Advance of research on Hereditary spastic paraplegia type 4 / 中华医学遗传学杂志

Spastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.

Inhibitory effects of Ginkgo biloba extract on renal inflammation in diabetic nephropathy model mice and its mechanism / 中国药房

OBJECTIVE To investigate the inhibitory effects of Ginkgo biloba extract （GBE） on renal inflammation in diabetic nephropathy （DN） model mice， and its potential mechanism. METHODS KK/Ay mice were fed with high fat and high sugar to induce DN model. They were divided into model group， positive control group [metformin 200 mg/（kg·d）]， GBE low-dose and high-dose groups [100， 200 mg/（kg·d）]， with 6 mice in each group. Six C57BL/6J mice were fed with a regular diet as the control group. Administration groups were given relevant liquid intragastrically， control group and model group were given constant volume of normal saline intragastrically， once a day， for 8 consecutive weeks. The body weight， fasting blood glucose， 24-hour food intake， 24-hour urine output， monocyte chemoattractant protein-1 （MCP-1）， interleukin-12 （IL-12）， IL-10， advanced glycation end products （AGEs）， blood urea nitrogen （BUN） and serum creatinine （Scr） of mice were measured， and the ratio of bilateral kidneys to body weight was also calculated. The pathological injury and fibrotic changes of the renal cortex were observed， and the expressions of macrophage polarization marker proteins [type M1： inducible nitric oxide synthase （iNOS）； type M2： arginase-1 （Arg-1）] and AGEs-the receptor of advanced glycation end products （RAGE）/Ras homolog gene pharm_chenjing@163.com family member A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） signaling pathway-related proteins were determined in renal cortex. RESULTS Compared with the model group， the symptoms such as renal cortical hyperplasia， vacuoles， infiltration of inflammatory cells， and renal cortical fibrosis had been improved in GBE low-dose and high-dose groups； body weight， serum level of IL-10， the expression of Arg-1 in the renal cortex were significantly higher than model group （P＜ 0.01）； fasting blood glucose， 24-hour food intake， 24-hour urine output， serum levels of MCP-1， IL-12， BUN， Scr and AGEs， the ratio of bilateral kidneys to body weight， renal injury score， the proportion of renal interstitial fibrosis， the protein expressions of iNOS， RAGE， RhoA and ROCK1 （except for GBE low-dose group） in renal cortex were significantly lower than model group （P＜0.01）. CONCLUSIONS GBE could improve kidney damage and alleviate inflammatory response in DN model mice， the mechanism of which may be related to inhibiting the AGEs-RAGE/RhoA/ROCK signaling pathway and regulating macrophage polarization.

Application of Insect Medicines in Treatment of Coronary Microvascular Dysfunction Based on Comorbidity Theory of "Blood-Vessel-Cardiac Collaterals" / 中国实验方剂学杂志

Coronary microvascular dysfunction （CMD） is one of the important causes of myocardial ischemia and non-obstructive coronary artery ischemic symptoms. However， effective diagnostic methods and targeted treatment strategies for CMD are currently lacking. According to traditional Chinese medicine （TCM）， the comorbidity theory of "blood-vessel-cardiac collaterals" plays a central role throughout the entire development process of CMD. It suggests that in the clinical diagnosis and treatment of CMD， the treatment of blood， vessels， and cardiac collaterals should not be neglected. In light of this， insect medicines， known for their efficacy in promoting blood circulation， resolving stasis， and alleviating spasms， hold promise as a potential treatment for CMD. However， there is currently no research or summary on the use of insect medicines for the treatment of CMD. Therefore， this article took the comorbidity theory of "blood-vessel-cardiac collaterals" as the starting point and divided the pathogenesis of CMD into five evolution stages： Beginning in the blood （changes in blood components and hemorheology）， progressing in the vessels （atheromatous plaque formation and unstable plaques）， occurring in the cardiac collaterals （microvascular endothelial damage and microvascular constriction and spasms）， ending in the cardiac collaterals （microvascular remodeling）， and resulting in energy metabolism disorders throughout the process， so as to explore the pathogenesis and evolution of CMD. In addition， based on the modern pharmacological research on insect medicines， this article discussed the clinical application of insect medicines in the treatment of CMD from four aspects： Promoting blood circulation and removing blood stasis to relieve vessels' obstruction， relieving spasms to alleviate pain， combating poison with poison to disperse stagnation， and tonifying cardiac collaterals to nourish the heart， which aims to provide a theoretical basis for the use of TCM in treating CMD， broaden the scope of medication， and improve clinical efficacy.

