1.Coagulation abnormalities in acute decompensated cirrhosis comorbid with infection: A prospective observational study based on thromboelastography
Ruiqing ZHANG ; Shumin CAI ; Xiuhua JIANG ; Jianming HUANG ; Beiling LI ; Jinjun CHEN
Journal of Clinical Hepatology 2025;41(5):907-913
ObjectiveTo investigate the changes in coagulation system in acute decompensated cirrhosis (ADC) patients with or without sepsis and the association of these changes with short-term prognosis. MethodsA prospective study was conducted among 116 ADC patients who were hospitalized in Nanfang Hospital from January 2021 to July 2023, among whom there were 86 patients with sepsis and 30 patients without sepsis, and 54 patients with sepsis alone who had no chronic liver disease were enrolled as control group. Thromboelastography (TEG) and other conventional coagulation parameters were used to comprehensively evaluate the coagulation function of patients. The data including TEG results and short-term prognosis were collected, and a correlation analysis was performed. The independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. The Spearman correlation coefficient was calculated to investigate the correlation between different variables. The Logistic regression model was used to perform the univariate and multivariate analyses. ResultsFor the ADC patients with sepsis, the lungs and bloodstream were the main infection sites, and bacteria were the main pathogenic microorganism. TEG results showed that compared with the patients with sepsis alone, the patients with ADC and sepsis had a significant reduction in median maximum amplitude (MA), a significant increase in coagulation time (K time), and a significant reduction in α angle (all P<0.05); the patients with ADC and sepsis had a significantly longer reaction time (R time) than those with ADC alone (P=0.02), and the patients with sepsis alone had a significantly longer R time than those with ADC and sepsis (P=0.04). There was no correlation between MA and platelet count in the patients with ADC and sepsis (r=-0.133, P=0.057), while there was a significant correlation between MA and platelet count in the patients with sepsis alone (r=0.595, P=0.001). SOFA score was negatively correlated with MA in sepsis patients with or without ADC (r=-0.503 and -0.561, both P<0.001), and for the patients with ADC and sepsis, R time, K time, and α angle were weakly correlated with SOFA score and had a relatively strong correlation with APTT (all P<0.05). The patients with ADC alone all survived within 90 days, and compared with the death group, the patients with sepsis alone who survived had significantly higher values of MA and α angle (all P<0.05); there was a significant difference in α angle on day 90 between the survival group and the death group, no matter whether the patients were comorbid with ADC or not (both P<0.01), while for the patients with ADC and sepsis, there was no significant difference in MA value on day 90 between the survival group and the death group (P>0.05). ConclusionFor ADC patients comorbid with sepsis, coagulation function assessment and monitoring should be taken seriously in clinical practice, and TEG parameters and SOFA score should be monitored when necessary to develop individualized treatment regimens.
2.ResNet-Vision Transformer based MRI-endoscopy fusion model for predicting treatment response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A multicenter study.
Junhao ZHANG ; Ruiqing LIU ; Di HAO ; Guangye TIAN ; Shiwei ZHANG ; Sen ZHANG ; Yitong ZANG ; Kai PANG ; Xuhua HU ; Keyu REN ; Mingjuan CUI ; Shuhao LIU ; Jinhui WU ; Quan WANG ; Bo FENG ; Weidong TONG ; Yingchi YANG ; Guiying WANG ; Yun LU
Chinese Medical Journal 2025;138(21):2793-2803
BACKGROUND:
Neoadjuvant chemoradiotherapy followed by radical surgery has been a common practice for patients with locally advanced rectal cancer, but the response rate varies among patients. This study aimed to develop a ResNet-Vision Transformer based magnetic resonance imaging (MRI)-endoscopy fusion model to precisely predict treatment response and provide personalized treatment.
METHODS:
In this multicenter study, 366 eligible patients who had undergone neoadjuvant chemoradiotherapy followed by radical surgery at eight Chinese tertiary hospitals between January 2017 and June 2024 were recruited, with 2928 pretreatment colonic endoscopic images and 366 pelvic MRI images. An MRI-endoscopy fusion model was constructed based on the ResNet backbone and Transformer network using pretreatment MRI and endoscopic images. Treatment response was defined as good response or non-good response based on the tumor regression grade. The Delong test and the Hanley-McNeil test were utilized to compare prediction performance among different models and different subgroups, respectively. The predictive performance of the MRI-endoscopy fusion model was comprehensively validated in the test sets and was further compared to that of the single-modal MRI model and single-modal endoscopy model.
