Controversies regarding transplantation of mesenchymal stem cells

Mesenchymal stem cells(MSCs)have tantalized regenerative medicine with their therapeutic potential,yet a cloud of controversies looms over their clinical tran-splantation.This comprehensive review navigates the intricate landscape of MSC controversies,drawing upon 15 years of clinical experience and research.We delve into the fundamental properties of MSCs,exploring their unique immuno-modulatory capabilities and surface markers.The heart of our inquiry lies in the controversial applications of MSC transplantation,including the perennial debate between autologous and allogeneic sources,concerns about efficacy,and lingering safety apprehensions.Moreover,we unravel the enigmatic mechanisms surro-unding MSC transplantation,such as homing,integration,and the delicate balance between differentiation and paracrine effects.We also assess the current status of clinical trials and the ever-evolving regulatory landscape.As we peer into the future,we examine emerging trends,envisioning personalized medicine and innovative delivery methods.Our review provides a balanced and informed perspective on the controversies,offering readers a clear understanding of the complexities,challenges,and potential solutions in MSC transplantation.

Controversies and future directions in the management of gallbladder cancer

Gallbladder cancer(GBC)is a rare malignancy worldwide,with 140,000 new patients each year and more than 100,000 deaths annually.The review aims to address the controversial aspects of managing GBC.Regional differences of the study worldwide remain pending,and comparative mutational profiles will provide more information on the pathogenesis of GBC.However,certain pathologic aspects are discussed,such as the staging of early GBC,outcome differences between T2 pathologically staged patients,and the necessity of a uni-form pathologic report.The surgical management of GBC is still under debate.The extent of liver resection,type of lymphadenectomy,and selection of patients for extended resection are aspects of the disease that require revision.Laparoscopic and robotic approaches were initially slow to develop.However,with time,they have demonstrated their value in the surgical management of GBC.The OMEGA survey,performed to analyze the management practice of surgical treatment of GBC worldwide,demonstrated differences from the recom-mended guidelines.The OMEGA study,the largest cohort study,examined the outcomes of surgical intervention in 3676 patients from 133 centers.Regarding future directions,the value of collaborative efforts between centers and regions must be emphasized to better un-derstand the different aspects of the disease and globally improve therapeutic strategies for GBC.

Liver transplantation and alcoholic liver disease:History,controversies,and considerations

Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease(ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation(LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol-related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy.

Current Controversies and the State of the Art in Endovascular Treatment of Vascular Malformations

Vascular anomalies constitute some of the most difficult diagnostic and therapeutic enigmas that can be encountered in the practice of medicine. The clinical presentations are extremely protean and can range from an asymptomatic birthmark to fulminant。

Main controversies in breast cancer

In this article, we have reviewed available evidence for diagnosis, treatment, and follow-up in female breast cancer(BC). Into daily clinical practice some controversies are occurred. Especially, in the diagnosis field, despite the fact that the optimal age in which screening mammography should start is a subject of intense controversy, there is a shift toward the beginning at the age of 40 although it is suggested that the net benefit is small for women aged 40 to 49 years. In addition, a promising tool in BC screening seems to be breast tomosynthesis. Other tools such as 3D ultrasound and shear wave elastography(SWE) are full of optimism in BC screening although ultrasonography is not yet a first-line screening method and there is insufficient evidence to recommend the systemic use of the SWE for BC screening. As for breast magnetic resonance imaging(MRI), even if it is useful in BC detection in women who have a strong family history of BC, it is not generally recommended as a screening tool. Moreover, based on the lack of randomized clinical trials showing a benefit of presurgical breast MRI in overall survival, it's integration into breast surgical operations remainsdebatable. Interestingly, in contrast to fine needle aspiration, core biopsy has gained popularity in presurgical diagnosis. Furthermore, after conservative surgery in patients with positive sentinel lymph nodes, the recent tendency is the shift from axillary dissection to axillary conserving strategies. While the accuracy of sentinel lymph node after neoadjuvant chemotherapy and second BC surgery remains controversial, more time is needed for evaluation and for determining the optimal interval between the two surgeries. Additionally, in the decision between immediate or delayed breast reconstruction, there is a tendency in the immediate use. In the prevention of BC, the controversial issue between tamoxifen and raloxifene becomes clear with raloxifene be more profitable through the toxicities of tamoxifen. However, the prevention of bone metastasis with bisphosphonates is still conflicting. Last but not least, in the follow-up of BC survivors, mammography, history and physical examination are the means of an early detection of BC recurrence.