Two new flavonoid glycosides from Diphylleia sinensi / 药学学报

Five flavonoid glycosides were isolated from the methanol and ethyl acetate fractions of the ethanol extract of Diphylleia sinensi by using various chromatographic methods, including silica gel, MCI gel, Sephadex LH-20, ODS and semi-preparative HPLC. The structures of the isolated compounds were identified as diphyflavonoid A (1), diphyflavonoid B (2), quercetin-3-O-β-D-glucopyranoside (3), kaempferol-3-O-β-D-glucopyranoside (4), kaempferol-3-O-(6″-O-acetyl)-β-D-glucopyranoside (5) by spectroscopy methods (1D NMR, 2D NMR, UV, IR, and MS). Compounds 1 and 2 were two new flavonoid glycosides, and compounds 3 and 5 were isolated from the genus Diphylleia for the first time.

Synthesis and biological activity evaluation of phthalimide-donepezil hybrids / 药学学报

A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.

Thinking of Traditional Chinese Medicine in Prevention and Treatment of Panvascular Diseases Based on ''Blood Vessel-Zangfu Organ-Syndrome Differentiation and Treatment'' / 中国实验方剂学杂志

The term ''panvascular'' refers to the human vascular system， which is a complex network of arteries， veins， and lymphatic vessels. Panvascular diseases refer to a group of vascular system diseases， with vascular atherosclerosis as the common pathological feature. The panvascular diseases in target organs such as the heart， brain， kidney， and limbs are caused by ischemia or bleeding， including arterial system diseases， venous system diseases， microcirculation system diseases， and Zangfu organ-blood vessel diseases. The concept of panvascular diseases integrates vascular lesions and target organ damage. In clinical practice， blood vessels in multiple regions are regarded as a large vascular unit system， and vascular lesions and the induced target organ damage are considered as a whole. Based on the holistic concept and the Zangxiang theory in traditional Chinese medicine （TCM）， the ''blood vessel-Zangfu organ-syndrome differentiation and treatment'' network is built， on the basis of which a pattern of vascular disease-Zangfu organ dysfunction-syndrome differentiation and treatment is applied to the TCM diagnosis and treatment of panvascular diseases. The theory of treating arterial system diseases from the heart， venous system diseases from the kidneys， and microvascular system diseases from the liver is proposed. According to the causes identified based on syndrome differentiation， this paper summarizes the methods of reinforcing Yang and activating blood （including warming Yang and activating blood， replenishing Qi and activating blood， replenishing Qi， nourishing Yin and activating blood， activating Yang and blood， dispersing cold and activating blood）， cooling blood and resolving stasis， tonifying kidney and promoting urination coupled with activating blood and dredging vessels， nourishing Yin and tonifying kidney coupled with activating blood and dredging vessels， and soothing liver and regulating Qi coupled with activating blood and dredging collaterals， as well as wind-extinguishing medicines， applied to the treatment of panvascular diseases， aiming to provide methods and ideas for the treatment of vascular diseases with TCM.

Effect of miR-141-5p/ZNF705A on adhesion of bone marrow mesenchymal stem cells in chronic myeloid leukemia cell-derived exosomes / 中国药理学通报

Aim To investigate the effect of miR-141-5p/ZNF705A in chronic myeloid leukemia(CML)cell-derived exosome(Exo)on the adhesion of bone marrow mesenchymal stem cells(BMSCs). Methods The morphology and size of Exo in peripheral blood from CML patients and K562 cells were examined by electron microscopy and NTA particle size analysis. The expressions of Exo and BMSCs marker molecules and adhesion proteins in K562 cells were detected by qRT-PCR and Western blot before and after transfection. The adhesion ability of BMSCs was detected by cell adhesion assay, and the cellular activity of BMSCs was examined using CCK-8. miR-141-5p binding to ZNF705A was detected by luciferase assay. Results qRT-PCR results showed that miR-141-5p expression was significantly reduced in both CML patients and K562 cell-derived Exo. qRT-PCR, Western blot and other results showed that BMSCs in CML patients had significantly reduced the expression of adhesion proteins CD44 and CXCL12, and were able to phagocytose K562 cell-derived Exo. Further, K562-derived Exo was found to reduce CD44 and CXCL12 expression and adhesion in Exo-promoted BMSCs compared with CD34+ cells. Meanwhile, the results of dual luciferase reporter assay verified that miR-141-5p targeted binding to ZNF705A. Finally, we found ZNF705A could be targeted by up-regulating miR-141-5p expression in Exo of K562 cells, which in turn inhibited the adhesion of BMSCs. Conclusions K562 cells down-regulate miR-141-5p expression in Exo and inhibit the adhesion function of BMSCs by targeting ZNF705A, thus regulating the bone marrow hematopoietic function in CML patients.