RESULTS:
The MRI-endoscopy fusion model demonstrated favorable prediction performance. In the internal validation set, the area under the curve (AUC) and accuracy were 0.852 (95% confidence interval [CI]: 0.744-0.940) and 0.737 (95% CI: 0.712-0.844), respectively. Moreover, the AUC and accuracy reached 0.769 (95% CI: 0.678-0.861) and 0.729 (95% CI: 0.628-0.821), respectively, in the external test set. In addition, the MRI-endoscopy fusion model outperformed the single-modal MRI model (AUC: 0.692 [95% CI: 0.609-0.783], accuracy: 0.659 [95% CI: 0.565-0.775]) and the single-modal endoscopy model (AUC: 0.720 [95% CI: 0.617-0.823], accuracy: 0.713 [95% CI: 0.612-0.809]) in the external test set.
CONCLUSION
The MRI-endoscopy fusion model based on ResNet-Vision Transformer achieved favorable performance in predicting treatment response to neoadjuvant chemoradiotherapy and holds tremendous potential for enabling personalized treatment regimens for locally advanced rectal cancer patients.
Humans
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Rectal Neoplasms/diagnostic imaging*
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Magnetic Resonance Imaging/methods*
;
Male
;
Female
;
Middle Aged
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Neoadjuvant Therapy/methods*
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Aged
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Adult
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Chemoradiotherapy/methods*
;
Endoscopy/methods*
;
Treatment Outcome
3.Global, regional, and national burden of neglected tropical diseases and malaria, 1990-2021.
Talaiti TUERGAN ; Aimitaji ABULAITI ; Alimu TULAHONG ; Ruiqing ZHANG ; Yingmei SHAO ; Tuerganaili AJI
Environmental Health and Preventive Medicine 2025;30():54-54
BACKGROUND:
Neglected tropical diseases (NTDs) and malaria pose a major health challenge, especially in low- and middle-income countries.
METHODS:
Initially, we performed a descriptive analysis of the Global Burden of Disease (GBD) 2021 database, categorizing data by subtypes. Next, linear regression models were employed to analyze temporal trends. We then utilized four predictive models to forecast the future burden. Additionally, we explored the relationship between estimated annual percentage change (EAPCs) and age-standardized rates (ASRs), as well as Human Development Index (HDI) scores for 2021. Furthermore, decomposition analysis was applied to assess the influence of aging, population dynamics, and epidemiological changes. Lastly, frontier analysis was conducted to examine the connection between disease burden and sociodemographic development.
RESULTS:
In 2021, NTDs and malaria contributed significantly to the global disease burden, with considerable disparities across genders, age groups, Socio-demographic Index (SDI) regions, GBD regions, and individual countries. From 1990 to 2021, both the number of cases and the associated ASRs have shown a recent downward trend. The EAPCs are positively correlated with ASRs and HDI scores. Projections indicate a continued decline in disease burden through 2046. Additionally, our decomposition analysis highlighted the positive impact of aging and epidemiological shifts on the reduction of the disease burden. Finally, frontier analysis revealed that countries and regions with higher SDI scores have greater potential for further reducing their health burden.
CONCLUSION
While the global burden of NTDs and malaria has improved overall, significant disparities remain across regions and countries. Our findings highlight the importance of implementing targeted intervention strategies and maintaining sustained investments to tackle the ongoing challenges.
