndrome has been described following other protozoan infections such as giardiasis [The impact of recurrent diarrhea episodes in ardiasis , and couIt is difficult to compare our estimates with previous studies due to the multiple updates in the input parameters used for the model. The report on disease burden of food-related pathogens in the Netherlands for year 2017  estimateth place of the 14 food-related pathogens evaluated in the Netherlands for that year, only above Bacillus cereus and close to the 150 DALYs estimated for Shiga toxin-producing Escherichia coli (STEC) O157 [Campylobacter, Salmonella, STEC O157, Listeria monocytogenes and Toxoplasma gondii but not for any of the bacterial toxins, viral or protozoan pathogens, whose burden may be currently underestimated [Cryptosporidium, higher than our 0.6 estimated for 2013, more so taking into account that they did not consider long-term manifestations and the assumed incidence in our study was higher. This could be mostly explained by the different age distribution of fatal cases, which in European surveillance data occur at younger ages as compared to what is seen in the Netherlands, although differences in other assumptions could also play a role. In the ranking by Cassini et al. [Cryptosporidium had the lowest burden among the foodborne pathogens, including Campylobacter, Salmonella, STEC, Listeria, hepatitis A virus, Shigella, congenital toxoplasmosis, and Giardia. Among intestinal parasites, a recent prioritization exercise using multi-criteria decision analysis ranked Cryptosporidium in second place for the countries in Northern Europe, after Echinococcus multilocularis [The updated estimates accounting for long-term manifestations, of 137 DALYs for year 2017, would still have placed Cryptosporidium in the 13EC) O157 , althougstimated , 18. In ocularis .As an overall limitation, the uncertainty in some of the assumptions was high, and although we tried to account for this by using a probabilistic approach, still our results may be biased by the particular characteristics of the studies used to derive our input parameters. The uncertainty was also reflected in the wide variation when applying all scenarios simultaneously, which resulted in a number of DALYs as low as 61 or as high as 395, and a COI of 8 M€ up to 34 M€ in 2017. Finally, these estimations were very specific of a particular context and extrapolation to countries with different epidemiological profiles, different structure, accessibility and quality of health systems, or different age structure or share of immunocompromised patients, needs to be done with caution. In low-resource settings with high incidence in younger ages  the burdCryptosporidium BoD models which contribute close to 10% of the total DALYs and costs. The burden and costs of Cryptosporidium under our model was higher than previously estimated, reinforcing the need to consider it a priority organism with respect to public health surveillance, even in an industrialized country with high hygiene standards such as the Netherlands.In conclusion, current evidence supports the inclusion of long-term manifestations in S1 File(DOCX)Click here for additional data file.


Recurrent stroke is becoming an increasingly important public health issue owing to the increased risk of disability and death. However, population-based studies investigating the rate of recurrent stroke in China are rare. We explored the rate and determinants of recurrent stroke within 1 and 5 years after the initial stroke in a rural population in China. Data for stroke events were obtained from the Tianjin Brain Study, conducted between 1992 and 2016. The age-standardized rates of recurrent stroke within the first year and the first 5 years after the initial stroke were calculated for this period. Determinants of recurrent stroke were assessed using Cox regression analyses. The overall age-standardized rate of recurrent stroke within 1 year was 5.7% ; within 5 years, the overall recurrent stroke rate was 22.5% . The recurrence rate increased with advancing age and decreased with increased educational attainment. Age ≥65 years and a history of alcohol consumption were independent risk factors for recurrent stroke within 1 year after the incident stroke, after adjusting for age, sex, education, hypertension, diabetes, smoking, and alcohol consumption. However, the risk of recurrent stroke within 5 years after the incident stroke was positively associated with male sex, age ≥65 years, a lower level of education, known diabetes, and alcohol consumption, after adjusting for the previously indicated covariates. These findings suggest a crucial need to address risk factor management among stroke patients to reduce the burden of stroke, especially among low-income populations. Furthermore, a multicenter, large sample, nationwide study is urgently needed. Stroke is one of the leading causes of death and disability, worldwide  and is rEach year, there are ~2.5 million new stroke cases reported in China, and currently there are ~7.5 million stroke survivors; nationally, the stroke recurrence rate remains high (11.2%) . Over thThis study was a population-based stroke surveillance study that began in 1985 in Tianjin, China. The study design has been previously described –25. BrieThe study protocol was approved by the ethics committee of Tianjin Medical University General Hospital (TMUGH); written informed consent was obtained from each participant.All included stroke events were symptomatic and diagnosed using pre-established criteria, including clinical features and imaging evidence (MRI or CT scan). The initial (incident) stroke was defined as the first occurrence of rapidly developing signs of focal neurologic disturbances of presumed (no other apparent cause) vascular etiology lasting >24 h . TransieThe stroke types included ischemic stroke (IS), intracerebral hemorrhage (ICH), and unknown. IS was defined as a thrombotic brain infarction, cardioembolic stroke, or lacunar infarct.All incident stroke events included first-ever and recurrent strokes registered according to the previously published procedure . Stroke Information regarding stroke onset was obtained during interviews conducted by the community hospital physicians and the TMUGH neurologist; information included demographics, time of stroke onset, clinical signs, and previous stroke status. Other information, including imaging characteristics, prescribed therapy, and post-discharge outcomes, was obtained by the TMUGH neurologist during interviews with survivors, their family members, or a local health worker.The recruitment period was from January 1, 1992, to December 31, 2016, and follow-up was completed on December 31, 2017. During the surveillance period, all stroke events and all-cause deaths were registered and followed. The dates of death or emigration from the township were determined using population registries. All changes in demographic information were recorded, including births, deaths, immigrations (including that due to marriages), and emigrations (including that due to entering a high school or university or working in the city). Peasant workers were included in this study because all residents working in the city were seasonal workers who regularly returned to the township during traditional festivals and the farming season.Only patients who survived the index event were entered into the present analysis. Death was considered to have been caused by the incident stroke if it occurred within 28 days of symptom onset. All patients with at least 1 year of follow-up after their first-ever stroke events were included in this study. Follow-up evaluations were conducted every month, and recurrent strokes were classified using information from interviews, conducted directly during follow-up visits or by telephone calls to patients, next of kin, witnesses, or the attending physicians.All patients with TIAs; suspected stroke deaths without imaging evidence or confirmation by a TMUGH neurologist; and silent strokes, detected only by imaging, were excluded from this study. Patients suffering neuroimaging-confirmed strokes underwent computed tomography or magnetic resonance imaging examinations in the county central hospital.Categorical variables are presented as numbers (%), and continuous variables are presented as means . Patient ages were categorized into 3 subgroups  when the demographic features of this population were described and the rates of recurrent stroke were assessed; however, only 2 subgroups (<65 and ≥65 years) were used to assess the determinants of recurrent stroke. Education attainment was categorized into 3 subgroups . Smoking status was categorized into 3 subgroups ; similarly, drinking status was also categorized into 3 subgroups . The recurrent stroke incidence was calculated as the cumulative frequency of recurrent events at 1 and 5 years after the incident stroke. Association of education attainment with the risk of the recurrent stroke was assessed by Kaplan-Meier survival analysis and presented as log rank.P < 0.05.Multivariable Cox regression analyses were used to identify the predictors of recurrent stroke within both time periods after adjusted by covariates ; the risk of recurrent stroke occurrence is presented as adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The follow-up time was recorded in years and was calculated as the interval between the date of the initial stroke and the date of the recurrent stroke for those patients experiencing recurrent strokes within 1 and 5 years after the initial stroke. For those patients without recurrent strokes within 1 or 5 years after the initial stroke, the follow-up time was defined as 1 or 5 years, respectively. Moreover, for patients who died within 28 days after the initial stroke, the follow-up time was defined as the interval between the initial stroke and the date of death. During the study period, stroke patients who experienced initial strokes before immigrating to the township were included in the study; stroke patients who emigrated from the township after the initial stroke were excluded from the study. However, in this study, no stroke patients immigrated to or emigrated from the township during the study period. SPSS version 15.0 for Windows  was used for the analyses; statistical significance was defined as n = 899), were included in the determination of the 5 year recurrent stroke rate and its associated predictors.A total of 1,185 individuals experienced initial stroke events, including ICH, IS, and undefined events between 1992 and 2016. All 1,185 patients were included in the determination of the rate and associated predictors of recurrent stroke 1 year after the incident event; patients experiencing incident strokes between January 1, 1992, and December 31, 2012 ; in the 5 year group, the overall rate of recurrent stroke was 22.5% .P = 0.037) in the 1 year follow-up group.P = 0.576; P = 0.015; There was no significant association between the rate of recurrent stroke within 1 year and education attainment  after adjusting for age, sex, education level, hypertension, diabetes, smoking status, and drinking status; there was a lower risk of recurrence for those experiencing an IS than for those with an initial ICH. The risk of recurrent stroke within 5 years after the incident stroke was 1.65-fold higher among men than among women (P = 0.017). Compared with patients aged <65 years, the risk of recurrence in patients ≥65 years old increased 1.54-fold (P = 0.009). Similarly, the risk of recurrence in patients with <7 years of education was almost double that of patients with at least 7 years of education (P = 0.017). The risk was also 1.71-fold higher among those with a previous diabetes diagnosis than among those without diabetes (P = 0.008), and the risk of recurrence was more than two-fold higher among patients who ever drank compared to those who never drank .P = 0.033); this patient group also had a 79% lower risk of recurrent stroke among those who ever smoked than among those who had never smoked (P = 0.046). However, there was a 3.6-fold higher risk of recurrence for those who ever drank than among those who never drank (P = 0.025). The risk of recurrence within 5 years increased >2-fold among patients who ever drank compared to that among those who never drank (P = 0.021).Among patients aged ≥65 years, the risk of recurrence within the first post-stroke year was 57% lower in patients experiencing initial IS than in those experiencing initial ICH  and 5 (22.5%) years after the first-ever stroke. The recurrence rate over both time periods increased significantly with advancing age. After adjusting for age, sex, education level, hypertension, diabetes, smoking, and alcohol consumption, advanced age was an independent predictor of recurrent stroke within both time frames among the overall population. Moreover, male patients, patients with lower educational attainment, and those with a known diabetes history had higher risks of recurrent stroke within the 5 year period. Further, age-stratified analysis showed that known diabetes history was an independent risk factor of stroke recurrence at both 1 and 5 years after the initial stroke among stroke patients aged <65 years old. Moreover, patients with a lower educational attainment (1–6 years) had a high risk of stroke recurrence. However, for patients aged 65 years and over, ever drinking was an independent risk factor of recurrent stroke at both 1 and 5 years after initial stroke onset. In addition, experiencing initial IS and ever smoking were independent protective factors for risk of stroke recurrence among elderly individuals.The stroke recurrence rate remains controversial. The risk of stroke recurrence is reported to range from 7.0 to 20.6% over the first year , 12, 13,The disparity among the reported recurrence rates may be partially explained by the differing definitions of stroke recurrence. There is wide variation in the definition of recurrent stroke, ranging from any focal neurological deficit lasting >24 h and occurring after an initial stroke , 18, 30 In the present study, age was identified as a predictor of recurrent stroke. A previous study from northern Sweden indicated that the risk of stroke recurrence rose by 3% for every additional year of age . A similReports of sex-based differences in stroke outcomes are also inconsistent. Several previous studies have reported worse outcomes among women than among men, with women demonstrating greater functional impairment, mortality, recurrence, and dependency rates 3 and 12 months post-stroke , 35. HowThere is strong evidence for an inverse relationship between socioeconomic status (SES) and stroke incidence and mortality –39. HoweThe association between smoking and stroke risk remains controversial. In the Framingham Heart Study, smoking cessation was associated with a significantly lower risk of cardiovascular disease within 5 years among heavy smokers relative to current smokers; however, relative to never smokers, former smokers' cardiovascular disease risk remained significantly elevated beyond 5 years after smoking cessation . AnotherHeavy alcohol consumption is well-known risk factor for stroke , 50, butSeveral studies have suggested that diabetes mellitus is an important predictor of recurrent stroke –57. ConsThis study has several limitations. First, the study population was from a township in northern China, which is not representative of the overall population of China. However, the prospective study design and long study period may have decreased recall and selection bias. Moreover, the 362,596 person-years of total follow-up fulfill the 100,000 person-years of follow-up criterion for population studies . Second,This report assessed the rate of recurrent stroke in rural China using a population-based study design. The rates of recurrent stroke within 1 and 5 years after the first-ever stroke were 5.7 and 22.5% and increased significantly with advancing age. The determinants of stroke recurrence were associated with age. After adjusting for covariates, a known diabetes history was an independent risk factor for stroke recurrence at both 1 and 5 years after the initial stroke among patients aged <65 years old; moreover, lower educational attainment (1–6 years) increased the risk of stroke recurrence. However, for patients aged 65 years and over, ever drinking was an independent risk factor for recurrent stroke at both 1 and 5 years after the initial stroke onset; experiencing an initial IS and ever smoking were protective factors for the risk of stroke recurrence. These findings suggest a crucial need to address risk factor management among stroke patients to reduce the burden of stroke, especially among low-income populations. Furthermore, a multicenter, large sample, nationwide study is urgently needed.All datasets generated for this study are included in the artical/supplementary material.The study protocol was approved by the ethics committee of Tianjin Medical University General Hospital (TMUGH); written informed consent was obtained from each participant.JW and XN contributed to the study design, performed data collection, data interpretation, and critical review. JW performed data analysis. JH and WM contributed to drafting of the article. JH, WM, JN, YW, JL, LB, MS, and JT performed data collection, case diagnoses, and confirmation of case diagnoses. All authors read, revised, and approved the final version of the paper.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.


