Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

Mediating role of social support in dysphoria,despondency,and quality of life in patients undergoing maintenance hemodialysis

BACKGROUND Dysphoria and despondency are prevalent psychological issues in patients undergoing Maintenance Hemodialysis(MHD)that significantly affect their quality of life(QOL).High levels of social support can significantly improve the physical and mental well-being of patients undergoing MHD.Currently,there is limited research on how social support mediates the relationship between dysphoria,despondency,and overall QOL in patients undergoing MHD.It is imperative to investigate this mediating effect to mitigate dysphoria and despondency in patients undergoing MHD,ultimately enhancing their overall QOL.AIM To investigate the mediating role of social support in relationships between dysphoria,despondency,and QOL among patients undergoing MHD.METHODS Participants comprised 289 patients undergoing MHD,who were selected using a random sampling approach.The Social Support Rating Scale,Self-Rating Anxiety Scale,Self-Rating Depression Scale,and QOL Scale were administered.Correlation analysis was performed to examine the associations between social support,dysphoria,despondency,and QOL in patients undergoing MHD.To assess the mediating impact of social support on dysphoria,despondency,and QOL in patients undergoing MHD,a bootstrap method was applied.RESULTS Significant correlations among social support,dysphoria,despondency,and quality in patients undergoing MHD were observed(all P<0.01).Dysphoria and despondency negatively correlated with social support and QOL(P<0.01).Dysphoria and despondency had negative predictive impacts on the QOL of patients undergoing MHD(P<0.05).The direct effect of dysphoria on QOL was statistically significant(P<0.05).Social support mediated the relationship between dysphoria and QOL,and this mediating effect was significant(P<0.05).Similarly,the direct effect of despondency on QOL was significant(P<0.05).Moreover,social support played a mediating role between despondency and QOL,with a significant mediating effect(P<0.05).CONCLUSION These findings suggest that social support plays a significant mediating role in the relationship between dysphoria,despondency,and QOL in patients undergoing MHD.

Prevalence of amblyopia among preschool children in central south China

AIM: To determine the prevalence and factors associated with amblyopia among children aged 30-83 mo in central south of China.METHODS: A population-based, cross-sectional study was conducted in children aged 30-83 mo in Changsha(an urban city) and Zhangjiajie(a rural area) in central south of China. Clinical examinations including ocular alignment, ocular motility, visual acuity(VA), prism cover test, cycloplegic refraction, slit lamp examination and fundus examination were performed by trained study ophthalmologists and optometrists. Unilateral amblyopia was defined as a 2-line difference between eyes with VA<20/32 in the worse eye and with coexisting anisometropia [≥1.00 D spherical eutivalent(SE) for hyperopia, ≥3.00 D SE for myopia, and ≥1.50 D for astigmatism], strabismus, or past or present visual axis obstruction. Bilateral amblyopia was defined as VA in both eyes <20/40(≥ 48-month-old) and <20/50(< 48-month-old), with coexisting hyperopia ≥4.00 D SE, myopia ≤-6.00 D SE, and astigmatism ≥2.50 D, or past or present visual axis obstruction.RESULTS: There were 8042 children enrolled and 7713 children were screened. The amblyopia prevalence in children aged 30-83 mo was 1.09%(95% confidence interval, 0.86%-1.35%) with no age(P=0.81), gender(P=0.46) or area distribution(P=0.93) differences. Of these, 0.68% were unilateral cases and 0.41% were bilateral cases. Underlying causes included anisometropia(40%), binocular refractive error(36%), strabismus(14%) and deprivation(10%). Hyperopia combined with astigmatism was the frequent refractive error for ametropic and anisometropic amblyopia.CONCLUSION: In this rural and urban Chinese population, 1.09% of children with 30-83 mo of age had amblyopia, a prevalence rate similar to that of many other studies. Anisometropia and refractive error are the most common causes of unilateral and bilateral amblyopia respectively.

