Genetic Evidence for Causal Association Between Hypertension and Chronic Pain:A Bidirectional Two-Sample Mendelian Randomization Study

Objective The extent to which the association between hypertension and chronic pain in observational studies is either causally linked or influenced by other shared risk factors has not been substantially addressed.In the present study,Mendelian randomization(MR)was employed to examine the potential causal relationship between hypertension and risk of chronic pain.Methods The study data were derived from the pooled dataset of the genome-wide association study(GWAS),enabling the evaluation of the causal effects of hypertension on various types of chronic pain including chronic headache as well as chest,abdominal,joint,back,limb,and multisite chronic pain.We performed a bidirectional two-sample MR analysis using random effect inverse variance weighting(IVW),MR-Egger,weighted median,and weighted mode,quantified by odds ratio(OR).Results Genetically predicted essential hypertension was associated with an increased risk of chronic headache(OR=1.007,95%CI:1.003-1.011,P=0.002)and limb pain(OR=1.219,95%CI:1.033-1.439,P=0.019).No potential causal associations were identified between chronic pain and essential hypertension in the reverse direction MR(P>0.05).In addition,there was no potential causal association between secondary hypertension and chronic pain(P>0.05).Conclusion This study provided genetic evidence that a unidirectional causal relationship exists between essential hypertension and the increased risks of chronic headache and limb pain,and no causal relationship was found between secondary hypertension and chronic pain.These findings offer theoretical underpinnings for future research on managing hypertension and chronic pain.

Anesthesia Management in Hereditary Pheochromocytoma and Paraganglioma:Updated Insights into Clinical Features and Perioperative Care

Approximately 40% of pheochromocytoma and paraganglioma(PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical characteristics and perioperative care for PPGL. Pheochromocytoma in von Hippel-Lindau(VHL) disease exhibits heightened secretion activity without significant perioperative hemodynamic changes. Tumors in multiple endocrine neoplasia type 2(MEN2) have a stronger endocrine function, which may induce hemodynamic fluctuations during surgery. Therefore, pheochromocytoma screening is essential at all stages of MEN2. Neurofibromatosis type 1(NF1) often presents multisystem lesions and can result in difficult airway. Pheochromocytoma should be evaluated when NF1 patients present hypertension. Pheochromocytoma and paraganglioma type 5 may present multiple lesions of pheochromocytoma or paraganglioma. In summary, hereditary PPGLs may present with severe lesions in other systems, beyond tumor function. A multi-disciplinary team(MDT) approach is often invaluable in perioperative management.

BILL Strategy:Points to Consider During the Performance and Interpretation of Critical Care Echocardiography

The growing utilization of critical care echocardiography(CCE) by clinicians necessitates a meticulous review of clinical conditions in critically ill patients, both before and during the examination. The reviewing process of clinical conditions minimizes the risk of overlooking or misinterpreting crucial findings. This article proposes a comprehensive strategy, namely BILL strategy, to integrate into the CCE protocol, where "B" represents baseline respiratory and hemodynamic support, "I" signifies information gleaned from invasive monitoring, including central venous pressure and thermodilution-derived cardiac output, the first "L" denotes laboratory results such as central venous oxygen saturation, troponin, and brain natriuretic peptide, and the second "L" refers to lung ultrasound data. Combining the BILL strategy with CCE can enhance comprehensive understanding of critical conditions, potentially leading to improved diagnostic accuracy and patient outcomes.

Polypyrimidine Tract-Binding Protein Enhances Zika Virus Translation by Binding to the 5'UTR of Internal Ribosomal Entry Site

Objectives To identify the 5'untranslated region of Zika virus(ZIKV 5'UTR)RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site(IRES)located in ZIKV 5'UTR and virus production.Methods Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining,Subsequently,liquid chromatographytandem mass spectrometry(LC-MS/MS),bioinformatics analysis,and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR.Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production,respecitvely.Results tRSA RNA pull-down assay,LC-MS/MS,and Western blot analysis showed that polypyrimidine tractbinding protein(PTB)bound to the ZIKV 5'UTR.Furthermore,dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV(t=10.220,P<0.001),while PTB knockdown had the opposite effect(t=4.897,P<0.01).Additionally,virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer(t=6.400,P<0.01),whereas reducing PTB expression level weakened virus infectivity(t=5.055,P<0.01).Conclusion PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production.