Malaria/epidemiology*
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Humans
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Neglected Diseases/epidemiology*
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Global Burden of Disease/trends*
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Global Health/statistics & numerical data*
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Male
;
Female
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Tropical Medicine
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Adult
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Cost of Illness
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Child, Preschool
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Middle Aged
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Adolescent
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Young Adult
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Infant
4.Discussion on the Effect of Shugan Lipi Prescription on Patients with Diarrhea-predominant Irritable Bowel Syndrome of Liver Stagnation and Spleen Deficiency Type from the Disorder of Bile Acid-Intestinal Flora Axis
Ping LI ; Xile YANG ; Anqi ZHU ; Ruiqing ZHANG
Journal of Guangzhou University of Traditional Chinese Medicine 2025;42(1):94-100
Objective To investigate the effect of Shugan Lipi Prescription on patients with diarrhea-predominant irritable bowel syndrome(IBS-D)of liver stagnation and spleen deficiency type from the perspective of bile acid-intestinal flora axis imbalance.Methods From May 2022 to May 2023,a total of 122 patients with IBS-D of liver stagnation and spleen deficiency type admitted to the Xi'an No.9 Hospital were enrolled into the investigation.The patients were randomly divided into the control group and the observation group by random number table method,with 61 patients in each group.The control group was given conventional western medicine treatment with oral administration of Dicetel plus Compound Diphenoxylate Tablets and Bifidobacterium Quadruple Viable Tablets,and the observation group was treated with Shugan Lipi Prescription on the basis of treatment for the control group.One course of treatment covered seven days,and both groups were treated for four courses in total.The changes of Irritable Bowel Syndrome Symptom Severity Scale(IBS-SSS)score,levels of serum bile acid and the fecal levels of intestinal flora such as Bifidobacterium,Lactobacillus,and Enterococcus in the two groups of patients before and after treatment were observed.Moreover,the clinical efficacy and the incidence of adverse reactions during the treatment of the two groups were compared.Results(1)After four courses of treatment,the total effective rate of the observation group was 96.72%(59/61)and that of the control group was 83.61%(51/61),and the intergroup comparison(tested by chi-square test)showed that the efficacy of the observation group was significantly superior to that of the control group(P<0.05).(2)After treatment,the scores of IBS-SSS items such as abdominal pain,abdominal pain duration,abdominal distension,defecation satisfaction and life interference in the two groups were all decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.01).(3)After treatment,the levels of serum taurodeoxycholic acid(TDCA),taurocholic acid(TCA)and taurolithocholic acid(TLCA)in the two groups were decreased when compared with those before treatment(P<0.05),and the decrease in the observation group was significantly superior to that in the control group(P<0.01).(4)After treatment,the fecal level of Enterococcus,a kind of pathogenic bacterium,in both groups was decreased when compared with that before treatment(P<0.05),and the fecal levels of probiotics of Bifidobacterium and Lactobacillus in both groups were increased when compared with those before treatment(P<0.05).The effects on the decrease of fecal Enterococcus level and on the increase of fecal Bifidobacterium and Lactobacillus levels in the observation group were significantly superior to those in the control group(P<0.05 or P<0.01).(5)The incidence of adverse reactions in the observation group was 8.20%(5/61)and that in the control group was 6.55%(4/61),and the intergroup comparison showed that the difference was not statistically significant(P>0.05).Conclusion Shugan Lipi Prescription exerts certain therapeutic effect for IBS-D patients of liver stagnation and spleen deficiency type,and is with higher safety.Its therapeutic mechanism may be related to the restoration of the function of bile acid-intestinal flora axis.
5.Research progress in hypoxia inducible factors and body hypoxia tolerance
Zhaxi RENQING ; Hao YANG ; Rui WANG ; Ya'nan LIANG ; Ruiqing CHAI ; Peiran ZHANG ; Tongmei ZHANG ; Xingcheng ZHAO
Military Medical Sciences 2025;49(3):233-238
Hypoxia inducible factors(HIFs)are core molecules that enable the body to adapt to hypoxia environments.By sensing changes in intracellular oxygen pressure,HIFs regulate gene expression related to hypoxia adaptation,thereby enhancing the body's hypoxia tolerance at cellular,tissue and organ levels.On the other hand,HIFs promote the generation of red blood cells,angiogenesis,and regulate the body's energy metabolism,thereby improving its hypoxia tolerance.The enhancement of hypoxia tolerance is of great significance for the prevention and treatment of hypoxia-related diseases,upgrading of athletes'performance,enhancement of workers'efficiency at high-altitudes,and the improvement of individu-als'quality of life.This article reviews the relationships between HIFs and hypoxia tolerance as well as related mechanisms in order to provide strategies for enhancing hypoxia tolerance in the body.