Expressions of peripheral blood lymphocytes in high-grade squamous intraepithelial lesions of the cervix and early cervical cancer and their significances / 肿瘤研究与临床

Objective:To investigate the expression levels of peripheral blood lymphocytes in patients with high-grade squamous intraepithelial lesions (HSIL) of the cervix and early cervical cancer, and to analyze their correlation with the clinicopathological characteristics of cervical cancer.Methods:The clinical data of 65 patients with HSIL and 78 patients with early cervical cancer (2018 International Federation of Gynecology and Obstetrics stage ≤ stage Ⅱ A) treated in Shanxi Province Cancer Hospital from October 2020 to November 2021 were retrospectively analyzed, and 31 healthy people undergoing physical examination during the same period were treated as the healthy control group. The expressions of CD3 + T cells, CD4 + T cells, CD8 + T cells, NK cells, NK/T cells and other immune cells in fasting peripheral blood of the patients were detected by using flow cytometry. Results:The expression levels of CD3 + T cells, CD4 + T cells, CD4 +/CD8 + and NK cells were 71±8, 39±7, 1.5±0.5, 16±7, respectively in HSIL group, and 73±9, 41±9, 1.5±0.6, 16±9, respectively in early cervical cancer group, which were lower than those in the healthy control group (76±9, 45±10, 2.0±1.3, 20±7) (all P < 0.05). The expression levels of CD8 + T cells was 28±7, 29±8, respectively in HSIL group and early cervical cancer group, which were higher than those in the healthy control group (24±7) (all P < 0.05). The expression level of total B cells in early cervical cancer group was lower than that in healthy control group (10±4 vs.12±3, P < 0.05). The expression level of CD3 + T cells in peripheral blood of early cervical cancer patients with tumor diameter >4 cm and nerve/vascular invasion was 71±10 and 72±8, which was lower than that of patients with tumor diameter 2-4 cm, ≤2 cm and without nerve/vascular invasion (72±8, 75±8, 78±7); the expression level of CD8 + T cell was 32±8 and 35±4, which was higher than that of patients with tumor diameter 2-4 cm, ≤2 cm, and without nerve/vascular invasion (28±8, 28±7, 29±8) (all P < 0.05). The levels of CD3 + T cells and total B cells were negatively correlated with the tumor diameter (all P < 0.05), while the level of CD8 + T cells was positively correlated with tumor diameter ( P < 0.05); the levels of CD3 + T cells and NK cells were negatively correlated with nerve/vascular invasion (all P < 0.05). Conclusions:The immune function of the body starts to change in the early progression of cervical cancer, and is related to the tumor diameter and nerve/vascular invasion of cervical cancer.

Effects of long-time needle retaining at Baihui(GV20)on post-stroke cognitive impairment / 针灸推拿医学（英文版）