Preliminary clinical application of total free-breathing cardiac MR examination

Objective To observe the clinical application value of total free-breathing cardiac MR(CMR)examination preliminarily.Methods Two patients who underwent CMR scanning under free-breathing state,including cine,motion correction T1 and T2 mapping,blood flow imaging,and late gadolinium enhancement scanning were retrospectively enrolled,and the qualities of the above images were evaluated and compared with that of conventional CMR images under breath-holding state.Results No significant difference of imaging quality was found between total free-breathing and conventional breath-holding CMR.The differences of left ventricular ejection fraction,cardiac output,left ventricular end-diastolic volume index and left ventricular mass measured based on CMR images under different breath conditions were limited.Conclusion Total free-breathing CMR was feasible in clinical practice,which could provide"one-stop"evaluation of cardiac structure,function and myocardial histological characteristics,hence having promising clinical prospects.

Antidepressant effects of Yuanzhi (Polygalae Radix) extract on chronic unpredictable mild stress-induced depression in rats: modulation of the NLRP3 inflammasome and NF-κB pathway

Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.

超声心动图评价汉族、满族和朝鲜族健康成人心脏结构及功能

目的采用二维超声心动图(2D-TTE)评价汉族、满族及朝鲜族健康成人心脏结构及功能参数特点及差异。方法纳入1476名河北省及黑龙江省无民族间通婚的汉族、满族及朝鲜族健康成人,对比不同民族间及同民族不同性别间2D-TTE参数的差异,分析超声参数与年龄的相关性。结果汉族与满族人超声各参数差异均无统计学意义(P均>0.05);朝鲜族人左心房前后径(LAD)及室间隔舒张末期厚度(IVSD)均明显大于汉族及满族人(P均<0.05)。同民族内,男性除左心室射血分数外其余各超声参数均显著高于女性(P均<0.05)。LAD、右心室前后径(RVD)、IVSD及左心室后壁舒张末期厚度(LVPWD)均与年龄呈正相关(r均>0,P均<0.05)。结论满族与汉族人心脏结构及功能差异较小;朝鲜族人与汉、满族人存在一定差异;同民族心脏结构与功能变化规律均满足一般趋势。

Review of Neuromyelitis Optica Spectrum Disorder with Pain-Depression Comorbidity

Neuromyelitis optica spectrum disorder(NMOSD)is an inflammatory disorder of the central nervous system predominantly targeting optic nerves and the spinal cord.The prevalence of the disease is much higher in Asia than in other parts of the world.Pain can be detected in more than 80%of NMOSD patients,with evoked pain mostly being caused by painful tonic muscle spasms and neuropathic pain as the most characteristic types.Depression is often comorbid with pain,and their comorbidity can severely influence quality of life.In recent years,studies have found considerable overlaps between the mechanisms of pain and depression;however,their association remains unclear.This article reviews the epidemiology,mechanism,evaluation and treatment of paindepression comorbidity in NMOSD patients.

Association between Air Pollution and Type 2 Diabetes Mellitus in Developing Countries:A Systematic Review and Meta-Analysis

Objective In recent years,many studies have reported that air pollution is a risk factor for type 2 diabetes mellitus(T2DM).The aim of this systematic review and meta・analysis is to summarize the evidence about the association between exposure to air pollution andT2DM in developing countries.Methods The databases,including PubMed,EMBASE and Web of Science,were systematically searched for studies published up to 31 March 2022.Studies about the association between air pollution andT2DM prevalence or incidence in developing countries were included.The odds ratio(OR)was used as effect estimate.We synthesized the included studies in the meta-analysis.Results We included 8 cross-sectional studies and 8 cohort studies,all conducted in developing countries.Meta-analysis of 8 studies on PM_(2.5)(particulate matter ≤2.5 μm in diameter)showed that T2DM prevalence was significantly associated with PM_(2.5)exposure(OR=1.12;95%CI:1.07,1.17;P<0.001).The association between air pollutants andT2DM incidence was not estimated due to the limited relevant studies.Conclusions The exposure to PM_(2.5)would be positively associated with an increased prevalence of T2DM in developing countries.Some effective measures should be taken to reduce air pollutant exposure in people who are vulnerable to diabetes.