Solid-Tubulocystic carcinoma:A new variant of intrahepatic cholangiocarcinoma

A new variant of intrahepatic cholangiocarcinoma(iCCA)has been recognized in recent years presenting predominantly as a large hepatic mass in young woman with the characteristic expression of inhibin by immunohistochemistry.This variant iCCA was originally termed as cholangioblastic variant of iCCA,and subsequently proposed to be renamed as inhibin-positive hepatic carcinoma or solid-tubulocystic variant of iCCA to better reflect its immunohistochemical profile or morphologic spectrum.The tumor histologically is composed of small to medium sized cells with scant to moderate amount of eosinophilic cytoplasm heterogeneously organized in solid,tubular,and cystic growth patterns.The tumor cells are positive for biliary markers,inhibin and albumin,and have a novel recurrent gene fusion,NIPBL::NACC1.Awareness of this new iCCA variant and its clinicopathologic features will aid in the diagnostic work-up and avoid confusion with other primary and metastatic hepatic neoplasms.

Left bundle branch pacing vs biventricular pacing in heart failure patients with left bundle branch block:A systematic review and meta-analysis

BACKGROUND Left bundle branch pacing(LBBP)is a novel pacing modality of cardiac resynchronization therapy(CRT)that achieves more physiologic native ventricular activation than biventricular pacing(BiVP).AIM To explore the validity of electromechanical resynchronization,clinical and echocardiographic response of LBBP-CRT.METHODS Systematic review and Meta-analysis were conducted in accordance with the standard guidelines as mentioned in detail in the methodology section.RESULTS In our analysis,the success rate of LBBP-CRT was determined to be 91.1%.LBBP CRT significantly shortened QRS duration,with significant improvement in echocardiographic parameters,including left ventricular ejection fraction,left ventricular end-diastolic diameter and left ventricular end-systolic diameter in comparison with BiVP-CRT.CONCLUSION A significant reduction in New York Heart Association class and B-type natriuretic peptide levels was also observed in the LBBP-CRT group vs BiVP-CRT group.Lastly,the LBBP-CRT cohort had a reduced pacing threshold at follow-up as compared to BiVP-CRT.

Trypsin in pancreatitis:The culprit,a mediator,or epiphenomenon?

Pancreatitis is a common,life-threatening inflammatory disease of the exocrine pancreas.Its pathogenesis remains obscure,and no specific or effective treatment is available.Gallstones and alcohol excess are major etiologies of pancreatitis;in a small portion of patients the disease is hereditary.Pancreatitis is believed to be initiated by injured acinar cells(the main exocrine pancreas cell type),leading to parenchymal necrosis and local and systemic inflammation.The primary function of these cells is to produce,store,and secrete a variety of enzymes that break down all categories of nutrients.Most digestive enzymes,including all proteases,are secreted by acinar cells as inactive proforms(zymogens)and in physiological conditions are only activated when reaching the intestine.The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens.It was proposed that pancreatitis results from proteolytic autodigestion of the gland,mediated by premature/inappropriate trypsinogen activation within acinar cells.The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis,and in human disease.On the basis of these observations,it has been considered the central pathogenic mechanism of pancreatitis-a concept with a century-old history.This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis,particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis;analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its’damaging effects;discusses the gaps in our knowledge,potential therapeutic approaches,and directions for future research.We conclude that trypsin is not the culprit in the disease pathogenesis but,at most,a mediator of some pancreatitis responses.Therefore,the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes,such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.

Embracing different languages and local differences:Coconstructive patient simulation strengthens host countries’clinical training in psychiatry