Objective:To observe the clinical efficacy of long-time needle retaining at Baihui(GV20)on post-stroke cognitive impairment(PSCI)and its effects on the cognitive ability and living ability of the patients.Methods:A total of 62 PSCI patients were divided into a control group and an observation group by the random number table method,with 31 cases in each group.The control group was treated with routine treatment for stroke in the recovery period plus cognitive training.The observation group received additional acupuncture at Baihui(GV20)with long-time needle retaining based on the same intervention in the control group.The Montreal cognitive assessment(MoCA)was used to evaluate the cognitive ability of patients.The activities of daily living(ADL)scale was used to evaluate the living ability of patients.And the mini-mental state examination(MMSE)scale was used to evaluate the mental state,concentration,language,and abstraction cognition of patients.After 4 weeks,the curative efficacy was observed,and the scores of cognitive level,living ability,mental state and concentration,language,and abstraction understanding ability were compared between the two groups.Results:During the trial,1 patient in each group dropped out due to personal reasons and was unable to continue the treatment.After 4 weeks of treatment,the total effective rate was 83.3%in the observation group and 66.7%in the control group,and the difference between the two groups was statistically significant(P<0.05);the scores of MoCA,ADL,and MMSE,and scores of concentration,language ability,and abstraction understanding ability were all increased,and were statistically different from those before treatment in each group(P<0.05);the scores in the observation group were all higher than those in the control group,and the differences between the groups were statistically significant(P<0.05).Conclusion:On the basis of routine treatment and cognitive training,the clinical efficacy of additional acupuncture at Baihui(GV20)with long-time needle retaining in the treatment of PSCI is better than that of routine treatment plus cognitive training;the treatment can better improve the cognitive function and mental state of patients,and improve their living ability.

Prevalence of respiratory viruses and atypical pathogens in hospitalized children with acute respiratory tract infections: impact of SARS-CoV-2 pandemic in single center in Shanghai / 中华微生物学和免疫学杂志

Objective:To investigate the impact of SARS-CoV-2 pandemic on the prevalence of viral pathogens in hospitalized children with acute respiratory tract infections (ARTIs) in Shanghai.Methods:A total of 6 020 throat swab specimens were collected from hospitalized children with ARTIs in Shanghai Children′s Hospital from August 1, 2019 to February 28, 2022. Eleven common respiratory pathogens were detected using multiplex PCR and capillary electrophoresis. Pre-epidemic data referred to the data from August to December, 2019, and the data from August to December, 2020 and August to December, 2021 were used as the post-epidemic data for comparison. Based on the data from March 2020 to February 2022 (the epidemic period), the epidemiology of respiratory pathogens in children with ARTIs in different seasons were compared (spring: March to May, summer: June to August, autumn: September to November, winter: December to February of the next year).Results:Of the 6 020 specimens obtained from the patients, 3 753 (62.34%) were positive for at least one pathogen. Human rhinovirus (HRV) was the most commonly detected pathogen (22.76%, 1 442/6 020), followed by human respiratory syncytial virus (HRSV) (16.05%, 966/6 020). From August to December, the detection rate of single respiratory pathogen was 87.94% (569/647) in 2019, 66.21% (480/725) in 2020 and 60.33% (1 075/1 782) in 2021, and the co-infection rate was 25.66% (166/647) in 2019, 9.93% (72/725) in 2020 and 8.87% (158/1 782) in 2021, showing a decreasing trend (χ 2=165.19 and 127.79, P<0.01). Compared with the pre-epidemic period, human metapneumovirus (HMPV), HRV and human parainfluenza virus (HPIV) were the most prevalent pathogens in 2020 [4.97%(36/725), 34.21%(248/725) and 14.48%(105/725); χ 2=26.16, 42.04 and 60.52; P<0.01] and HRSV was the predominant pathogen in 2021 [21.27%(387/1 782), χ 2=44.26, P<0.01]. During the epidemic period, the detection rate of pathogens was 64.49%(1 340/2 078) in 2020, which was significantly higher than that in 2021 [57.48%(1 771/3 081), χ 2=25.43, P<0.01]. Only two respiratory pathogens, Mycoplasma pneumonia and human coronavirus, were detected in the spring of 2020; HRV, human adenovirus and HPIV were detected since the summer of 2020; influenza virus B was detected since the spring of 2021; influenza virus A was detected in only one case in 2020 and other respiratory pathogens were detected since the autumn of 2020. HRV+ HRSV were the main pathogens of co-infections. Conclusions:A series of prevention and control measures taken after the SARS-CoV-2 epidemic caused major changes in the prevalence and the epidemiology of respiratory pathogens in hospitalized children in Shanghai. With the normalization of epidemic prevention and control, the cancellation of strict epidemic prevention policy might lead to the outbreak of some pathogens (HMPV, HRV, HPIV and HRSV) and much attention should be paid to the outbreaks of other respiratory pathogen infections in children.