To evaluate the accuracy of multidetector computed tomography with a stomachprotocol in staging of gastric cancer.We evaluated 14 patients who underwent computed tomography in a 16-channelscanner for preoperative staging of gastric adenocarcinoma between September2015 and December 2016. All images were analyzed by the same radiologist,who had extensive experience in abdominal cancer imaging. The sensitivity,specificity, and accuracy of the method were calculated by comparing it withthe pathology result. All patients underwent partial or totalgastrectomy.The mean age was 61.5 years, and 53.8% of the patients were male. The gastriclesions were classified as T1/T2 in 35.7% of the cases, as T3 in 28.5%, andas T4 in 35.7%. Eleven patients (68.7%) had suspicious (N positive) lymphnodes. The accuracy of the T1/T2, T3, T4, and lymph node staging tests was85%, 78%, 90%, and 78%, respectively. The respective sensitivity andspecificity values were 71% and 100% for T1/T2, 66% and 81% for T3, 100% and90% for T4, and 88% and 60% for lymph nodes.Multidetector computed tomography with a stomach protocol, used inconjunction with virtual gastroscopy, shows good accuracy in the tumor andlymph node staging of gastric adenocarcinoma. Although mortalityis decreasing, it is an aggressive tumor, usually detected in advanced stages; andless than 20% of gastric cancer patients survive five years,3,4. If the disease isdiagnosed early, however, treatment has curative potential, with an average survivalof five years in over 90% of cases,3.Gastric cancer is one of the most prevalent cancers in the world and one of theleading causes of cancer-related death,6. In Brazil, thetumor-node-metastasis (TNM) system, maintained jointly by the International Unionfor Cancer Control and the American Joint Committee on Cancer,8, currently in its eighth edition, is used for cancer staging,although the classification presented in the seventh edition is maintained, asfollows:The main factors related to prognosis and therapeutic planning are tumor depth, lymphnode involvement, and distant metastasisT1 - Tumor invades the lamina propria, muscularis mucosa, orsubmucosa:T1a: tumor invades the lamina propria or muscularis mucosaT1b: tumor invades the submucosaT2 - Tumor invades the muscularis propriaT3 - Tumor invades the subserosa without invading the visceralperitoneumT4a - Tumor invades the serosa T4b - Tumor invades adjacent structures,4,9. However,it has disadvantages: it is an invasive method, is operator dependent, requiressedation, and is limited to stenotic lesions,9. In spite ofrevealing detail of the lesion, it is not suitable for evaluating distantmetastases, lymph node involvement, or peritoneal dissemination,11. In addition, its availability is limited in Brazil, evenin large population centers, and it is quite costly.Since 1980, endoscopic ultrasound has been used as the gold standard method toevaluate the depth of gastric wall involvement and the local extent (T stage) ofgastric tumors,12. However, therehave been great technological advances in recent decades. Multidetector CT (MDCT)allows the acquisition of thinner slices and shorter acquisition times,significantly improving image resolution, as well as the use of multiplanarreformatting techniques and three-dimensional reconstruction. The use of thesedifferent reconstruction techniques increases the diagnostic precision for thedetection of subtle mucosal lesions that can not be detected on two-dimensionalimages, providing an overall view of the stomach, with the exact location of thetumor, and precise staging, thus contributing to effective treatmentplanning,14. Currently, with high-qualityMDCT studies, it is possible to evaluate the extent to which the lesion has invadedthe perigastric fat tissue, as well as to detect regional lymph node disease andsigns of limited peritoneal carcinomatosis,12,15,16.Computed tomography (CT) is routinely used for cancer staging. Specifically forgastric cancer, it is useful for identifying distant metastases and the directinvasion of the tumor into adjacent organs,10,15,16. MDCT with a stomach protocolalso allows the use of virtual gastroscopy (VG), a three-dimensional reconstructiontechnique with intraluminal navigation, specific software being employed to detectalterations in the mucosa and submucosa of the gastric wall,9,10,17.In recent years, studies have demonstrated that with adequate gastric distension,MDCT is capable of detecting small lesions, as well as evaluating the depth of tumorinvasion of the gastric wall layers, differentiating T1/T2 lesions from T3 and T4lesionsThis was a retrospective, cross-sectional, single-center study, involving the reviewof CT images with a stomach protocol and VG for the staging of gastric cancer, withpathological correlation. Prior to the collection of data, the study was approved bythe ethics committee of the institution.The study included 16 patients who underwent MDCT with a stomach protocol, at areferral center for cancer, between September 2015 and December 2016. Of those 16patients, two were excluded: one for being lost to follow-up; and the other for notundergoing surgery. All of the patients included in the study underwent total orpartial gastrectomy, together with lymphadenectomy. In all cases, the surgicalspecimen was submitted to a standard histopathological study, with evaluation of thedepth of the lesion in the layers of the gastric wall, tumor extension into theperigastric peritoneum, and lymph node involvement, as well as TNM classification.The T and N staging by MDCT with a stomach protocol was compared with the finalpathological stage, for analysis of the sensitivity, specificity, and accuracy ofthe technique.CT scans were performed in a 16-channel multidetector scanner , in an axial plane volumetricacquisition with 1.25 mm collimation. For a better evaluation of the gastricwall, we used a stomach protocol with the following specifications: an 8-h fast;intravenous administration of an antispasmodic agent 10 min prior to theexamination; and ingestion of two effervescent salt envelopes, diluted in 10 mLof water, immediately prior to image acquisition.After images of the upper abdomen had been acquired in the pre-contrast phase, adynamic study was performed with the following parameters: intravenous injectionof nonionic iodinated contrast ,at a volume of 85-100 mL (depending on patient weight) and a flow velocity of2.5-3.0 mL/s; images of the upper abdomen acquired in the arterial phase; imagesof the upper abdomen and pelvis acquired in the portal phase; and images of theupper abdomen and pelvis acquired in the equilibrium phase.In the equilibrium phase, images should be acquired in the supine position thatwhich ensures the best distension of the stomach portion where the lesion islocated .All images were analyzed by the same radiologist, who had extensive experience inabdominal cancer imaging. The radiologist was aware that the images correspondedto the examinations of patients diagnosed with gastric cancer, as well as havingaccess to information regarding the size and location of the lesion atendoscopy. However, the radiologist was blinded to the pathology findings.,5,6,9,17, consistent with the TNMclassification,8 and characterized asfollows:The T staging was performed through analysis of axial images, as well as andcoronal and sagittal reformatted images, followed by intraluminal navigationthrough threedimensional reconstruction using specific software- AquariusiNtuition program  or Vitrea Workstation. Imaging criteria forevaluation of the extent of lesions in the gastric wall were the same as thoseused in previous MDCT studiesT1 - No changes seen in the gastric wall-There is focal thickening ofthe wall, with or without enhancement of the inner layer, and a lowdensity band at the base of the lesion corresponding to thepreserved submucosal layer; that is, focal enhancement only, withoutwall thickening.T2 - Complete thickening of the gastric wall, accompanied bydisappearance or interruption of the low density range, the externalcontour remaining well-defined and smooth-There is no bulging of theexternal gastric contour by the tumor, and the perigastric fattissue is preserved.T3 - Complete thickening of the gastric wall, accompanied bydisappearance or interruption of the low density range, the externalcontour remaining well-defined, albeit with slight bulging of theouter layer caused by the tumor-The perigastric fat tissue ispreserved.T4 - Nodular or irregular thickening of the outer layer of thegastric wall surrounding the tumor-There is increased density of theperigastric fat tissue or invasion of adjacentstructures/organs.During the study period, 19 patients underwent MDCT with a stomach protocol. Of those19 patients, three had no histological diagnosis of adenocarcinoma by endoscopicbiopsy  and were excluded from the