Objective This study investigated the regulatory effect of high mobility group protein B1 (HMGB1) in the peripheral blood of patients with primary immune thrombocytopenia (ITP) on myeloid dendritic cells (mDC) and Th17/regulatory T cells (Treg) balance. Methods The study enrolled 30 newly diagnosed ITP patients and 30 healthy controls.Flow cytometry was used to measure the proportion of mDC, Th17, and Treg cells in the peripheral blood of ITP patients and healthy controls. ELISA was conducted to quantify the serum levels of HMGB1, interleukin 6 (IL-6), IL-23, IL-17, and transforming growth factor β(TGF-β). The mRNA levels of retinoic acid-related orphan receptor γt(RORγt) and forehead box P3(FOXP3) were detected by real-time PCR. The correlation between the abovementioned cells, cytokines, and platelet count was assessed using Pearson linear correlation analysis. Results The proportion of Th17 cells and the expression levels of HMGB1, IL-6, IL-23, IL-17 and the level of RORγt mRNA in the peripheral blood of ITP patients were higher than those in healthy controls. However, the Treg cell proportion and TGF-β level were lower in ITP patients than those in healthy controls. In patients with ITP, the proportion of mDC and the level of FOXP3 mRNA did not show significant changes. The proportion of mDC cells was significantly correlated with the expression of IL-6 and IL-23. Moreover, the expression of HMGB1 showed a significant correlation with the expression of mDC, IL-6, IL-23, RORγt mRNA, and IL-17. Notably, both the proportion of mDC cells and the expression of HMGB1 were negatively correlated with platelet count. Conclusion The high expression of HMGB1 in peripheral blood of ITP patients may induce Th17/Treg imbalance by promoting the maturation of mDC and affecting the secretion of cytokines, thereby potentially playing a role in the immunological mechanism of ITP.
Humans ; Th17 Cells/cytology* ; HMGB1 Protein/genetics* ; T-Lymphocytes, Regulatory/cytology* ; Female ; Male ; Dendritic Cells/metabolism* ; Adult ; Middle Aged ; Purpura, Thrombocytopenic, Idiopathic/genetics* ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics* ; Young Adult ; Interleukin-23/blood* ; Interleukin-17/blood* ; Interleukin-6/blood* ; Forkhead Transcription Factors/genetics* ; Myeloid Cells/cytology* ; Aged

Objective:To investigate intraoperative pathological findings and the interventional effects of "deep cervical lymphaticovenous anastomosis+" (dcLVA+) on deep cervical lymphatic drainage as well as the blood flow of carotid artery and jugular vein in elderly patients with cognitive impairment, and to put forward the thoughts based on the findings from the surgery.Methods:Between May 2024 and December 2024, retrospective analysis of Microsurgery Hospital, Fengcheng Hospital, Xi'an Medical College performed dcLVA+ between the deep cervical lymphatics or lymph nodes and jugular veins in 50 elderly patients with cognitive impairment (19 males and 31 females, aged 55-88 years with 69.94 years in average). Nine patients were found with Clinical Dementia Rating (CDR) score at 1 (mild), 7 with CDR score at 2 (moderate) and 34 with CDR score at 3 (severe). Intraoperative observations based on literature reviews had identified anatomical relationships between the lymphatic sacs containing cervical lymphatic chain and the carotid sheath. The lymph node count, size, distribution, thickness of fat tissue and conditions of lymphatic vessels were documented. Ultrasound was used to compare the blood flow of carotid artery and jugular vein as well as the cross-sectional areas at the planes of hyoid and cricoid cartilage before and after the closure of incisions under anaesthesia in 39 patients. Correlation analyses for Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCa), Activities of Daily Living (ADL) and Agitation behavior score before and 1 week after surgery were performed using Spearman's correlation and Wilcoxon paired tests. P<0.05 was considered statistically significant. Postoperative follow-ups were conducted via the visit of outpatient clinic and WeChat and telephone interviews. Results:In surgery, the cervical lymphatic chain was found running within an almost enclosed sac surrounding the carotid sheath. There were enlarged lymph nodes, increased fat deposition, lymphatic dilation or fibrosis in the sac. The preoperative blood flow in the carotid artery at the planes of hyoid and cricoid cartilage in the 39 patients was recorded at 150.52 ml/min±40.33 ml/min and 358.29 ml/min±129.30 ml/min, while that in the jugular