Correlation of serum antibody titers with clinical features and prognosis of anti leucine-rich glioma inactivated 1 antibody encephalitis / 中华神经科杂志

Objective:To analyze the relationship between serum antibody titers, clinical characteristics, and prognosis in patients with encephalitis induced by anti leucine-rich glioma inactivated 1 (LGI1) antibody.Methods:Clinical data of 20 patients diagnosed with encephalitis in the Department of Neurology, First Hospital of Shanxi Medical University from February 2015 to February 2021 were collected and retrospectively analyzed. Patients were divided into 2 groups based on their serum anti LGI1 antibody titers, namely the high titer group (1∶100, 1∶320) and the low titer group (1∶10, 1∶32). The clinical characteristics, laboratory test results, and prognosis of the 2 groups of patients were compared. Relusts The age of the 20 patients with anti LGI1 antibody encephalitis ranged from 27 to 69 (53.5±11.2) years, with a male to female ratio of 1∶1. There were 9 patients in the low titer group and 11 patients in the high titer group. There was no statistically significant difference in the types and quantities of clinical symptoms between the 2 groups. Patients in the high titer group were more prone to abnormal lesions on cranial magnetic resonance imaging (10/11 vs 3/9, P=0.014). There was no statistically significant difference between the 2 groups in the presence or absence of cerebrospinal fluid anti LGI1 antibodies (9/11 vs 4/9, P=0.160). During the follow-up, it was found that 1/20 patient died of pulmonary embolism, 7/20 of patients were able to recover to their predisease state, and 9/20 of patients had residual memory impairment. In the high titer group, 3/11 of patients experienced recurrence, while there was no recurrence in the low titer group. There was no statistically significant difference in the neurological prognosis between the 2 groups at 3 months of discharge and follow-up (the number of patients whose modified Rankin Scale score≤2: 10/10 vs 8/9, P=0.474). Conclusions:Patients with high serum anti LGI1 antibody titers are more likely to develop intracerebral lesions. Higher antibody titers may be associated with a higher risk of disease recurrence. There was no significant correlation between serum antibody titers and neurological outcomes.

Advances in relapse risk factors of anti-N-methyl-D-aspartate receptor encephalitis / 中华神经科杂志

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis mediated by anti-NMDAR antibody. Current studies have found that most patients with anti-NMDAR encephalitis have a good prognosis after immunotherapy and tumor therapy, but there are still 4.5%-36.4% patients with relapse. It is important to identify the risk factors for the prevention of relapse. This article aims to review the relapse risk factors of NMDAR encephalitis in order to provide help for the prevention of relapse.

Anatomical classification of and laparoscopic surgery for left-sided colorectal cancer with persistent descending mesocolon / 中华胃肠外科杂志

Objective: To investigate anatomical morphology and classification of persistent descending mesocolon (PDM) in patients with left-sided colorectal cancer, as well as the safety of laparoscopic radical surgery for these patients. Methods: This is a descriptive study of case series. Relevant clinical data of 995 patients with left colon and rectal cancer who had undergone radical surgery in Fujian Medical University Union Hospital from July 2021 to September 2022 were extracted from the colorectal surgery database of our institution and retrospectively analyzed. Twenty-four (2.4%) were identified as PDM and their imaging data and intra-operative videos were reviewed. We determined the distribution and morphology of the descending colon and mesocolon, and evaluated the feasibility and complications of laparoscopic surgery. We classified PDM according to its anatomical characteristics as follows: Type 0: PDM combined with malrotation of the midgut or persistent ascending mesocolon; Type 1: unfixed mesocolon at the junction between transverse and descending colon; Type 2: PDM with descending colon shifted medially (Type 2A) or to the right side (Type 2B) of the abdominal aorta at the level of the origin of the inferior mesentery artery (IMA); and Type 3: the mesocolon of the descending-sigmoid junction unfixed and the descending colon shifted medially and caudally to the origin of IMA. Results: The diagnosis of PDM was determined based on preoperative imaging findings in 9 of the 24 patients (37.5%) with left-sided colorectal cancer, while the remaining diagnoses were made during intraoperative assessment. Among 24 patients, 22 were male and 2 were female. The mean age was (63±9) years. We classified PDM as follows: Type 0 accounted for 4.2% (1/24); Type 1 for 8.3% (2/24); Types 2A and 2B for 37.5% (9/24) and 25.0% (6/24), respectively; and Type 3 accounted for 25.0% (6/24). All patients with PDM had adhesions of the mesocolon that required adhesiolysis. Additionally, 20 (83.3%) of them had adhesions between the mesentery of the ileum and colon. Twelve patients (50.0%) required mobilization of the splenic flexure. The inferior mesenteric artery branches had a common trunk in 14 patients (58.3%). Twenty-four patients underwent D3 surgery without conversion to laparotomy; the origin of the IMA being preserved in 22 (91.7%) of them. Proximal colon ischemia occurred intraoperatively in two patients (8.3%) who had undergone high ligation at the origin of the IMA. One of these patients had a juxta-anal low rectal cancer and underwent intersphincteric abdominoperineal resection because of poor preoperative anal function. Laparoscopic subtotal colectomy was considered necessary for the other patient. The duration of surgery was (260±100) minutes and the median estimated blood loss was 50 (20-200) mL. The median number of No. 253 lymph nodes harvested was 3 (0-20), and one patient (4.2%) had No.253 nodal metastases. The median postoperative hospital stay was 8 (4-23) days, and the incidence of complications 16.7% (4/24). There were no instances of postoperative colon ischemia or necrosis observed. One patient (4.2%) with stage IIA rectal cancer developed Grade B (Clavien-Dindo III) anastomotic leak and underwent elective ileostomy. The other complications were Grade I-II. Conclusions: PDM is frequently associated with mesenteric adhesions. Our proposed classification can assist surgeons in identifying the descending colon and mesocolon during adhesion lysis in laparoscopic surgery. It is crucial to protect the colorectal blood supply at the resection margin to minimize the need for unplanned extended colectomy, the Hartmann procedure, or permanent stomas.