Controversies in diagnosis and management of Kawasaki disease

Kawasaki disease(KD) is a common medium vessel systemic vasculitis that usually occurs in small children. It has a predilection for the coronary arteries, but other medium sized arteries can also be involved. The etiology of this disorder remains a mystery. Though typical presentation of KD is quite characteristic, it may also present as incomplete or atypical disease in which case the diagnosis can be very challenging. As both incomplete and atypical forms of KD can be associated with serious coronary artery complications, the pediatrician can ill afford to miss these diagnoses. The American Heart Association has enunciated consensus guidelines to facilitate the clinical diagnosis and treatment of this condition. However, there are still several issues that remain controversial. Intravenous immunoglobulin remains the cornerstone of management but several other treatment modalities, especially glucocorticoids, are increasingly finding favour. We review here some of the contemporary issues, and the controversies thereon, pertaining to management of KD.

Controversies in the diagnosis and management of early gastric cancer

Early diagnosis and treatment is the key to improving the prognosis of gastric cancer. The past decades have wimessed the rapid advances in the diagnosis and management of early gastric cancer （EGC）： endoscopy has played an increasingly important role, whereas laparoscopic techniques have also been introduced for EGC treatment. In China, the proportion of EGC is gradually increasing, and this condition will soon become a hot research topic. In this article, we will elucidate some major controversies in the diagnosis and management of EGC.

Extended-spectrum β-lactamase controversies

G.A.Jacoby 教授毕业于美国哈佛医学院,为国际知名的传染病学、微生物学和免疫学专家,曾长期担任美国麻省总医院传染病科医师,现任麻省 Lahey 医学中心传染病实验室主任,中国感染与化疗杂志特邀编委。长期以来 Jacoby 教授对细菌耐药机制有深入研究,尤其对细菌(肺炎克雷伯菌、大肠埃希菌等)产生质粒介导的超广谱β内酰胺酶(ESBL)以及喹诺酮类的耐药机制研究。曾发表多篇有关上述专题的权威性论著。此次本刊特邀 Jacoby 教授撰写有关 ESBL 的新进展,文中阐述目前 ESBLs 除通常所指质粒介导β内酰胺酶中扩大了酶水解的底物谱导致细菌对头孢噻肟、头孢他啶、氨曲南等抗生素耐药外,还包括许多具有不同特点的β内酰胺酶,其中某些酶产自共生菌。除 ESBL 外,AmpC 酶和各种碳青霉烯β内酰胺酶也可导致细菌对上述抗生素耐药,因此临床微生物实验室准确检出和鉴别各种β内酰胺酶,对于临床选用适宜的抗茵药十分重要。美国 CLSI(过去称为 NCCLS)推荐采用两步法(筛选及确证)检测细菌产 ESBL;但有的学者认为测定抗茵药物对细菌的 MIC,如用药后 T>MIC 在50%以上即可达到满意疗效,无需检测细菌是否产 ESBL。目前认为碳青霉烯类抗生素治疗产 ESBL 菌感染的疗效最为满意,但由此可能引起细菌对该类药物耐药,值得关注。采用大剂量头孢吡肟或哌拉西林-三唑巴坦治疗产ESBL 菌感染是否有效尚有争论,临床上对β内酰胺类最为耐药的菌株往往对几乎所有现用抗菌药耐药。黏菌素(或多黏菌素 B)曾成功的用于治疗此种多重耐药菌感染。此外替莫西林(temocillin,一种对β内酰胺酶稳定的青霉素类)与替加环素(tigecvcline,为米诺环素衍生物)体外对产 ESBL 菌有抗菌作用,但尚无临床研究资料。

New developments and controversies in iron metabolism and iron chelation therapy

Iron is essential for all organisms including microbial,cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.

Current controversies and advances in the management of pancreatic adenocarcinoma

Pancreatic adenocarcinoma is a lethal disease with a mortality rate that has not significantly improved over decades.This is likely due to several challenges unique to pancreatic cancer.Most patients with pancreatic cancer are diagnosed at a late stage of disease due to the lack of specific symptoms prompting an early investigation.A small subset of patients who are diagnosed at an early stage have a better chance at survival with curative surgical resection,but most patients still succumb to the disease in a few years.The dismal overall prognosis is due to suspected micro-metastasis at an early stage.Due to this reason,there is a recent interest in treating all patients with pancreatic cancers with systemic therapy upfront(including the ones that are surgically resectable).This approach is still not the standard of care due to the lack of robust prospective data available.Recent advancements in treatment regimens of chemotherapy,radiation and immunotherapy have improved the overall short-term survival but the long-term survival still remains poor.Novel approaches in diagnosis and treatment have shown promise in clinical studies but long-term clinical data is lacking.The following manuscript presents an overview of the epidemiology,diagnosis,staging,recent advances,novel approaches and controversies in the management of pancreatic adenocarcinoma.