analysis. Of the remaining 16 patients, one was lostto follow-up and was therefore also excluded. Another patient was excluded due to M1clinical staging, based on a finding of peritoneal carcinomatosis on tomography, andtherefore received only systemic treatment with chemotherapy.The final sample comprised 14 patients. The mean age was 61.5 years , and 53.8% were male. All patients had histological confirmation ofadenocarcinoma, and the majority (55.2%) had poorly or moderately differentiatedadenocarcinoma. In all cases, the MDCT images acquired with a stomach protocol andVG made it possible to identify the gastric tumor and were considered appropriatefor staging.The gastric lesions were classified as T1/T2 in 35.7% of the cases, as T3 in 28.5%,and as T4 in 35.7%. In terms of the lymph node staging, 11 patients (correspondingto 68.7% of the cases) were classified as N-positive (with suspicious lymph nodes).In 75% of the cases, abdominal CT did not show distant metastases (M0). Thirteenpatients underwent surgical resection, and eight (61.5%) of those patients receivedneoadjuvant chemotherapy. The pathological staging showed the following: signs ofinvasion of the submucosa or lamina propria mucosae (T1) in five patients (35.7%);signs of invasion of the muscle layer (T2) in two (14.2%); invasion of the serosa(T3) in three (21.4%); and signs of invasion of the peritoneum or neighboringstructures (T4) in three (21.4%). A patient with T4N+ staging by CT had a proposedsurgical resection canceled after the identification of a T4 lesion , together with peritoneal carcinomatosis in a staginglaparoscopy, as confirmed through biopsy. That patient was therefore classified ascT4yN3pM1.The sensitivity and specificity were calculated separately for three groups-T1/T2,T3, and T4-as shown in .With advances in therapeutic modalities and greater evidence of the benefit ofneoadjuvant chemotherapy for the T3, T4, and N+ stages of gastric cancer, imagingtechniques now contribute significantly to the therapeutic decision-makingprocess.The gold standard technique for local staging of gastric cancer is endoscopicultrasound. In a systematic meta-analysis, Kwee et al. demonstrated that endoscopicultrasound has variable rates of accuracy in the diagnosis of T staging (65-92%), aswell as a sensitivity of 70.8% and a specificity of 84.6% for the detection ofperigastric lymph node involvement.However, in recent years, there have been great technological advances in MDCT,allowing the acquisition of high-resolution images with fine slices, as well asmultiplanar and three-dimensional reconstructions. All of those improvements,combined with the development of new protocols, have contributed to an increase inCT sensitivity and accuracy in the local staging of gastric cancer. In addition, software forintraluminal navigation has facilitated the detection of early lesions of the mucosaand submucosa (T1/T2 lesions), as shown in . CT also has theadvantages of being noninvasive, widely available, and relatively inexpensive.Initial studies comparing local staging by endoscopic ultrasound and CT have produceddisappointing resultsApplication of a stomach protocol guarantees optimum gastric distension, beingfundamental for the adequate evaluation of focal thickening of the gastric wall andvisualization of the internal surface of the stomach through VG. A collapsed stomachcan obscure an injury or mimic an illness.,22. Kim etal. reported that MDCTwith a stomach protocol has a sensitivity of 62-93% and a specificity of 90-97%.Another study evaluating the accuracy of MDCT in the T staging of gastric cancer,using axial analysis  alone or in combination with multiplanaranalysis and three-dimensional reconstruction, also showed significant improvement in diagnosticperformance (73% vs. 89% for the combination), reaffirming the importance ofcombining these techniques in the evaluation of images.Recent studies have demonstrated that MDCT with a stomach protocol has an accuracysimilar to that of endoscopic ultrasoundOur work did not focus on differentiating between T1 and T2 lesions, although someauthors have argued that MDCT with a stomach protocol can achieve the imageresolution necessary for such a distinction. From a clinical point of view, thedifferentiation between T1 and T2 lesions is not fundamental, given that neoadjuvanttherapy is not recommended in either stage. We designated the groups T1/T2, T3, andT4, using the new criteria for patterns of gastric wall involvement. The values ofsensitivity, specificity, and accuracy were similar to those reported in otherstudies. In three patients, there was disagreement between the MDCT staging and thepathological staging. Two of those patients were staged as T3 by MDCT, whereas theywere staged as T1b and T2, respectively, in the final pathological staging. Thethird patient was staged as T4 by MDCT and as T3 in the final pathologic staging. Itis noteworthy that all three of those patients were submitted to neoadjuvantchemotherapy after the MDCT staging, and the disagreement between the two stagingmethods might result in downstaging due to the therapeutic response. There were nocases of lesions for which the pathological staging was higher than that of theimaging. In the remaining patients, there was agreement between the MDCT staging andthe pathological staging.. For borderline lesions, there can still be difficulty inquantifying the blurring of the perigastric plane. Some T2 lesions may causediscrete blurring of the perigastric fat by a desmoplastic reaction. Habermann etal. used the samecriterion employed in endoscopic ultrasound to differentiate between desmoplasticreaction and tumor infiltration; that is, when the blurring affects less thanonethird of the tumor border, the lesion is classified as T2, and when it is moreextensive, the lesion is classified as T3. The authors found that there was noincorrect staging of T2 tumors when that criterion was applied.Some borderline T2/T3 lesions can be difficult to define in MDCT. There are factorsthat can hamper differentiation, such as the variation in the amount of fat tissuefrom patient to patient and a reduced area of enhancement if there is exaggerateddistension of the gastric chamber,12. For T4b lesions, there is directinvasion of adjacent structures or organs. Three-dimensional reconstruction isuseful and should be used in order to differentiate between these forms ofinvolvement.The differentiation between T3  and T4lfound that, for lymph node staging, MDCT has a sensitivityof 62.5-93.0% and a specificity of 90.5-97.9%. One of the reasons for thedifferences across studies is the variety of criteria used in order to classify alymph node as affected, the most widely used parameter being the size, with acut-off threshold ranging from 5 to 10 mm at its smallest diameter. We defined affected perigastriclymph nodes as those measuring > 6 mm at their smallest diameter or ≥ 8 mmat their largest diameter. Another valued criterion is the presence ofnecrosis. In ourstudy, the sensitivity and specificity values were 60% and 80%, respectively.Lymph node involvement is one of the factors that directly influences patientprognosis. In a meta-analysis, Kwee et al.. Other limitations of VG are related to thespecific examination protocol, which requires preparation of the patient withprolonged fasting (for 8 h), the use of additional medications, and the presence ofa radiologist. It also requires additional radiologist time to performthree-dimensional reconstruction and intraluminal navigation, adding an average of20-30 min per patient.It should be borne in mind that VG does not allow the evaluation of perigastric tumorinvolvement, diagnosis of regional lymph node diseases, or identification of distantmetastases; VG findings should always be interpreted together with the analysis ofaxial plane images and multiplanar reconstructionsOur study has certain limitations. The small number of patients and the fact thatsome underwent neoadjuvant chemotherapy increased the likelihood of disagreementamong the findings. Despite our initial experience, we believe that MDCT with astomach protocol brings benefits in the clinical staging of gastric cancer, asdemonstrated in several international studies. Further studies with larger patientsamples may help confirm the results that have been presented in recent years, aswell as allowing the impact of CT on the management of these patients to beevaluated.In conclusion, MDCT has become an accessible, noninvasive method for the evaluationof the local extent and lymph node involvement in gastric cancer staging. Whenperformed with a stomach protocol, MDCT provides additional information to improvethe therapeutic decisionmaking process, showing good accuracy when differentiatingamong T1/T2, T3, and T4 lesions, and should be considered a viable alternative toendoscopic ultrasound.