Anatomical and histological investigation of the area anterior to the anorectum passing through the levator hiatus / 中华胃肠外科杂志

Objective: To document the anatomical structure of the area anterior to the anorectum passing through the levator hiatus between the levator ani slings bilaterally. Methods: Three male hemipelvises were examined at the Laboratory of Clinical Applied Anatomy, Fujian Medical University. (1) The anatomical assessment was performed in three ways; namely, by abdominal followed by perineal dissection, by examining serial cross-sections, and by examining median sagittal sections. (2) The series was stained with hematoxylin and eosin to enable identification of nerves, vessels, and smooth and striated muscles. Results: (1) It was found that the rectourethralis muscle is closest to the deep transverse perineal muscle where the longitudinal muscle of the rectum extends into the posteroinferior area of the membranous urethra. The communicating branches of the neurovascular bundle (NVB) were identified at the posterior edge of the rectourethralis muscle on both sides. The rectum was found to be fixed to the membranous urethra through the rectourethral muscle, contributing to the anorectal angle of the anterior rectal wall. (2) Serial cross-sections from the anal to the oral side were examined. At the level of the external anal sphincter, the longitudinal muscle of the rectum was found to extend caudally and divide into two muscle bundles on the oral side of the external anal sphincter. One of these muscle bundles angled dorsally and caudally, forming the conjoined longitudinal muscle, which was found to insert into the intersphincteric space (between the internal and external anal sphincters). The other muscle bundle angled ventrally and caudally, filling the gap between the external anal sphincter and the bulbocavernosus muscle, forming the perineal body. At the level of the superficial transverse perineal muscle, this small muscle bundle headed laterally and intertwined with the longitudinal muscle in the region of the perineal body. At the level of the rectourethralis and deep transverse perineal muscle, the external urethral sphincter was found to occupy an almost completely circular space along the membranous part of the urethra. The dorsal part of the external urethral sphincter was found to be thin at the point of attachment of the rectourethralis muscle, the ventral part of the longitudinal muscle of the rectum. We identified a venous plexus from the NVB located close to the oral and ventral side of the deep transverse perineal muscle. Many vascular branches from the NVB were found to be penetrating the longitudinal muscle and the ventral part of rectourethralis muscle at the level of the apex of the prostate. The rectourethral muscle was wrapped ventrally around the membranous urethra and apex of the prostate. The boundary between the longitudinal muscle and prostate gradually became more distinct, being located at the anterior end of the transabdominal dissection plane. (3) Histological examination showed that the dorsal part of the external urethral sphincter (striated muscle) is thin adjacent to the striated muscle fibers from the deep transverse perineal muscle and the NVB dorsally and close by. The rectourethral muscle was found to fill the space created by the internal anal sphincter, deep transverse perineal muscle, and both levator ani muscles. Many tortuous vessels and tiny nerve fibers from the NVB were identified penetrating the muscle fibers of the deep transverse perineal and rectourethral muscles. The structure of the superficial transverse perineal muscle was typical of striated muscle. These findings were reconstructed three-dimensionally. Conclusions: In intersphincteric resection or abdominoperineal resection for very low rectal cancer, the anterior dissection plane behind Denonvilliers' fascia disappears at the level of the apex of the prostate. The prostate and both NVBs should be used as landmarks during transanal dissection of the non-surgical plane. The rectourethralis muscle should be divided near the rectum side unless tumor involvement is suspected. The superficial and deep transverse perineal muscles, as well as their supplied vessels and nerve fibers from the NVB. In addition, the cutting direction should be adjusted according to the anorectal angle to minimize urethral injury.