vein was at 172.50 ml/min±63.94 ml/min and 317.00 ml/min±105.21 ml/min, respectively, both were far lower than the normal blood flow. There were statistically significant differences in the blood flow of carotid artery and jugular vein before and after surgery ( P<0.01). It was found that the preoperative blood flow of the internal carotid artery at the plane of hyoid was positively correlated with the preoperative scores of MMSE ( P<0.01), MoCa ( P<0.05) and ADL ( P<0.01). The blood flow of the common carotid artery at the plane of cricoid cartilage was found significantly and positively correlated with the preoperative scores of MMSE ( P<0.05). It was also noted that the blood flow of the internal carotid artery at the plane of hyoid was significantly and positively correlated with the postoperative ADL ( P<0.01) but negatively correlated with the Agitation behavior score ( P<0.05). The blood flow of the common carotid artery at the plane of cricoid cartilage was significantly and positively correlated with the postoperative scores of MMSE and MoCa ( P<0.05). The blood flow of the internal jugular vein at the plane of hyoid was negatively correlated with the Agitation behavior score ( P<0.01). The cross-sectional area of carotid artery at the plane of left hyoid was significantly and positively correlated with the MMSE score ( P<0.05). Statistically significant differences were observed in MMSE, MoCa, ADL and Agitation behavior score before and after surgery ( P<0.01). Conclusion:dcLVA+ shows a certain therapeutic benefit to the elderly patients with cognitive impairment. The intraoperatively observed pathological changes in cervical lymphatic sacs affect deep cervical lymphatic drainage and the blood flow of carotid artery and jugular vein. Further studies are necessary to find out whether the findings from this study would be the specific pathological changes and the morbidity mechanisms among the elderly patients with cognitive impairment.

Objective:To investigate intraoperative pathological findings and the interventional effects of "deep cervical lymphaticovenous anastomosis+" (dcLVA+) on deep cervical lymphatic drainage as well as the blood flow of carotid artery and jugular vein in elderly patients with cognitive impairment, and to put forward the thoughts based on the findings from the surgery.Methods:Between May 2024 and December 2024, retrospective analysis of Microsurgery Hospital, Fengcheng Hospital, Xi'an Medical College performed dcLVA+ between the deep cervical lymphatics or lymph nodes and jugular veins in 50 elderly patients with cognitive impairment (19 males and 31 females, aged 55-88 years with 69.94 years in average). Nine patients were found with Clinical Dementia Rating (CDR) score at 1 (mild), 7 with CDR score at 2 (moderate) and 34 with CDR score at 3 (severe). Intraoperative observations based on literature reviews had identified anatomical relationships between the lymphatic sacs containing cervical lymphatic chain and the carotid sheath. The lymph node count, size, distribution, thickness of fat tissue and conditions of lymphatic vessels were documented. Ultrasound was used to compare the blood flow of carotid artery and jugular vein as well as the cross-sectional areas at the planes of hyoid and cricoid cartilage before and after the closure of incisions under anaesthesia in 39 patients. Correlation analyses for Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCa), Activities of Daily Living (ADL) and Agitation behavior score before and 1 week after surgery were performed using Spearman's correlation and Wilcoxon paired tests. P<0.05 was considered statistically significant. Postoperative follow-ups were conducted via the visit of outpatient clinic and WeChat and telephone interviews. Results:In surgery, the cervical lymphatic chain was found running within an almost enclosed sac surrounding the carotid sheath. There were enlarged lymph nodes, increased fat deposition, lymphatic dilation or fibrosis in the sac. The preoperative blood flow in the carotid artery at the planes of hyoid and cricoid cartilage in the 39 patients was recorded at 150.52 ml/min±40.33 ml/min and 358.29 ml/min±129.30 ml/min, while that in the jugular vein was at 172.50 ml/min±63.94 ml/min and 317.00 ml/min±105.21 ml/min, respectively, both were far lower than the normal blood flow. There were statistically significant differences in the blood flow of carotid artery and jugular vein before and after surgery ( P<0.01). It was found that the preoperative blood flow of the internal carotid artery