Reliability and Validity of the Chinese Version of the Lymphedema Quality of Life Questionnaire

Objective To study the reliability and validity of the Chinese version of the Lymphedema Quality of Life Questionnaire(LYMQOL)in lymphedema patients.Methods LYMQOL was translated into Chinese.The Chinese version of the LYMQOL was distributed with the official Wechat account"Lymphedema Channel"to lymphedema patients who were recruited from October 28^(th),2020 to February 23^(rd),2021.Patients with upper limb lymphedema and lower limb lymphedema completed the LYMQOL-ARM subscale and the LYMQOL-LEG subscale separately,at enrollment,1 week later,and 1 month later.Reliability,validity,feasibility,responsiveness and average time required for completing the questionnaire were assessed.Results A total of 195 patients participated in the study.The Chinese questionnaire showed high reliability with Cronbach’sαcoefficients of 0.849-0.902 for the LYMQOL-ARM and intraclass correlation coefficient(ICC)of 0.848-0.884 and Cronbach’sαcoefficients of 0.726-0.902 for the LYMQOL-LEG and ICC of 0.863-0.900.The LYMQOL showed moderate to good correlations with the EQ-5 D(0.4<r<0.6,P<0.01;for the LYMQOLARM,n=95,for the LYMQOL-LEG,n=102).Responsiveness analysis suggested that quality of life of upper limb lymphedema patients decreased after 1 month(P<0.05).The average time of patients to finish the questionnaire was approximately 12 minutes.Conclusions The Chinese version of the LYMQOL is easy to answer,comprehensive and appropriate in length,and has good reliability and validity.It may be utilized to assist treatment decision-making and track changes in clinical setting or research for lymphedema.

A Decade of Scien tific and Tech no logical Inno vati on at Chin ese Academy of Medical Sciences&Peking Union Medical College:Retrospect and Prospect

Focusing on the reform initiatives of Chinese Academy of Medical Sciences(CAMS) & Peking Union Medical College(PUMC) in medical scientific and technological innovation from perspectives of deepening the reform and optimizing the ecosystem of science and technology innovation,this article summarizes the highlights of CAMS & PUMC’s efforts in safeguarding people’ s health and promoting the Healthy China 2030 strategy through scientific and technological innovation in the fields including basic research,disease prevention and treatment,and medical technology in the past ten years.These achievements embody the endeavors and responsibility of CAMS& PUMC in realizing self-reliance and self-improvement of Chinese medical science and technology and highlight its contributions to the development of medical science and technology of China.

Zhang Weishe n:A Pion eer in the Developme nt and In dustrial Production of Penicillin in New China

The research and development of penicillin started with dificulty before 1949 and achieved certain results.In 1951,after the founding of the People’ s Republic of China,Zhang Weishen,as the only Chinese scientist who had been trained and worked in a penicillin research and development center in the United States for many years,overcame many difficulties and returned to China.In 1953,with the efforts of Zhang Weishen and his colleagues,China realized the industrialized production of penicillin,alleviating the urgent needs of the masses.Antibiotics has also become the first discipline to achieve major scientific and technological achievements after the founding of the New China.In the mid-1950s,the technical breakthrough in the localization of lactose substitutes marked the localization of the raw materials of the penicillin-producing culture medium,which paved the way for the industrialized production of penicillin with Chinese characteristics.Antibiotics have become one of the most widely used and affordable drugs for hundreds of millions of patients in China,and China has since ended the humiliating history of the "Sick Man of East Asia".

Patient Blood Management:Single Center Evidence and Practice at Fuwai Hospital

Blood loss and blood transfusion requirement are important quality control indicators of cardiovascular surgery and cardiovascular anesthesia.Patient blood management(PBM)is an evidence-based,multidisciplinary approach to optimizing the care of patients who may need transfusion,which encompasses anemia management,hemodilution,cell salvage,hemostatic treatment,and other approaches to reducing bleeding and minimizing blood transfusion.PBM in cardiovascular surgery is a"team sport"that involves cardiac and vascular surgeons,anesthesiologists,perfusionist,intensivists,and other health care providers.The current work provides an overview of evidence and practice of PBM at Fuwai Hospital.Implementation of PBM should also take local resource availability and costeffectiveness of different devices,drugs,technologies,and techniques into consideration.