Supplemental Digital Content is available in the text Peptic ulcer disease (PUD) is a major burden worldwide. Several challenges remain with standard Western treatment of PUD, such as persistent weakness, fatigue, and relapse. A dietary traditional Chinese medicine (TCM) formula, Hou Gu Mi Xi (HGMX), has been developed as a complementary treatment for PUD.This multicenter, double-blind, randomized controlled trial will assess efficacy and safety of HGMX in patients with PUD.t tests, Pearson χ2 test and the rank-sum test will be used to compare between-group differences. The P value will be adjusted using the O’Brien & Fleming method for multiple comparisons.Three hundred sixty eligible patients will be assigned to receive HGMX, placebo, HGMX + rabeprazole or placebo + rabeprazole for 4 weeks after 2 weeks of standard Western treatment. This first step, with a 2 × 2 factorial design, will focus on assessing the main and interaction effects of HGMX and rabeprazole on ulcer healing. Then, rabeprazole will be stopped, and HGMX will be continued for up to 1 year. The second step, with a placebo-controlled design, will compare the long-term effects of HGMX and placebo. Extended follow-up with no treatment will continue for up to 2 years. Independent and paired Helicobacter pylori eradication rate, gastric function, body weight, and body mass index. Adverse events (AEs), severe AEs, treatment-related AEs, and withdrawal owing to AEs will be recorded to assess treatment safety.The primary outcomes are total efficacy rate of PUD treatment, quality of ulcer healing, and changes in spleen qi deficiency symptoms. The secondary outcomes include ulcer area, PUD recurrence, The trial results will provide high-quality evidence for HGMX, as a complementary therapy, for the long-term management of PUD and will be valuable for the development of related guidelines and regulations.The protocol of this trial was approved in all research hospitals and was registered in ClinicalTrials.gov at October 25, 2017(No. NCT03320538). PUD is a major problem in China, in which the prevalence was up to 17.2% in 2010. The pathogenesis of PUD is chronic damage to the gastroduodenal mucosa, which is mainly attributed to Helicobacter pylori (H pylori) infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs); 72.2% of H pylori-positive patients and 25% of patients with long-term NSAID use ultimately develop PUD.,5Peptic ulcer disease (PUD) is a common digestive system disease that mostly involves the stomach and duodenum, corresponding to a gastric ulcer (GU) and a duodenal ulcer (DU). PUD may occur at any age, but more than half of patients are diagnosed at an age of 30 to 49 years. PUD can progress to severe complications, including bleeding, perforation, pyloric stenosis, and even cancerization, which may have life-threatening outcomes. Routine treatment of PUD involves a combination of H pylori eradication, acid suppression , and gastric mucosa protection . This regimen shows definite efficacy, with an ulcer healing rate >90%. However, there are still some concerns with the routine treatment. Gastrointestinal symptoms generally improve significantly after treatment, but systemic symptoms (such as weakness and fatigue) can persist. Moreover, PUD relapse is not uncommon in patients who fail to eradicate H pylori and exhibit poor ulcer healing.The typical symptoms of PUD are chronic, rhythmic, and periodic upper abdominal pain, as well as distension, belching, and inappetence. A number of animal and human studies have shown that TCM therapies, such as Chinese herbal medicine and acupuncture, have anti-ulcer effects and can reduce the recurrence of ulcers.–17 In TCM theory, most cases of PUD can be classified as spleen qi deficiency (SQD) syndrome, in which the patient's spleen (an abstract organ responsible for transporting and transforming food and water that differs from the organ in Western medicine) and qi (a kind of abstract energy that sustains life) are weakened by disease to the point that are unable to function normally, resulting in a range of gastrointestinal and systemic symptoms. Therefore, the TCM treatment of SQD syndrome emphasizes invigorating spleen and replenishing qi to improve immunity and self-healing, and integrated TCM and routine treatments are expected to have greater efficacy against PUD.In China, combinations with traditional Chinese medicine (TCM) have become an important complement to prevent and solve the above conditions. Animal studies have shown that Shen Ling Bai Zhu San regulates absorption, mucosal ultrastructure, and the flora balance in the gastrointestinal tract to improve the ability to self-repair ulcers.,21 However, there is a lack of high-quality randomized controlled trial (RCT) evidence on the efficacy and safety of this formula for PUD. Moreover, the powder preparation of Shen Ling Bai Zhu San is difficult to take and tastes bad, which is disadvantageous for the long-term management of PUD.Shen Ling Bai Zhu San is a classic TCM formula originally documented in the Song Dynasty (1102 AD). More than 3000 years of ancient experience has shown that Shen Ling Bai Zhu San has the functions of invigorating spleen and replenishing qi and can be used to treat PUD.Baizhu), the only component in Shen Ling Bai Zhu San forbidden to use as food according to the regulations in China, with orange peel (Jupi) and is made into cornmeal with japonica rice and oats to improve patient compliance. As a result, HGMX is composed of 10 dietary herbs: ginseng (Renshen), tuckahoe (Fuling), coixenolide (Yiyiren), Chinese yam (Shanyao), lotus seed (Lianzi), Amomum (Sharen), Platycodon (Jiegen), white hyacinth bean (Baibiandou), liquorice (Gancao), and orange peel. In this formula, ginseng and tuckahoe play roles in invigorating qi and nourishing spleen; coixenolide, Chinese yam, lotus seed, and Amomum help improve the effects of ginseng and tuckahoe; and Platycodon, white hyacinth bean, liquorice and orange peel assist in promoting lung qi and regulating the waterway to improve the absorption of the herbs. The combination of these dietary herbs is expected to be efficacious at improving immunity and ulcer healing. In addition, HGMX should have a good safety profile because of its dietary property, and no adverse events (AEs) related to HGMX have been reported in the 3 years of post-market safety monitoring.Hou Gu Mi Xi (HGMX), a dietary TCM formula modified from Shen Ling Bai Zhu San, was developed in 2016. HGMX replaces Atractylodes  on October 25, 2017, and we report the protocol according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) criteria.2.1The participants will be enrolled from 11 hospitals in 3 cities in Jiangxi Province: the First Affiliated Hospital of Nanchang University, the Second Affiliated Hospital of Nanchang University, the Third Affiliated Hospital of Nanchang University, Jiangxi Hospital of Traditional Chinese Medicine, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang Hospital of Integrated Traditional Chinese and Western Medicine, The Nanchang Third Hospital, Xinyu People's Hospital, Xinyu Hospital of Traditional Chinese Medicine, Jiujiang No.1 People's Hospital, and Jiujiang Hospital of Traditional Chinese Medicine. Trial enrolment will be advertised through oral promotion by researchers, hospital posters, and web page advertising. The recruitment was started at July 10, 2017 and is expected to be completed in July 2020.2.2Patients will be deemed eligible after screening according to the inclusion and exclusion criteria.2.2.11.2 with no indications of bleeding or perforation.Diagnosed with GU or DU by endoscopy and ulcer area from 0.3 to 1.0 cm2.Diagnosed with SQD according to the criteria in the Consensus on Integrated Traditional Chinese and Western Medicine, as follows:Main spleen deficiency (SD) symptoms: poor appetite; stomach or abdominal distention; loose stools