at the plane of hyoid was positively correlated with the preoperative scores of MMSE ( P<0.01), MoCa ( P<0.05) and ADL ( P<0.01). The blood flow of the common carotid artery at the plane of cricoid cartilage was found significantly and positively correlated with the preoperative scores of MMSE ( P<0.05). It was also noted that the blood flow of the internal carotid artery at the plane of hyoid was significantly and positively correlated with the postoperative ADL ( P<0.01) but negatively correlated with the Agitation behavior score ( P<0.05). The blood flow of the common carotid artery at the plane of cricoid cartilage was significantly and positively correlated with the postoperative scores of MMSE and MoCa ( P<0.05). The blood flow of the internal jugular vein at the plane of hyoid was negatively correlated with the Agitation behavior score ( P<0.01). The cross-sectional area of carotid artery at the plane of left hyoid was significantly and positively correlated with the MMSE score ( P<0.05). Statistically significant differences were observed in MMSE, MoCa, ADL and Agitation behavior score before and after surgery ( P<0.01). Conclusion:dcLVA+ shows a certain therapeutic benefit to the elderly patients with cognitive impairment. The intraoperatively observed pathological changes in cervical lymphatic sacs affect deep cervical lymphatic drainage and the blood flow of carotid artery and jugular vein. Further studies are necessary to find out whether the findings from this study would be the specific pathological changes and the morbidity mechanisms among the elderly patients with cognitive impairment.

ObjectiveThis study aims to examine the effect of Rhei Radix et Rhizoma-Coptidis Rhizoma on reducing insulin resistance in db/db mice by regulating the adenylate activated protein kinase （AMPK）/UNC-51-like kinase 1 （ULK1）/key molecule of autophagy， benzyl chloride 1 （Beclin1） pathway and elucidate the underlying mechanism. MethodSixty 6-week-old male db/db mice were studied. They were randomly divided into the model group， metformin group （0.26 g·kg^-1）， and low-， middle-， and high-dose groups （2.25， 4.5， 9 g·kg^-1） of Rhei Radix et Rhizoma-Coptidis Rhizoma. A blank group of db/m mice of the same age was set， with 12 mice in each group. After eight weeks of continuous intragastric administration， the blank group and model group received distilled water intragastrically once a day. The survival status of the mice was observed， and fasting blood glucose （FBG） was measured using a Roche blood glucose device. Fasting serum insulin （FINS） was measured using an enzyme-linked immunosorbent assay， and the insulin resistance index （HOMA-IR） was calculated. Hematoxylin-eosin （HE） staining was performed to observe the pathological changes in the liver of the mice. The protein expression levels of AMPK， Beclin1， autophagy associated protein 5 （Atg5）， and p62 in liver tissue were determined by using Western blot. The protein expression levels of autophagy associated protein 1 light chain 3B （LC3B） and ULK1 in liver tissue were determined using immunofluorescence. Real-time fluorescence quantitative PCR （Real-time PCR） was used to measure mRNA expression levels of AMPK， Beclin1， Atg5， ULK1， and p62. ResultCompared with the blank group， the model group exhibited a significant increase in body mass （P<0.01）. Additionally， the levels of FBG， FINS， and HOMA-IR significantly changed （P<0.01）. The structure of liver cells was disordered. The protein expression levels of AMPK， Beclin1， and Atg5 in liver tissue were significantly decreased （P<0.01）， while the expression level of p62 protein was significantly increased （P<0.01）. The expression levels of mRNA and proteins were consistent. Compared with the model group， the body mass of the metformin group and high and medium-dose groups of Rhei Radix et Rhizoma-Coptidis Rhizoma was significantly decreased （P<0.05）. FBG， FINS， and HOMA-IR were significantly decreased （P<0.05，P<0.01）. After treatment， the liver structure damage in each group was alleviated to varying degrees. The protein expressions of AMPK， Beclin1， Atg5， LC3B， and ULK1 were increased （P<0.05，P<0.01）， while the protein expression of p62 was decreased （P<0.01）. The expression levels of mRNA and proteins were generally consistent. ConclusionThe combination of Rhei Radix et Rhizoma-Coptidis Rhizoma can effectively improve liver insulin resistance， regulate the AMPK autophagy signaling pathway， alleviate insulin resistance in db/db mice， and effectively prevent the occurrence and development of type 2 diabetes.