Anesthesia Management at Fuwai Hospital:Practice,Evidence and Outcomes

Fuwai Hospital was established in 1956 and the Anesthesia Department of Fuwai Hospital was one of the earliest anesthesia departments then in China.Under the leadership of several department directors and with the concerted efforts of all generations of colleagues,the Anesthesia Department of Fuwai Hospital has dramatically transformed,upgraded and modernized.For more than six decades,the Anesthesia Department has been providing high-quality peri-operative anesthesia care for cardiovascular surgeries,conducting innovative experimental and clinical researches,and offering comprehensive training on cardiovascular anesthesiology for professionals across China.Currently,Fuwai Hospital is the National Center for Cardiovascular Diseases of China and one of the largest cardiovascular centers in the world.The present review introduces the Anesthesia Department of Fuwai Hospital,summarizes its current practice of anesthesia management,the outcomes of cardiovascular surgeries at Fuwai Hospital,accumulates relevant evidence,and provides prospects for future development of cardiovascular anesthesiology.

External and Internal Validation of a Computer Assisted Diagnostic Model for Detecting Multi-Organ Mass Lesions in CT images

Objective We developed a universal lesion detector(ULDor)which showed good performance in in-lab experiments.The study aims to evaluate the performance and its ability to generalize in clinical setting via both external and internal validation.Methods The ULDor system consists of a convolutional neural network(CNN)trained on around 80 K lesion annotations from about 12 K CT studies in the DeepLesion dataset and 5 other public organ-specific datasets.During the validation process,the test sets include two parts:the external validation dataset which was comprised of 164 sets of non-contrasted chest and upper abdomen CT scans from a comprehensive hospital,and the internal validation dataset which was comprised of 187 sets of low-dose helical CT scans from the National Lung Screening Trial(NLST).We ran the model on the two test sets to output lesion detection.Three board-certified radiologists read the CT scans and verified the detection results of ULDor.We used positive predictive value(PPV)and sensitivity to evaluate the performance of the model in detecting space-occupying lesions at all extra-pulmonary organs visualized on CT images,including liver,kidney,pancreas,adrenal,spleen,esophagus,thyroid,lymph nodes,body wall,thoracic spine,etc.Results In the external validation,the lesion-level PPV and sensitivity of the model were 57.9%and 67.0%,respectively.On average,the model detected 2.1 findings per set,and among them,0.9 were false positives.ULDor worked well for detecting liver lesions,with a PPV of 78.9%and a sensitivity of 92.7%,followed by kidney,with a PPV of 70.0%and a sensitivity of 58.3%.In internal validation with NLST test set,ULDor obtained a PPV of 75.3%and a sensitivity of 52.0%despite the relatively high noise level of soft tissue on images.Conclusions The performance tests of ULDor with the external real-world data have shown its high effectiveness in multiple-purposed detection for lesions in certain organs.With further optimisation and iterative upgrades,ULDor may be well suited for extensive application to external data.

Comparison of Mortality Predictive Models of Sepsis Patients Based on Machine Learning

Objective To compare the performance of five machine learning models and SAPSⅡ score in predicting the 30-day mortality amongst patients with sepsis.Methods The sepsis patient-related data were extracted from the MIMIC-Ⅳ database.Clinical features were generated and selected by mutual information and grid search.Logistic regression,Random forest,LightGBM,XGBoost,and other machine learning models were constructed to predict the mortality probability.Five measurements including accuracy,precision,recall,F1 score,and area under curve(AUC) were acquired for model evaluation.An external validation was implemented to avoid conclusion bias.Results LightGBM outperformed other methods,achieving the highest AUC(0.900),accuracy(0.808),and precision(0.559).All machine learning models performed better than SAPSⅡ score(AUC=0.748).LightGBM achieved 0.883 in AUC in the external data validation.Conclusions The machine learning models are more effective in predicting the 30-day mortality of patients with sepsis than the traditional SAPS Ⅱ score.