BACKGROUND Global education in psychiatry is heavily influenced by knowledge from Western,high-income countries,which obscures local voices and expertise.AIM To adapt a human simulation model to psychiatric education in a context that is specific to local languages and cultures.METHODS We conducted an observational study consisting of six human simulation sessions with standardized patients from two host countries,speaking their native languages,and following an adaptation of the co-constructive patient simulation(CCPS)model.As local faculty became increasingly familiar with the CCPS approach,they took on the role of facilitators—in their country’s native language.RESULTS Fifty-three learners participated:19 child and adolescent psychiatry trainees and 3 faculty members in Türkiye(as a group that met online during 3 consecutive months);and 24 trainees and 7 faculty in Israel(divided into 3 groups,in parallel in-person sessions during a single training day).Each of the six cases reflected local realities and clinical challenges,and was associated with specific learning goals identified by each case-writing trainee.CONCLUSION Human simulation has not been fully incorporated into psychiatric education:The creation of immersive clinical experiences and the strengthening of reflective practice are two areas ripe for development.Our adaptations of CCPS can also strengthen local and regional networks and psychiatric communities of practice.Finally,the model can help question and press against hegemonies in psychiatric training that overshadow local expertise.

Recipient functional status impacts on short and long-term intestinal transplant outcomes in United States adults

BACKGROUND Recipient functional status prior to transplantation has been found to impact post-transplant outcomes in heart,liver and kidney transplants.However,information on how functional status,before and after transplant impacts post-transplant survival outcomes is lacking.AIM To investigate the impact of recipient functional status on short and long term intestinal transplant outcomes in United States adults.METHODS We conducted a retrospective cohort study on 1254 adults who underwent first-time intestinal transplantation from 2005 to 2022.The primary outcome was mortality.Using the Karnofsky Performance Status,functional impairment was categorized as severe,moderate and normal.Analyses were conducted using Kaplan-Meier curves and multivariable Cox regression.RESULTS The median age was 41 years,majority(53.4%)were women.Severe impairment was present in 28.3%of recipients.The median survival time was 906.6 days.The median survival time was 1331 and 560 days for patients with normal and severe functional impairment respectively.Recipients with severe impairment had a 56%higher risk of mortality at one year[Hazard ratio(HR)=1.56;95%CI:1.23–1.98;P<0.001]and 58%at five years(HR=1.58;95%CI:1.24–2.00;P<0.001)compared to patients with no functional impairment.Recipients with worse functional status after transplant also had poor survival outcomes.CONCLUSION Pre-and post-transplant recipient functional status is an important prognostic indicator for short-and long-term intestinal transplant outcomes.

Treatment of portal hypertension

Portal hypertension is the main complication of cirrhosis and is defined as an hepatic venous pressure gradient （HVPG） of more than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. Over the last decades significant advancements in the field have led to standard treatment options. These clinical recommendations have evolved mostly as a result of rando.mized controlled trials and consensus conferences among experts where existing evidence has been reviewed and future goals for research and practice guidelines have been pro- posed. Management of varices/variceal hemorrhage is based on the clinical stage of portal hypertension. No specific treatment has shown to prevent the formation of varices. Prevention of first variceal hemorrhage depends on the size/characteristics of varices. In patients with small varices and high risk of bleeding, nonselective β-blockers are recommended, while patients with medium/large varices can be treated with either β-blockers or esophageal band ligation. Standard ofcare for acute variceal hemorrhage consists of vasoacrive drugs, endoscopic band ligation and antibiotics prophylaxis. Transjugular intrahepatic portosystemic shunt （TIPS） is reserved for those who fail standard of care or for patients who are likely to fail （＂early TIPS＂）. Prevention of recurrent variceal hemorrhage consists of the combination of β-blockers and endoscopic band ligation.

Era of universal testing of microsatellite instability in colorectal cancer

Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United States. Recent rapid declines in CRC incidence rates have largely been attributed to increases in screening that can detect and remove precancerous polyps, and the decrease in death rates for CRC largely reflects improvements in early detection, treatment and the understanding of molecular/genetic basis of CRC. One of the important molecular/genetic findings is the presence of microsatellite instability (MSI) in CRCs. Many studies have shown the importance of MSI testing in diagnosing Lynch syndrome and predicting prognosis and response to chemotherapeutic agents in CRCs. Increased emphasis has been placed on the importance of MSI testing for all newly diagnosed individuals with CRCs. Both immunohistochemical staining (IHC) and polymerase chain reaction (PCR)-based MSI testing show high sensitivity and specificity in detecting MSI. The current clinical guidelines and histopathology features are indicative of, but not reliable in diagnosing Lynch syndrome and CRCs with MSI. Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is getting widely accepted.