Significant research progress has been made in the development of antibody-drug conjugates (ADCs) for the treatment of ad-vanced breast cancer (ABC),ushering new hope for patients with this refractory disease. Through the conjugation of specific antibodies with highly potent cytotoxic drugs,tumor cells can be precisely targeted and killed while minimizing damage to normal tissues. ADCs such as trastuzumab-emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd),have shown excellent efficacy in the treatment of HER2-positive ABC,significantly prolonging patient survival. Furthermore,ADCs targeting triple-negative breast cancer (TNBC),such as sacituzumab govitecan (SG),have also achieved positive results in clinical trials. With the continuous research,development,and optimization of ADCs,as well as the exploration of combination treatment strategies,ADCs are expected to play an increasingly important role in the treatment of ABC in the future. This article provides an overview of the research progress of ADCs in the treatment of ABC,exploring their efficacy and safety. We aim to offer more treatment options and renewed hope for patients with ABC.

Significant research progress has been made in the development of antibody-drug conjugates (ADCs) for the treatment of ad-vanced breast cancer (ABC),ushering new hope for patients with this refractory disease. Through the conjugation of specific antibodies with highly potent cytotoxic drugs,tumor cells can be precisely targeted and killed while minimizing damage to normal tissues. ADCs such as trastuzumab-emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd),have shown excellent efficacy in the treatment of HER2-positive ABC,significantly prolonging patient survival. Furthermore,ADCs targeting triple-negative breast cancer (TNBC),such as sacituzumab govitecan (SG),have also achieved positive results in clinical trials. With the continuous research,development,and optimization of ADCs,as well as the exploration of combination treatment strategies,ADCs are expected to play an increasingly important role in the treatment of ABC in the future. This article provides an overview of the research progress of ADCs in the treatment of ABC,exploring their efficacy and safety. We aim to offer more treatment options and renewed hope for patients with ABC.

ObjectiveTo explore the mechanism of Dahuang Mudantang in alleviating the intestinal injury in the rat model of acute pancreatitis via the high-mobility group box 1 （HMGB1）/receptor for advanced glycation endproduct （RAGE）/nuclear factor-κB （NF-κB） signaling pathway. MethodOne hundred and twenty SPF-grade Wistar rats received retrograde injection of 5% sodium taurocholate into the biliopancreatic duct for the modeling of intestinal injury in acute pancreatitis. The rats were randomized into blank， model， low-， medium-， and high-dose （3.5， 7， 14 g·kg^-1， administrated by gavage） Dahuang Mudantang， and octreotide （1×10^-5 g·kg^-1， subcutaneous injection） groups （n=20）. The rats in blank and model groups received equal volume of distilled water by gavage. Drugs were administered 1 h before and every 12 h after modeling， and samples were collected 24 h after modeling. The general status of the rats was observed. The biochemical methods were employed to measure the levels of amylase （AMS） and C-reactive protein （CRP） in the serum. The enzyme-linked immunosorbent assay （ELISA） was employed to measure the levels of tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-6 in the colon tissue. The morphological changes of pancreatic and colon tissues were observed by hematoxylin-eosin （HE） staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to measure the expression levels of HMGB1， RAGE， inhibitor of NF-κB kinase （IKK）， and NF-κB suppressor protein α（IκBα）in the colon tissue. ResultThe rats in the model group showed poor general survival， writhing response， reduced frequency of defecation， and dry stool. The symptoms of rats in the model group were mitigated in each treatment group， and the high-dose Dahuang Mudantang showed the most significant effect. Compared with the normal group， the model group had elevated AMS and CRP levels （P<0.05）， which were lowered by Dahuang Mudantang （P<0.05）， especially that at the high dose （P<0.05）. Compared with the normal group， the modeling elevated that levels of TNF-α， IL-1β， and IL-6 （P<0.05）. Such elevations were lowered by Dahuang Mudantang （P<0.05）， and the high-dose group and the octreotide group showed better performance （P<0.05）. The modeling caused necrotic， congested， and destructed pancreatic and colonic tissues， which were ameliorated by the drugs， especially high-dose Dahuang Mudantang. Compared with the normal group， the modeling up-regulated the mRNA levels of HMGB1， RAGE， IKK， IκBα， and NF-κB （P<0.05）. Compared with the model group， Dahuang Mudantang and octreotide down-regulated the mRNA levels of HMGB1， RAGE， IKK， IκBα， and NF-κB （P<0.05）， and the high-dose Dahuang Mudantang demonstrated the best performance （P<0.05）. Western blot results showed a trend consistent with the results of Real-time PCR. ConclusionDahuang Mudantang can improved the general status， reduce inflammation， and alleviate histopathological changes in the pancreatic and colon tissues in the rat model of acute pancreatitis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.