Treatment controversies in a rare case of a simultaneous branch retinal artery and vein occlusion secondary to hyperhomocysteinemia and hypertension

Dear Editor,Combined vascular occlusions involving retinal arteries and veins have been reported in the past. Combined occlusion of the central retinal vein （CRVO） and artery （CRAO）is well described;. Cilioretinal artery occlusion along with CRVO is frequently reported and is well characterized;.

Mechanical Eye Trauma Epidemiology, Prognostic Factors, and Management Controversies—An Update

Purpose of Review: The management of eye injuries is both difficult and argumentative. This study attempts to highlight the management of ocular trauma using currently available information in the literature and author experience. This review presents a workable framework from the first presentation, epidemiology, classification, investigations, management principles, complications, prognostic factors, final visual outcome and management debates. Review Findings: Mechanical ocular trauma is a leading cause of monocular blindness and possible handicap worldwide. Among several classification systems, the most widely accepted is Birmingham Eye Trauma Terminology (BETT). Mechanical ocular trauma is a topic of unsolved controversy. Patching for corneal abrasion, paracentesis for hyphema, the timing of cataract surgery and intraocular lens implantation are all issues in anterior segment injuries. Regarding posterior segment controversies, the timing of vitrectomy, use of prophylactic cryotherapy, the necessity of intravitreal antibiotics in the absence of infection, the use of vitrectomy vs vitreous tap in traumatic endophthalmitis is the issues. The pediatric age group needs to be approached by a different protocol due to the risk of amblyopia, intraocular inflammation, and significant vitreoretinal adhesions. The various prognostic factors have a role in the final visual outcome. B scan is used to exclude R.D, Intraocular foreign body (IOFB), and vitreous haemorrhage in hazy media. Individual surgical strategies are used for every patient according to the classification and extent of the injuries. Conclusion: This article examines relevant evidence on the management challenges and controversies of mechanical trauma of the eye and offers treatment recommendations based on published research and the authors’ own experience.

Common controversies in total knee replacement surgery: Current evidence

Total knee replacement(TKR) is a widely used operation that has radically improved the quality of life of millions of people during the last few decades. However, some technical details, concerning the surgical procedure and the rehabilitation following total knee arthroplasty, are still a matter of a strong debate. In this review of the literature, we have included the best evidence available of the last decade, in an effort to shed light on some of the most controversial subjects related to TKR surgery. Posterior-stabilized or cruciate-retaining prosthesis? To use a tourniquet during operation or not? Do patients need continuous passive motion for their post-surgery rehabilitation? To resurface patella or not? These are some of the most controversial topics that until now have been persistent dilemmas for the orthopedic surgeon. Results of this systematic review of the literature are highly controversial. These conflicting results are an indication that larger and more well conducted high quality trials are needed in order to gain more secure answers. At the same time, it is becoming apparent that a meticulous operative technique, respecting the soft tissue envelope and knowing the principles of alignment and soft tissue balancing, aresome of the parameters that might contribute more to achieving the optimal results for the patients.

Acute appendicitis–advances and controversies

Being one of the most common causes of the acute abdomen,acute appendicitis(AA)forms the bread and butter of any general surgeon’s practice.With the recent advancements in AA’s management,much controversy in diagnostic algorithms,possible differential diagnoses,and weighing the management options has been generated,with no absolute consensus in the literature.Since Alvarado described his eponymous clinical scoring system in 1986 to stratify AA risk,there has been a burgeoning of additional scores for guiding downstream management and mortality assessment.Furthermore,advancing literature on the role of antibiotics,variations in appendicectomy,and its adjuncts have expanded the surgeon’s repertoire of management options.Owing to the varied presentation,diagnostic tools,and management of AA have also been proposed in special groups such as pregnant patients,the elderly,and the immunocompromised.This article seeks to raise the critical debates about what is currently known about the above aspects of AA and explore the latest controversies in the field.Considering the ever-evolving coronavirus disease 2019 situation worldwide,we also discuss the pandemic’s repercussions on patients and how surgeons’practices have evolved in the context of AA.

The temperature record of the Holocene: progress and controversies

The pattern of temperature variation during the Holocene, the most recent geological epoch, has been studied intensively, partly because of its significance for the development of human civilization. Prior to the 1980s, based on ice core records in Greenland and Antarctica, the climate of the Holocene was thought to have been rather stable (1)However, this view was challenged by the discovery of a substantial amount of contrary evidence.