6.Application of cross bar technique in repair of pectus excavatum
Tianjun ZHOU ; Dan TIAN ; Ruiqing SHI ; Zihao ZHOU ; Jiming TANG ; Dongkun ZHANG ; Xiaosong BEN ; Guibin QIAO ; Gang CHEN ; Liang XIE
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2025;32(11):1572-1578
Objective To explore the indication, surgical technique, and clinical efficacy of the cross bar based on the Nuss procedure in pectus excavatum. Methods The clinical data of patients who underwent cross bar based on the Nuss procedure from August 2023 to August 2024 in Guangdong Provincial People's Hospital were retrospectively analyzed. Results A total of 88 patients including 85 males and 3 females with a mean age of (17.56±5.20) years were enrolled. All operations were performed successfully without intraoperative cardiac injury, pericardial injury or diaphragmatic injury. The mean operation time was (147.65±47.75) min. The mean blood loss was (13.30±9.06) mL. The mean postoperative hospitalization stay was (4.81±1.55) days, without perioperative death. Six (6.82%) patients developed early postoperative complications, including 3 patients of pleural effusion, 1 patient of subcutaneous hematoma, 1 patient of suffocation and 1 patient of bar rotation. The postoperative outcomes were excellent in 71 (80.68%) patients, good in 16 (18.18%) patients and moderate in 1 (1.13%) patient. The excellent and good rate was 98.86%. Conclusion The cross bar technique is safe and convenient, with satisfactory results. It is worth promoting in clinical application.
7.Coagulation abnormalities in acute decompensated cirrhosis comorbid with infection:A prospective observational study based on thromboelastography
Ruiqing ZHANG ; Shumin CAI ; Xiuhua JIANG ; Jianming HUANG ; Beiling LI ; Jinjun CHEN
Journal of Clinical Hepatology 2025;42(5):907-913
Objective To investigate the changes in coagulation system in acute decompensated cirrhosis(ADC)patients with or without sepsis and the association of these changes with short-term prognosis.Methods A prospective study was conducted among 116 ADC patients who were hospitalized in Nanfang Hospital from January 2021 to July 2023,among whom there were 86 patients with sepsis and 30 patients without sepsis,and 54 patients with sepsis alone who had no chronic liver disease were enrolled as control group.Thromboelastography(TEG)and other conventional coagulation parameters were used to comprehensively evaluate the coagulation function of patients.The data including TEG results and short-term prognosis were collected,and a correlation analysis was performed.The independent-samples t test was used for comparison of normally distributed continuous data between two groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups;the chi-square test was used for comparison of categorical data between two groups.The Spearman correlation coefficient was calculated to investigate the correlation between different variables.The Logistic regression model was used to perform the univariate and multivariate analyses.Results For the ADC patients with sepsis,the lungs and bloodstream were the main infection sites,and bacteria were the main pathogenic microorganism.TEG results showed that compared with the patients with sepsis alone,the patients with ADC and sepsis had a significant reduction in median maximum amplitude(MA),a significant increase in coagulation time(K time),and a significant reduction in α angle(all P<0.05);the patients with ADC and sepsis had a significantly longer reaction time(R time)than those with ADC alone(P=0.02),and the patients with sepsis alone had a significantly longer R time than those with ADC and sepsis(P=0.04).There was no correlation between MA and platelet count in the patients with ADC and sepsis(r=-0.133,P=0.057),while there was a significant correlation between MA and platelet count in the patients with sepsis alone(r=0.595,P=0.001).SOFA score was negatively correlated with MA in sepsis patients with or without ADC(r=-0.503 and-0.561,both P<0.001),and for the patients with ADC and sepsis,R time,K time,and α angle were weakly correlated with SOFA score and had a relatively strong correlation with APTT(all P<0.05).The patients with ADC alone all survived within 90 days,and compared with the death group,the patients with sepsis alone who survived had significantly higher values of MA and α angle(all P<0.05);there was a significant difference in α angle on day 90 between the survival group and the death group,no matter whether the patients were comorbid with ADC or not(both P<0.01),while for the patients with ADC and sepsis,there was no significant difference in MA value on day 90 between the survival group and the death group(P>0.05).Conclusion For ADC patients comorbid with sepsis,coagulation function assessment and monitoring should be taken seriously in clinical practice,and TEG parameters and SOFA score should be monitored when necessary to develop individualized treatment regimens.