Clinical application and standardized implementation of intersphincteric resection / 中华胃肠外科杂志

Intersphincteric resection (ISR) is the ultimate sphincter-preserving surgical technique for low rectal cancer. To promote the standardized implementation of ISR, this review discusses the important issues regarding the clinical application of ISR with reference to the latest Chinese expert consensus on ISR. In terms of ISR-related pelvic anatomy of the rectum/anal canal, hiatal ligament is not identical with the anococcygeal ligament. At the level where the rectourethralis muscle continuously extends to the posteroinferior area of the membranous urethra from the rectum, the neurovascular bundle is identified between the posterior edge of rectourethralis muscle and the anterior edge of the longitudinal muscle of the rectum. This knowledge is crucial to detect the anterior dissection plane during ISR at the levator hiatus level. The indication criteria for ISR included: (1) stage I early low rectal cancer; (2) stage II-III low rectal cancer undergoing neoadjuvant treatment, and supra-anal tumors and juxta-anal tumors of stage ycT3NxM0, or intra-anal tumors of stage ycT2NxM0. However, signet ring cell carcinoma, mucinous adenocarcinoma and undifferentiated carcinoma should be contraindicated to ISR. For locally advanced low rectal cancer (especially anteriorly located tumor), neoadjuvant treatment should be carried out in a standardized manner. However, it should be recognized that neoadjuvant chemoradiotherapy was a risk factor for poor anal function after ISR. For surgical approaches for ISR, including transanal, transabdominal, and transanal transabdominal approaches, the choice should be based on oncological safety and functional consequences. While ensuring the negative margin, maximal preservation of rectal walls and anal canal contributs to better postoperative anorectal function. Careful attention must be paid to complications regarding ISR, with special focus on the anastomotic complications. The incidence of low anterior resection syndrome (LARS) was higher than 40%. However, this issue is often neglected by clinicians. Thus, management and rehabilitation strategies for LARS with longer follow-ups were required.

Research progress in anti-reflux reconstructions and mechanism after proximal gastrectomy / 中华胃肠外科杂志

The electrophysiological activity of the gastrointestinal tract and the mechanical anti-reflux structure of the gastroesophageal junction are the basis of the anti-reflux function of the stomach. Proximal gastrectomy destroys the mechanical structure and normal electrophysiological channels of the anti-reflux. Therefore, the residual gastric function is disordered. Moreover, gastroesophageal reflux is one of the most serious complications. The emergence of various types of anti-reflux surgery through the mechanism of reconstructing mechanical anti-reflux barrier and establishing buffer zone, and the preservation of, the pacing area and vagus nerve of the stomach, the continuity of the jejunal bowel, the original gastroenteric electrophysiological activity of the gastrointestinal tract, and the physiological function of the pyloric sphincter, are all important measures for gastric conservative operations. There are many types of reconstructive approaches after proximal gastrectomy. The design based on the anti-reflux mechanism and the functional reconstruction of mechanical barrier, and the protection of gastrointestinal electrophysiological activities are important considerations for the selected of reconstructive approaches after proximal gastrectomy. In clinical practice, we should consider the principle of individualization and the safety of radical resection of tumor to select a rational reconstructive approaches after proximal gastrectomy.

Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH) / 中华胃肠外科杂志

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.