Objective:To explore the feasibility and clinical effect of emergency lateral thigh muscle transfer in functional reconstruction of major traumatic muscle defects.Methods:Emergency surgeries for 8 patients(7 males and 1 female) with muscle defects were carried out subject to emergently reconstruct the power of lateral femoral muscle superficial region, between March 2020 and December 2021, in the Department of Hand and Foot Microsurgery Hospital, Xi'an Fengcheng Hospital. The 8 patients were 23 to 52 years old with an average of 37.6 years old. Five patients injured by machine crush, 2 by heavy object crush and 1 by traffic accident. Five patients were in Gustilo III B injury in forearm, including 2 with flexor muscle group defects, 2 with extensor muscle group defects and 1 with defect of dorsal metacarpal flexor muscle and extensor muscle. Among the 5 patients, 2 patients had the defects in left forearm and 3 in right forearm. One patient had defect of right 1st metacarpal bone and skin and thenar muscle. One patient suffered a complete right upper arm detachment with musculocutaneous nerve being drawn out from the bicipital muscle. One patient had Gustilo III C injury in the right calf with defects of extensor hallucis longus and extensor digitorum. The areas of soft tissue defect were 10.0 cm×8.0 cm-36.0 cm×11.0 cm and the size of flaps was 12.0 cm×6.0 cm-38.0 cm×12.0 cm with the volumes of excised muscle at 18.0 cm×9.0 cm×1.5 cm-10.0 cm×2.0 cm×1.0 cm. The anatomical cross-section and length of the corresponding muscle on the healthy side were measured by musculoskeletal ultrasound. The chimeric tissue flap was designed on the anterolateral side of the thigh. The flap was designed according to the size of the wound and the corresponding flap. Then 1 or 2 muscle tissue blocks were designed and cut from the superficial region of the lateral femoral muscle according to the condition of the muscle defect, to cover the wound and reconstruct the muscle power. Postoperative follow-ups were conducted by scheduled hospital visit. The contents of follow-up included dynamic observation, evaluation and record through musculoskeletal ultrasound, electromyography and strength of muscle.Results:For the 8 patients who were subject to a muscle reconstruction, the transferred muscles and flaps survived in stage-one without vascular event. Postoperative follow-ups lasted for 10 to 32 months with an average of 19.6 months. The strength of muscle was evaluated according to the M 4 strength of muscle. Strength of muscle restored to M 4 or above in 7 patients who could lift, hook or push a heavy object in 5-30 kg of weight, with free joint movement. One patient restored the strength of muscle to M 3+. Muscle contraction was detected 2-4 months after surgery by musculoskeletal B ultrasound. The average ratio of contraction to resting cross sectional area in 5 cases was 1.45±0.42. The shape of limb was bilaterally symmetrical. There was no discomfort in the donor site and knee joint. The flaps were soft and glossy, with protective sensation restored. Conclusion:Muscle transfer from the lateral femoral muscle superficial region in emergency surgery for functional reconstruction of traumatic muscle defects is feasible and effective with a good clinical effect.