Effect of Focused Cardiac Ultrasound in Combination with Lung Ultrasound on Critically Ill Patients: A Multicenter Observational Study in China

Objective Focused cardiac ultrasound(FCU)and lung ultrasound(LU)are increasingly being used in critically ill patients.This study aimed to investigate the effect of FCU in combination with LU on these patients and to determine if the timing of ultrasound examination was associated with treatment change.Methods This is a multicenter cross-sectional observational study.Consecutive patients admitted to the intensive care unit(ICU)were screened for enrollment.FCU and LU were performed within the first 24 h,and treatment change was proposed by the performer based on the ultrasound results and other clinical conditions.Results Among the 992 patients included,502 were examined within 6 h of ICU admission(early phase group),and 490 were examined after 6 h of admission(later phase group).The early phase group and the later phase group had similar proportions of treatment change(48.8%vs.49.0%,χ^(2)=0.003,P=0.956).In the multivariable analysis,admission for respiratory failure was an independent variable associated with treatment change,with an odds ratio(OR)of 2.357[95%confidence interval(CI):1.284-4.326,P=0.006];the timing of examination was not associated with treatment change(OR=0.725,95%CI:0.407-1.291,P=0.275).Conclusions FCU in combination with LU,whether performed during the early phase or later phase,had a significant impact on the treatment of critically ill patients.Patients with respiratory failure were more likely to experience treatment change after the ultrasound examination.

Traditional Chinese Medicine(TCM)Domain Ontology:Current Status and Rethinking for the Future Development

The past twenty years have seen the increasingly important role of ontology in traditional Chinese medicine(TCM).However,the development of TCM ontology faces many challenges.Since the epistemologies dramatically differ between TCM and contemporary biomedicine,it is hard to apply the existing top-level ontology mechanically.“Data silos”are widely present in the currently available terminology standards,term sets,and ontologies.The formal representation of ontology needs to be further improved in TCM.Therefore,we propose a unified basic semantic framework of TCM based on in-depth theoretical research on the existing top・level ontology and a re-study of important concepts in TCM.Under such a framework,ontologies in TCM subdomains should be built collaboratively and be represented formally in a common format.Besides,extensive cooperation should be encouraged by establishing ontology research communities to promote ontology peer review and reuse.

BAG3-Related Myofibrillar Myopathy Presenting as Hypercapnia:A Case Report and Literature Review

Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide.The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia.Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209 Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation.Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation.The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209 Leu mutation in BAG3.Totally twentyone patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date,including this patient and literature review.The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life.Most patients presented toe/clumsy walking or running as the onset symptom,followed by muscle weakness or atrophy.Creatine kinase levels were elevated in fourteen patients and were normal in three.Eighteen patients developed respiratory insufficiency during the disease course and thirteen(one could not tolerate non-invasive assisted ventilation)required non-invasive assisted ventilation for treatment.Except for one not reported,heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation.Z-disk streaming and aggregation could be observed in most of the patients’muscle histology.In the long-term follow-up,five patients died of cardiac or respiratory failure.Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy.It should be considered as a rare differential diagnosis of hypercapnia.

The Great Imitator:Atypical Cutaneous Manifestations of Primary Syphilitic Chancre

Objective To analyze the reasons of misdiagnosis of primary syphilitic chancre and strengthen the understanding of atypical features of this disease.Methods A case series of twenty-seven challenging primary syphilis patients who were not immediately recognized as chancre was included in our study.The clinical data including the patients’age,sex,skin lesions,HIV status,syphilis serologic test results,treatment,and follow-up results were collected.Hematoxylin-eosin and immunohistochemistry staining of skin biopsy sections were reviewed.Results Four female cases with extragenital chancres presenting as erythema or erosive skin lesions on the nipple were misdiagnosed as Paget’s disease or eczema.The disorder of missed or misdiagnosed male cases manifested as syphilitic balanitis or multiple chancres on the penis root and adjacent pubis rather than coronal sulcus or frenum.Patients with nonreactive nontreponemal tests at initial presentation were also easily missed or misdiagnosed.Conclusion Primary syphilis presenting as multiple lesions rather than a single chancre,at atypical locations,or with a nonreactive nontreponemal test result,tends to be missed or misdiagnosed.