or diarrhea.Main qi deficiency (QD) symptoms: physical fatigue and weakness; mental fatigue and taciturnity.Secondary symptoms: loss of taste or hypodipsia; stomach or abdominal pain; stomach tightness; nausea or vomiting; abnormal bowel sounds; lean or puffiness; sallow complexion; powerless defecation; facial or limb oedema.Tongue symptoms: pale, swollen, or scalloped tongue with a thin, white coating.Patients will be diagnosed with SQD if they meet: 2 main SD symptoms + 2 main QD symptoms; 2 main SD symptoms + 1 main QD symptom + 1 tongue symptom; or 1 main SD symptom + 1 main QD symptom + 2 secondary symptoms + 1 tongue symptom.3.Aged from 18 to 70 years.2.2.21.Complex peptic ulcer .2.History of ulcer complications .3.2).Indications of ulcer complications, including bleeding and perforation , aspartate aminotransferase >2× ULN, or serum creatinine >ULN.8.Other severe diseases .9.Unwilling to provide personal information.2.3Patients who pass the eligibility assessment will be randomly and proportionally divided into four groups: Group A, B, C, and D. We generated a block randomization sequence using Microsoft Excel that was saved as enciphered data. For allocation concealment, we will adopt centralized random assignment. Independent researchers who do not participate in trial procedures other than the randomization process will recode the random sequence into continuous numbers and label the boxes of trial samples. Samples will be allocated sequentially to participants. In this way, no one will know the group into which the next participant will be assigned.This trial will have 3 intervention periods: standard treatment period, maintenance treatment period, and recuperation treatment period. The standard treatment period will be open-label. During the maintenance and recuperation treatment period, the clinicians, patients, outcome assessors, and data collectors will be blinded in terms of the assignment of HGMX or placebo but the administration of rabeprazole will be open-label. Except in instances of a severe AE, all the participants, medical providers, data collectors, and outcome reviewers will strictly adhere to the blinded de∗sign until the trial has been completed. In addition, an independent committee will supervise the allocation concealment and blinding, and if blinding is violated, the corresponding patient will be excluded. Figure 2.42.4.1H pylori-positive patients will also receive 1 mg amoxicillin b.i.d. and 0.1 g furazolidone b.i.d. for 2 weeks to eradicate H pylori.All eligible patients will receive standard Western treatment. Specifically, all patients will receive 20 mg rabeprazole b.i.d. and bismuth potassium citrate 0.3 g b.i.d. for 2 weeks. 2.4.2The patients in the 4 groups will receive the following intervention for 4 weeks as maintenance treatment to further facilitate ulcer healing.1.Group A: HGMX 30 g b.i.d.2.Group B: HGMX placebo 30 g b.i.d.3.Group C: HGMX 30 g b.i.d. + rabeprazole 10 mg q.d.4.Group D: HGMX placebo 30 g b.i.d. + rabeprazole 10 mg q.d.HGMX is an oatmeal-like solid food (eaten dry or mixed with a liquid) that contains 10.1 g dietary herb material per 30 g. Table 2.4.3All participants will enter the recuperation treatment period at the beginning of week 7. In this period, the doses of HGMX and placebo will remain unchanged  for all groups for a 46-week recuperation treatment. Rabeprazole will not be administered to the corresponding groups during this period.2.4.4This is an observational period. All the interventions will be stopped, but follow-ups and outcome assessments will continue.2.4.5If participants have comorbidities not specified in the exclusion criteria, they will be allowed to receive targeted therapy, such as oral hypoglycemic drugs and insulin for diabetes, hypotensive drugs for hypertension, and antiallergy drugs for asthma.Medicines that may damage the gastrointestinal tract, such as NSAIDs, theophylline and potassium supplements, and those that have a similar effect as our treatment, such as other PPIs, bismuth, and other Chinese herbal medicines, are prohibited.2.52.5.11. First, ulcer healing status will be classified into 6 categories:The total effective rate of PUD treatment will be calculated as /total number of participants. Efficacy will be assessed by Sakita–Miwa's method.A1: the ulcer is round or elliptical, with a thick and white covering in the center; it can be accompanied by errhysis or blood clots and surrounded by obvious swelling, hyperemia, and oedema.A2: the ulcer is covered by yellow or white patches, with no bleeding and less swelling and edema.H1: the ulcer is healing; the coating of the ulcer becomes thin and subsides, hyperemia and edema disappear around the ulcer, and new capillaries appear.H2: the ulcer becomes shallow and small; the surrounding mucosa plica is central to the ulcer.S1: the white coating of the ulcer disappears, and the new ulcer mucosa is red.S2: the new ulcer mucosa changes from red to white.Then, the efficacy will be ranked according to the following 4 levels based on ulcer rehabilitation and recovery:Clinical cure: the ulcer completely heals with or without a scar.Markedly effective: the ulcer heals to grade H2 or improves 2 grades.Effective: the ulcer heals to grade H1 or improves by 1 grade.Noneffective: no efficacy by endoscopic observation.2.:The quality of ulcer healing will be classified as follows by histopathological examination using Pan's criteriaGood: integral villus and epithelium, many glands, good morphology, many capillaries, and limited inflammatory cell infiltration.Fair: short villus, incomplete or rough epithelium, fewer glands, structural distortion, few capillaries, and moderate inflammatory cell infiltration.Poor: few new epithelial cells, poor epithelium integrity, poor morphology of villus and glands, very few capillaries, and a large number of inflammatory cells.3. This is a modified version of the classic scale that has a total of 15 items to assess 7 main symptoms and 8 secondary symptoms. Four aspects of SQD symptoms will be assessed, including severity, duration per episode, number of attacks per day, and number of affected days per week. The total score of each item is the sum of points for the 4 aspects in all items (items assessing the main symptoms receive double weight). The score ranges from 0 to 283 points, and a higher score indicates worse symptoms (see details in Supplementary file).The changes in SQD symptoms will be assessed based on the Spleen Qi Deficiency Symptoms Grading and Quantifying Scale  score.2.5.21.2) measured by endoscopy.Ulcer area  value to <4 in the 13C-urea breath test during follow-up for H pylori-positive patients.5.Gastric function evidenced by analysis of gastrin-17 (pg/mL), pepsinogen I (ng/mL), and pepsinogen II (ng/mL).6.Changes in body weight (kilogram) and body mass index (kilogram per meter square).2.5.31.AEs, which will be assessed in 2 ways: significant abnormality  in the results of routine blood, urine or stool examinations, liver or kidney function tests, or electrocardiogram; AEs reported by clinicians and patients.2.Severe AEs (SAEs), which are defined as AEs that are life-threatening or lead to admission to the intensive care unit, prolonged hospitalization, or physical or mental disability. Once an SAE occurs, the principal investigator will report it to the hospital institutional review board and submit the appropriate paperwork to the Food and Drug Administration, Department of Jiangxi Province, within 24 hours.3.Treatment-related AEs, which must meet all the following criteria: the AE has reasonable time causality with treatment administration; comorbidities and co-interventions are not related to the AE; the symptoms of the AE improved or recovered when treatment was stopped; and the causality can be explained by pharmacological, biological, or phenomenological mechanisms.4.Withdrawal owing to AEs.2.6H pylori