Research on multi-class orthodontic image recognition system based on deep learning network model / 中华口腔医学杂志

Objective: To develop a multi-classification orthodontic image recognition system using the SqueezeNet deep learning model for automatic classification of orthodontic image data. Methods: A total of 35 000 clinical orthodontic images were collected in the Department of Orthodontics, Capital Medical University School of Stomatology, from October to November 2020 and June to July 2021. The images were from 490 orthodontic patients with a male-to-female ratio of 49∶51 and the age range of 4 to 45 years. After data cleaning based on inclusion and exclusion criteria, the final image dataset included 17 453 face images (frontal, smiling, 90° right, 90° left, 45° right, and 45° left), 8 026 intraoral images [frontal occlusion, right occlusion, left occlusion, upper occlusal view (original and flipped), lower occlusal view (original and flipped) and coverage of occlusal relationship], 4 115 X-ray images [lateral skull X-ray from the left side, lateral skull X-ray from the right side, frontal skull X-ray, cone-beam CT (CBCT), and wrist bone X-ray] and 684 other non-orthodontic images. A labeling team composed of orthodontic doctoral students, associate professors, and professors used image labeling tools to classify the orthodontic images into 20 categories, including 6 face image categories, 8 intraoral image categories, 5 X-ray image categories, and other images. The data for each label were randomly divided into training, validation, and testing sets in an 8∶1∶1 ratio using the random function in the Python programming language. The improved SqueezeNet deep learning model was used for training, and 13 000 natural images from the ImageNet open-source dataset were used as additional non-orthodontic images for algorithm optimization of anomaly data processing. A multi-classification orthodontic image recognition system based on deep learning models was constructed. The accuracy of the orthodontic image classification was evaluated using precision, recall, F1 score, and confusion matrix based on the prediction results of the test set. The reliability of the model's image classification judgment logic was verified using the gradient-weighted class activation mapping (Grad-CAM) method to generate heat maps. Results: After data cleaning and labeling, a total of 30 278 orthodontic images were included in the dataset. The test set classification results showed that the precision, recall, and F1 scores of most classification labels were 100%, with only 5 misclassified images out of 3 047, resulting in a system accuracy of 99.84%(3 042/3 047). The precision of anomaly data processing was 100% (10 500/10 500). The heat map showed that the judgment basis of the SqueezeNet deep learning model in the image classification process was basically consistent with that of humans. Conclusions: This study developed a multi-classification orthodontic image recognition system for automatic classification of 20 types of orthodontic images based on the improved SqueezeNet deep learning model. The system exhibitted good accuracy in orthodontic image classification.

Automated diagnostic classification with lateral cephalograms based on deep learning network model / 中华口腔医学杂志

Objective: To establish a comprehensive diagnostic classification model of lateral cephalograms based on artificial intelligence (AI) to provide reference for orthodontic diagnosis. Methods: A total of 2 894 lateral cephalograms were collected in Department of Orthodontics, Capital Medical University School of Stomatology from January 2015 to December 2021 to construct a data set, including 1 351 males and 1 543 females with a mean age of (26.4± 7.4) years. Firstly, 2 orthodontists (with 5 and 8 years of orthodontic experience, respectively) performed manual annotation and calculated measurement for primary classification, and then 2 senior orthodontists (with more than 20 years of orthodontic experience) verified the 8 diagnostic classifications including skeletal and dental indices. The data were randomly divided into training, validation, and test sets in the ratio of 7∶2∶1. The open source DenseNet121 was used to construct the model. The performance of the model was evaluated by classification accuracy, precision rate, sensitivity, specificity and area under the curve (AUC). Visualization of model regions of interest through class activation heatmaps. Results: The automatic classification model of lateral cephalograms was successfully established. It took 0.012 s on average to make 8 diagnoses on a lateral cephalogram. The accuracy of 5 classifications was 80%-90%, including sagittal and vertical skeletal facial pattern, mandibular growth, inclination of upper incisors, and protrusion of lower incisors. The acuracy rate of 3 classifications was 70%-80%, including maxillary growth, inclination of lower incisors and protrusion of upper incisors. The average AUC of each classification was ≥0.90. The class activation heat map of successfully classified lateral cephalograms showed that the AI model activation regions were distributed in the relevant structural regions. Conclusions: In this study, an automatic classification model for lateral cephalograms was established based on the DenseNet121 to achieve rapid classification of eight commonly used clinical diagnostic items.

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions / 医学前沿

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.