Objective:To discuss outcomes of emergency repairing for Gustilo III B and III C fractures of forearm with complicated tissue defects and the related influence factors.Methods:From January 2014 to Feburary 2022, data of 98 cases of Gustilo III B and III C fractures with large compound defects of soft tissue, blood vessel, bone, tendon or muscle from elbow to wrist were collected. Primary debridement, bone fixation, wound coverage by free flap, bone transfer(or bone cement filling) or dynamic reconstruction of muscle were completed with emergency surgery in Department of Hand and Foot Microsurgery, Xi'an Fengcheng Hospital. Postoperative follow-ups were conducted through outpatient clinic visits, telephone and WeChat reviews. Video clips, questionnaires and the latest information of patients were also analysed. Rank sum test and Chi-square test were used to examine the relationship between independent variables such as general condition, disease condition and surgical procedures of chimeric tissue transfer group and simple flap transfer group, together with dependent variables such as limb salvage, number of surgery, wound healing, function scores, and complications. P<0.05 were further included in the regression equation to discover the relationship between multiple independent variables and dependent variables. Results:Follow-up lasted for 6-96 months, with an average of 71.1 months. In the chimeric group, the limb salvage rate was at 95.1%, with an infection rate of 8.50% and an average number of surgery was 2.13±0.89. In the simple flap transfer group, the limb salvage rate was at 87.5%, with an infection rate of 15.38% and an average number of surgery was 2.62±0.64. The good rate of Anderson score was 65.3% and the average score of Disability of the Arm, Shoulder and Hand(DASH) was 32.9(0-60) points for all the patients. There were significant differences in dependent variables of limb salvage and infection rate between the 2 groups ( P<0.05). Ischemia time and method of bone fixation led to significant differences in number of surgery ( P<0.05). Methods of bone fixation and the types of flap made significant differences in wound healing ( P<0.05). Underlying disease, bonedefect, Gustilo classification and method of bone fixation all contributed to the significant differences in function score ( P<0.05 or P<0.01) . Conclusion:Emergency surgery for repair of serious injury of forearm has a relatively high limb salvage rate and good functional effects. The limb salvage rate is not correlated with independent variables such as severity of injury, Mangledextremity Severity Score (MESS) and ischemia time, while transfer of a simple flap or a chimeric flap is significantly correlated with the limb salvage rate, infection and wound healing. The severity of injury, ischemia time and bone defect are correlated with functional assessment, number of surgery and bone healing.

Objective: To evaluate the dietary risk of neonicotinoid insecticides in market-sold vegetables in Guangzhou City, so as to provide insights into ensuring food safety for residents. Methods: Forty-five samples of 21 kinds of vegetables were collected from supermarkets and farmer's markets in Guangzhou City from June to September in 2022, and 10 kinds of neonicotinoid insecticides were determined using liquid chromatography-mass spectrometry (LC-MS). The vegetable consumption was obtained through the survey of food consumption and nutrients intake of residents in Guangzhou City. The dietary risk was evaluated by calculating daily exposure and non-carcinogenic risk quotients of neonicotinoid insecticides. Results: A total of 27 samples of vegetables were detected with neonicotinoid insecticides, and the detection rate was 60.00%. Among 10 kinds of neonicotinoid insecticides, 6 kinds were identified, including clothianidin, thiamethoxam, imidacloprid, acetamiprid, dinotefuranand and nitenpyram. The detection rates of clothianidin, thiamethoxam and imidacloprid were relatively high (26.67%, 11.11% and 6.67%), and some samples exceeded the standard, with the rate of 4.44%, 2.22% and 2.22%, respectively. The total exposure of neonicotinoid pesticides (IMIRPF) was 3 053.00 ng/g, and the contents and IMIRPF of imidacloprid were the highest in roots and tubers. The daily exposure of imidacloprid, acetamiprid, dinotefuran, clothianidin, thiamethoxam and nitenpyram was 34.58, 3.85, 1.20, 6.87, 7.19 and 0.86 ng/(kg·d). Non-carcinogenic risk quotients of imidacloprid, acetamiprid, dinotefuran, clothianidin, thiamethoxam and nitenpyram was 5.76×10-4, 0.55×10-4, 0.06×10-4, 0.69×10-4, 0.90×10-4 and 0.02×10-4, respectively, which was lower than 1; and the sum of non-carcinogenic risk quotients was 7.98×10-4, which was lower than 1. Conclusions The dietary risk of neonicotinoid pesticides is low in 21 kinds of market-sold vegetables in Guangzhou City; however, the contents of neonicotinoid insecticides in some vegetable samples exceed the standard. The supervision of vegetable markets should be strengthened.