infection and gastric function and perform gastroscopy at weeks 12, 26, 52, and 104. SQD symptoms, AEs, and concomitant treatments will be assessed or recorded at all follow-up visits. Table We will visit patients at baseline and at weeks 6, 12, 26, 52, and 104. In addition to the baseline measures of the outcomes, patients will undergo an eligibility assessment and provide demographic data, including gender, age, marital status, living situation, complications, medication history, and allergy history at baseline. During follow-up, we will examine ulcer histopathology at weeks 12 and 26; perform physical examinations, laboratory tests, and an electrocardiogram at weeks 12, 26, and 52; and examine 2.7Anyone who reports any of the following conditions during follow-up will be classified as withdrawal, and the patient will discontinue the trial.1.Acute recurrent ulcer .2.SQD symptoms constantly worsen and require other interventions.3.Patient took <80% of the prescribed dose or any prohibited drug.4.Withdrawal owing to AEs.5.Patient request for withdrawal.2.8Data collection and management will be carried out by a collaboration of research associates, coordinators and clinicians. All the investigators will undergo standard operating procedure (SOP) training based on the study protocol. During the trial, subject recruitment, intervention, follow-up, data collection and data management will be performed in strict accordance with the SOPs.The clinicians will be responsible for the baseline and outcome examinations, including SQD symptom assessments, biological sample collections, and laboratory examinations. All these data will be entered on pilot-tested case report forms. The research coordinators will be student volunteers from Jiangxi University of Traditional Chinese Medicine and will be responsible for contacting patients and helping with communication between patients and doctors. We will assign to each study center a research associate selected from researchers at Jiangxi University of Traditional Chinese Medicine who will be responsible for monitoring the follow-up process, standard performance, patient compliance, and completeness of data collection. We will develop a specialized computer system for data entry that will support data query and verification. Once verified, data will be locked and accessible to only data analysts during the data analysis period. In special cases and emergency conditions, such as SAEs, the database will be temporarily accessible, and data for the corresponding participant will be unblinded.2.9 Because there are no previous studies available for reference, we estimated a P of .85  and a P0 of .65  according to the results of our pilot survey and expert opinions. In addition, we adopted a type I error (α) of 0.05, a type II error (β) of 0.2, and a maximum drop-out rate of 15%. Based on these assumptions and our funding constraints, we computed a sample size of 360, with 90 in each group.The main objective of this trial is to assess the effects of HGMX compared with placebo on the total effective rate. Therefore, the sample size estimation is based on the formula for a superiority design.2.10The primary outcome data will be analyzed using the intention-to-treat population, in which all patients will be maintained in their initial group assignment regardless of compliance and contamination, and missing data will be imputed using the last observation carried forward method. Meanwhile, we will also conduct a sensitivity analysis with the per-protocol population. The safety outcomes will be analyzed using a safety population including all participants who received treatment at least once. Mid-term and final data analyses will be performed at the end of week 52 and 104, respectively.t test or analysis of variance. Non-normal continuous variables will be described using the median and interquartile range and analyzed with the Mann–Whitney U test. Categorical variables will be presented as the frequency and percentage and compared using Pearson χ2 test. The boundary of significance for the P value will be .05, which will be adjusted using the O’Brien & Fleming method for multiple comparisons.Normality will be detected using the Kolmogorov-Smirnov method. Normal continuous variables will be described using the mean and standard deviation and compared using a H pylori infection status (yes vs no). All statistical analyses will be conducted in Stata v14.0 software.According to our factorial design, we will explore whether there exists an interaction between HGMX and rabeprazole. If there are no significant interaction effects, we will compare the main effects of HGMX and rabeprazole. In addition, we will perform subgroup analysis stratified by type of PUD (GU vs. DU) and 2.11An independent data monitoring committee (DMC) will be found, which will be responsible to supervise the overall efficacy and safety of the trial. The DMC will have right to decide an interim data analysis and to stop the trial if obvious benefits or harms are observed.2.12This trial protocol was approved by the Ethics Committee in the 11 research hospitals: Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine (JZFYLL2017071406), First Affiliated Hospital of Nanchang University (2017YYLS028), Second Affiliated Hospital of Nanchang University (2017YYLS1011), Nanchang First Hospital (KYC2017302), Nanchang Third Hospital (2017KYLS001), Nanchang Hongdu Hospital of Traditional Chinese Medicine (KY-2017-004), Nanchang Hospital of Integrated Traditional Chinese and Western Medicine (2017YYLS001), Xinyu People's Hospital (2017LLS002), Xinyu Hospital of Traditional Chinese Medicine (2017YYLS1), Jiujiang No.1 People's Hospital (JJSDYRMYY-LL-2017-007), and Jiujiang Hospital of Traditional Chinese Medicine (JJSZYYY20170721).3The main purpose of this study is to clarify the efficacy and safety profile of HGMX, a dietary TCM formula, in patients with PUD and SQD syndrome and assess their treatment compliance. The assessment at week 12 will focus on the main and interaction effects of HGMX and rabeprazole on the quality of ulcer healing, and the following assessments are designed to assess the long-term effects of HGMX compared with placebo on the total effective rate, quality of ulcer healing, SQD symptoms, and PUD recurrence rate. Owing to manufacturing limitations, we cannot produce a placebo for rabeprazole and thus cannot utilize a blinded design for rabeprazole treatment, which will be a main limitation of our study and may lead to potential bias due to placebo effects. Another underlying limitation is that we chose a self-modified scale that lacks confirmation of reliability and validity and thus may introduce measurement bias.Dietary TCM formulas are widely used for chronic disease management in China. However, the use of dietary TCM formulas is challenged by the lack of high-quality research evidence and related regulations. To produce high-quality evidence to increase the clinical use of HGMX, we will conduct a series of RCTs involving participants with PUD, nonorganic gastrointestinal disorders (NOGDs), and radical gastrectomy for gastric cancer. These are the first RCTs committed to evaluating a dietary TCM formula, and they will hopefully establish an evidence-based clinical research model for dietary TCM formulas and be valuable for the development of related guidelines and regulations.The authors thank 10 student volunteers from Jiangxi University of Traditional Chinese Medicine  for their great efforts on the patient enrollment.Conceptualization: Xu Zhou, Weifeng Zhu.Investigation: Nonghua Lv, Nian Fang, Jinhua Gong, Jianwei Yu, Yiping Jiang, Zhijun Liu, Huihu Gan, Ying Fu, Deping Yang, Yan Xiong, Dunju Liu, Ming Chen.Supervision: Jianhe Fang, Wenjun Liu, Heyun Nie, Yanping Wang.Writing – original draft: Xiaofan Chen, Dongmei Yan, Yang Wang.Writing – review & editing: Xin Sun, Xu Zhou, Weifeng Zhu.