8.Identification of Jr(a-) rare blood type antibodies against anti-Jra: serological and molecular biology analysis and transfusion strategy.
Yunxiang WU ; Hua WANG ; Ruiqing GUO ; Zhicheng LI ; Qing LI ; Dong XIANG ; Yanli JI ; Aijing LI ; Fengyong ZHAO ; Fei WANG ; Jiangtao ZUO ; Yi XU ; Yajun LIANG ; Demei ZHANG
Chinese Journal of Medical Genetics 2025;42(2):145-150
OBJECTIVE:
To report the blood group antigen and antibody specificity identification methods for a patient with high-frequency antibodies, and the process of finding and providing compatible blood for the patient.
METHODS:
A patient sent from the Blood Transfusion Department of Shanxi Provincial People's Hospital to Blood Transfusion Technology Research Laboratory of Taiyuan Blood Center in November 2022 was selected for the study. Classical serological methods were used to determine the patient's blood type, screen for unexpected antibodies, identify antibodies, and perform crossmatching. High-frequency antibody identification was carried out using red blood cells treated with various enzymes. Blood group genotyping was conducted using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF) and Sanger sequencing. Multiple strategies were employed to address the patient's blood source problem. The study was approved by the Medical Ethics Committee of Taiyuan Blood Center [Ethics No. 2024 Ethics Review No.(2)].
RESULTS:
The patient's blood type was B, RhD positive. Initial screening of the patient's serum with multiple screening cells and antibody identification cells in saline medium was negative, but positive in antiglobulin medium. The patient's serum showed varying reaction intensities with red blood cells treated with different enzymes. MALDI-TOF mass spectrometry and Sanger sequencing revealed a homozygous nonsense variant c.376C>T (p.Gln126Ter) in the ABCG2 gene, resulting in the Jr(a-) phenotype. During family donor selection, the patient's son was found to have a heterozygous variant c.376C>T (p.Gln126Ter), and another heterozygous variant c.421C>A (p.Gln141Lys), which predicted a Jr(a+w) phenotype. Crossmatch tests confirmed the compatibility of blood from the patient's son, which was used to address the urgent blood requirement. Later, rare blood from a Jr(a-) donor from the Guangzhou Blood Center was used for the patient's ongoing treatment, saving the patient's life.
CONCLUSION
Combining classic serological testing with blood group gene typing techniques successfully identified the rare Jr(a-) blood type and high-frequency anti-Jra antibodies. Enzyme-treated red blood cell identification methods confirmed the presence of anti-Jra antibodies. By searching within the family and seeking help from other blood centers, compatible blood was found. This approach may provide insights for resolving similar complex blood matching problems in the future.
Humans
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Blood Grouping and Crossmatching/methods*
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Blood Group Antigens/immunology*
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Blood Transfusion
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Male
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Isoantibodies/blood*
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Female
;
Genotype
9.Effect of variants in the non-coding region of ABO blood group alleles on the weak expression of antigens.
Hua WANG ; Yunxiang WU ; Fei WANG ; Yajun LIANG ; Qing LI ; Jiangtao ZUO ; Yi XU ; Zhicheng LI ; Ruiqing GUO ; Xin ZHANG ; Demei ZHANG
Chinese Journal of Medical Genetics 2025;42(5):628-632
OBJECTIVE:
To explore the regulatory mechanisms underlying the weak expression of ABO blood group antigens due to variants in the non-coding regions of the ABO gene.
METHODS:
From June 2014 to October 2023, a total of 29 samples from the Taiyuan Blood Center and local hospitals, which were serologically identified as having weak ABO antigen expression without detectable coding region mutations, were selected for this study. Full-length ABO gene sequencing was performed using third-generation long-read sequencing technology (Pacific Biosciences) to obtain complete haplotype sequences of the ABO gene. Variants in the non-coding regions were compared and identified to infer their regulatory effects on weak antigen expression. The procedures followed in this study were in accordance with the ethical standards of the World Medical Association's Declaration of Helsinki (2013 revision). The Medical Ethics Committee of Taiyuan Blood Center has granted an exemption from ethical review.