Clinical controversies in endoscopic ultrasound

The field of diagnostic and therapeutic endoscopic ultrasound(EUS)is growing rapidly.Although EUS has enhanced our ability to diagnose and treat a wide variety of GI conditions,there are many controversial issues regarding the appropriate application of EUS techniques.In this review we discuss five controversial topics in EUS:the utility of EUS in staging of esophageal and gastric cancer;selection of appropriate needle gauge for fine needle aspiration(FNA);use of the stylet in FNA;and the emerging role of contrast agents in endoscopic ultrasound.

The Controversies and Challenges in the Management of Twin Pregnancy: From the Perspective of International Federation of Gynecology and Obstetrics Guidelines

The rate of multiple pregnancy is increasing, mainly because of the widespread use of assisted reproduction techniques and families’ desire for twins. Twin pregnancy accounts for a higher risk of chromosomal abnormalities, structural malformations, and neonatal adverse events than singleton pregnancy. The presence of artery-vein anastomoses, unbalanced placenta sharing, and abnormal cord insertion in monochorionic twins is associated with twin complications such as twin-to-twin transfusion syndrome, selective intrauterine growth restriction, and twin anemia polycythemia sequence. Although many guidelines and studies have established and improved the processes about the antenatal surveillance and management of twin pregnancy, they also raise more controversies and challenges. This review aims to highlight the international consensus on the antenatal care of twin pregnancies and analyze the controversies and predicaments based on the published International Federation of Gynecology and Obstetrics guidelines and research.

South China Sea: Controversies And Solutions

Disputes have recently broken out between China and some Southeast Asian countries and the United States in the South China Sea. The Beijing-based Economic Information Daily spoke to Liu Nanlai, a research fellow at the Institute of International Law under the Chinese Academy of Social Sciences, on the origin of the South China Sea issue and China’s position on it. Excerpts follow:

Bufo gargarizans:What’s in a Name?

The taxonomic status of Bufo species in East Asia,particularly those closely related to B.gargarizans,has been controversial for over half a century,and recent molecular studies further fueled the dispute.Whether B.andrewsi,B.bankorensis,B.minshanicus,B.sachalinensis,B.tibetanus,and B.tuberculatus constitute valid species or are geographic or ecological variants of B.gargarizans is at the centre of the discussion.Most of these forms possess morphological diagnostic traits,but those differences are minimal and often inconsistent.Molecular data produced many contradictory patterns.Lack of clear diagnostic characters,different usage or definition of various names,mis-identified specimens,limited amount of data or samples,and frequent inter-specific hybridization may all have contributed to the current controversies.Some contradiction may also result from differences between similarity-based clustering and gene tree-based branching patterns.Nevertheless,a dominant allopatric differentiation pattern within this species complex is apparent,and several regional population groups have been identified.Some of the groups resemble old names(e.g.B.minshanicus,B.tibetanus),while others are new.These groups may represent geographic or ecological variants,incipient species,or valid species,and the current data do not warrant a convincing taxonomic revision.To move forward,a single study with comprehensive sampling and genomic data is needed to establish a solid framework,which will define naturally existing population clusters/lineages,and detect their levels of divergence and approximate geographic boundaries.Morphological and ecological examination will follow to understand their biology,determine their taxonomic status,and identify consistent diagnostic characters if necessary.

DFE-GCN: Dual Feature Enhanced Graph Convolutional Network for Controversy Detection

With the development of social media and the prevalence of mobile devices,an increasing number of people tend to use social media platforms to express their opinions and attitudes,leading to many online controversies.These online controversies can severely threaten social stability,making automatic detection of controversies particularly necessary.Most controversy detection methods currently focus on mining features from text semantics and propagation structures.However,these methods have two drawbacks:1)limited ability to capture structural features and failure to learn deeper structural features,and 2)neglecting the influence of topic information and ineffective utilization of topic features.In light of these phenomena,this paper proposes a social media controversy detection method called Dual Feature Enhanced Graph Convolutional Network(DFE-GCN).This method explores structural information at different scales from global and local perspectives to capture deeper structural features,enhancing the expressive power of structural features.Furthermore,to strengthen the influence of topic information,this paper utilizes attention mechanisms to enhance topic features after each graph convolutional layer,effectively using topic information.We validated our method on two different public datasets,and the experimental results demonstrate that our method achieves state-of-the-art performance compared to baseline methods.On the Weibo and Reddit datasets,the accuracy is improved by 5.92%and 3.32%,respectively,and the F1 score is improved by 1.99%and 2.17%,demonstrating the positive impact of enhanced structural features and topic features on controversy detection.