Pharyngoesophageal diverticulum is an uncommon complication after anterior cervical discectomy and fusion surgery.. She was taken for open surgery with removal of screws and plates, cricopharyngeal myotomy, and esophageal repair. Streptococcus milleri grew in tissue and osteosynthetic material. She received 4 months of amoxicillin and probenecid and had a complete recovery. Since 1991, 19 similar cases have been reported with one fatality. To our knowledge, this is the first reported case of diverticulum complicated with fistula and secondary spondylitis.Our patient was a 48-year-old woman with two previous cervical surgeries with fixation of C4-C5 and C5-C6, the last one in 2003. Two years after surgery, she presented with arthralgia, arthritis, chills, and fluctuating rash. In 2007, she presented with dysphagia, halitosis, and sputum production. She was diagnosed with a pharyngoesophageal diverticulum with a fistula to C6 vertebra and secondary spondylitisIn patients with a history of anterior cervical discectomy and fusion complaining of dysphagia, even years after surgery, it is mandatory to perform an esophagogram. This symptom was referred to in 88% of the cases reported in the literature. Since the 1990s, the number of anterior cervical discectomy and fusion (ACDF) surgeries performed has dramatically increased. The Nationwide Inpatient Sample estimated 932,009 hospital discharges associated with cervical spine surgery from 1992 to 2001 in the United States. The overall rate of complications has been reported to be 3.93%, and mortality was estimated at 0.14%. Factors associated with complications were advanced age, primary diagnosis, and type of surgical procedure. The most common reported complication was dysphagia [3 , elevated C-reactive protein (CRP) 75 mg/dl , and erythrocyte sedimentation rate (ESR) 40 mm/h . Autoantibodies were negative, and complement levels were within normal range.Our patient was a 48-year-old woman with a history of two previous cervical surgeries, the first one in 1987 and the second in 2003, with placement of titanium plates and screws at C4-C5 and C5-C6. She was seen at the clinic in 2005 with a 2-month history of fatigue, chills, headache, nausea, and asymmetric arthralgia. She also had episodes of malar rash after sun exposure and cutaneous fluctuating rash in the trunk. Physical examination revealed arthritis of the left shoulder and left ankle, livedo reticularis, and erythematous cutaneous rash in the thorax. No infection foci were detected. Laboratory studies revealed thrombocytosis 485,000 cells/mmFrom 2005 to 2007, she had no treatment, and her symptoms had a fluctuating course. In 2007, fatigue, rash, and arthralgia appeared again, and she developed edema in her hands and feet. Rheumatology started prednisone and methotrexate without improvement. Six months later, dysphagia, halitosis, and “sputum” production of purulent aspect were added to the patient’s symptoms. She consulted an ear, nose, and throat specialist, who did not find any abnormality.She continued with elevated CRP, ESR, and thrombocytosis. Labeled leukocyte single-photon emission computed tomography (SPECT) suggested spondylitis in the cervical spine (C4-C6) and revealed an inflammatory process in the nasopharynx, an increase in the prevertebral space of > 2 cm, and free air in this area Fig. . An esopStreptococcus milleri. The patient was treated with oral amoxicillin 1 g every 8 h and probenecid for 4 months, until a gammagram was negative. Her fatigue, arthralgia, rash, and livedo reticularis as well as dysphagia disappeared. Her acute-phase reactants normalized.The patient was taken to surgery; screws and plates were removed from C4 to C6; surgical debridement was performed; and the fistula and diverticulum were removed with cricopharyngeal myotomy and esophageal repair. Esophagography with water-soluble contrast showed no leak after surgery, but the lumen of the esophagus at C4–C6 was increased in diameter with diminished compliance. Removed plates, screws, and tissue were cultured and grew We conducted research in the PubMed database using the following terms: pharyngoesophageal diverticulum, Zenker diverticulum, pharyngeal diverticulum, esophageal diverticulum, anterior cervical spine surgery, anterior cervical discectomy and fusion complications. We obtained 15 articles that were either case reports or case series of diverticulum formation after anterior cervical surgery with a total of 19 cases since 1991 [Of the 20 patients, including our patient, 10 were women (50%), and their mean age was 44 years with a range from 24 to 63 years. Seventeen cases 85%) reported dysphagia as the main symptom, and the mean time between the surgery and the symptoms was 4.4 years ; only one case did not specify time 5% report. EsophagIn our patient, cervical spondylitis developed due to fistulization at C6, allowing for contiguous spread of oral flora and infection toward the cervical spine and soft tissues. Chronic infection caused an immune complex disease, which resolved after removal of fixation plates and screws, surgical repair of the fistula and diverticulum, and prolonged antimicrobial therapy. The causative agent is part of the normal oral flora. Our hypothesis is that the esophageal diverticulum developed after the anterior cervical spine fixation performed in 2003, because the fixation plate’s position was too anterior (Fig. This case exemplifies how new therapeutic strategies cause problems not previously described and that meticulous clinical evaluation and rational use of diagnostic workup are necessary to solve clinical issues. Persistent dysphagia following anterior cervical surgery should alert the clinician to the possibility of having different possible complications and is mandatory for a complete diagnostic approach to rule out this possibility.