RESULTS:
18 bp deletions in the -35 to -18 region of the promoter were identified in 7 samples. Variants in intron 1 (+5.8 kb) were detected in 7 samples, including ABO*A (28+5792_5793delCT (1 case) and ABO*B (28+5793T>C) located in the GATA binding region; ABO*B (28+5808C>T) (1 case) in the E-box region; and ABO*B (28+5875C>T) (4 cases) in the RUNX1 binding region. Nucleotide variants at splice sites were detected in 2 samples, namely ABO*B (C.98+1G>A) and ABO*B (C.204-2A>C).
CONCLUSION
Variants in the non-coding regulatory sequences of the ABO gene are a significant factor contributing to weak ABO antigen expression. In clinical ABO sequencing, it is essential to screen not only the conventional coding regions but also the flanking sequences, introns, and splice sites of the ABO gene to facilitate precise blood transfusion.
ABO Blood-Group System/genetics*
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Humans
;
Alleles
;
Promoter Regions, Genetic
;
Haplotypes
;
Introns
10.A clinical and electrodiagnostic study of peripheral neuropathy in prediabetic patients
Fan JIAN ; Lin CHEN ; Na CHEN ; Jingfen LI ; Ying WANG ; Lei ZHANG ; Feng CHENG ; Shuo YANG ; Hengheng WANG ; Lin HUA ; Ruiqing WANG ; Yang LIU ; Hua PAN ; Zaiqiang ZHANG
Chinese Journal of Neurology 2024;57(3):248-254
Objective:To explore the clinical and electrophysiological characteristics of peripheral neuropathy in prediabetic patients.Methods:Subjects aged 20-65 years with high-risk factors of impaired glycemia enrolled in Beijing Tiantan Hospital, Capital Medical University from 2019 to 2022 were recruited to conduct oral glucose tolerance test, after excluding other causes of neuropathy or radiculopathy. Patients with impaired fasting glucose or impaired glucose tolerance were defined by American Diabetes Association criteria. These patients were divided into clinical polyneuropathy (PN) and clinical non-PN groups, according to the 2010 Toronto consensus criteria and the presence of PN symptoms and signs or not. Nerve conduction studies (NCS), F wave, sympathetic skin response (SSR), R-R interval variation (RRIV) and current perception thresholds (CPT) were performed and the abnormal rate was compared between different electrodiagnostic methods and between clinical subgroups.Results:Among the 73 prediabetic patients ultimately enrolled, only 20 (27.4%) can be diagnosed as clinical PN according to the Toronto consensus criteria. The abnormal rate of CPT (68.5%, 50/73) was significantly higher than those of F wave (2.7%, 2/73), lower limb NCS (0, 0/73), upper limb NCS changes of carpal tunnel syndrome (26.0%, 19/73), SSR (6.8%, 5/73) and RRIV (5.5%, 4/73; McNemar test, all P<0.001). With sinusoid-waveform current stimuli at frequencies of 2 000 Hz, 250 Hz and 5 Hz, the CPT device was used to measure cutaneous sensory thresholds of large myelinated, small myelinated and small unmyelinated sensory fibers respectively. CPT revealed a 21.9% (16/73) abnormal rate of unmyelinated C fiber in the hands of prediabetic patients, significantly higher than that of large myelinated Aβ fibers [8.2% (6/73), χ2=5.352, P=0.021]. Both abnormal rates of small myelinated Aδ [42.5% (31/73)] and unmyelinated C fibers [39.7% (29/73)] in the feet of prediabetic patients were significantly higher than that of large myelinated Aβ fibers [11.0% (8/73), χ2=18.508, 15.965, both P<0.001]. Compared with the clinical non-PN group, the abnormal rates of CPT [90.0% (18/20) vs 60.4% (32/53), χ2=5.904, P=0.015] and SSR [20.0% (4/20) vs 1.9% (1/53), P=0.016) were significantly higher in the clinical PN group. Conclusions:Peripheral neuropathies in prediabetic patients are usually asymptomatic or subclinical, and predispose to affect unmyelinated and small myelinated sensory fibers. Selective electrodiagnostic measurements of small fibers help to detect prediabetic neuropathies in the earliest stages of the disease.

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