Update in management of mesenteric ischemia

Mesenteric ischemia disorders are precipitated by a circulation insufficiency event that deprives one or several abdominal organs of adequate respiration to meet metabolic demands. Although mesenteric ischemia occurs infrequently, the mortality rate is from 60% to 100%, depending on the source of obstruction. The successful outcome is dependent upon a high index of suspicion and prompt management. We briefly review the pathophysiology and presentation of the various ischemic entities and review the current state of the art in diagnosis and treatment. Despite advances in both diagnosis and treatment, prompt diagnosis and supportive care remain critical for successful outcome. New imaging techniques, endovascular therapy and emerging research may improve our approach to this deadly condition.

Hydroxycut hepatotoxicity:A case series and review of liver toxicity from herbal weight loss supplements

Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxicity, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the setting of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements, and their individual components which have demon-strated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

Calcifying fibrous tumor of the gastrointestinal tract: A clinicopathologic review and update

Calcifying fibrous tumor(CFT)is a rare mesenchymal lesion that has been documented throughout the gastrointestinal tract.Gastrointestinal CFTs may occur at virtually any age,with a predilection for adults and for females.They occur most commonly in the stomach and the small and large intestines.CFTs are most often found incidentally,cured by local resection,and have a low risk of recurrence.Histology shows three characteristic features:Spindle cell proliferations within a densely hyalinized stroma,scattered calcifications,and lymphoplasmacytic inflammation.CFTs are immunoreactive for CD34,vimentin and factor XIIIa,helping to distinguish them from other benign mesenchymal neoplasms.The differential diagnosis of CFTs includes sclerosing gastrointestinal stromal tumor,leiomyoma,schwannoma,solitary fibrous tumor,inflammatory myofibroblastic tumor,plexiform fibromyxoma,fibromatosis,sclerosing mesenteritis,and reactive nodular fibrous pseudotumor.The pathogenesis of CFTs remains unclear,but some have hypothesized that they may be linked to IgG4-related disease,inflammatory myofibroblastic lesions,hyaline vascular type Castleman disease,sclerosing angiomatoid nodular transformation of the spleen,or trauma.

The role of Toll-like receptors in non-infectious lung injury

The role of Toll-like receptors （TLRs） in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan （HA） accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-κB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.

Less common neoplasms of the pancreas

Recently, there has been an increased recognition of neoplasms of the pancreas other than ductal adenocarcinorna. Although not as well studied or characterized as pancreatic adenocarcinorna there are many distinct lesions which exhibit diverse biological behaviors and varying degrees of malignancy. These lesions include： endocrine neoplasms, cystic tumors, solid pseudopapillary tumors, acinar cell carcinoma, squamous cell carcinoma, primary lymphoma of the pancreas, and metastatic lesions to the pancreas. These less common neoplasms are being diagnosed more frequently as the number and sensitivity of diagnostic imaging studies increase. This review article discusses the clinical course, diagnosis, and treatment of these less common, but quite relevant, neoplasms of the pancreas.

Evolution of surgical skills training

Surgical training is changing： one hundred years of tradition is being challenged by legal and ethical concerns for patient safety, work hours restrictions, the cost of operating room time, and complications. Surgical simulation and skills training offers an opportunity to teach and practice advanced skills outside of the operating room environment before attempting them on living patients. Simulation training can be as straight forward as using real instruments and video equipment to manipulate simulated ＂tissue＂ in a box trainer. More advanced, virtual reality simulators are now available and ready for widespread use. Early systems have demonstrated their effectiveness and discriminative ability. Newer systems enable the development of comprehensive curricula and full procedural simulations. The Accreditation Council of Graduate Medical Education＇s （ACGME） has mandated the development of novel methods of training and evaluation. Surgical organizations are calling for methods to ensure the maintenance of skills, advance surgical training, and to credential surgeons as technically competent. Simulators in their current form have been demonstrated to improve the operating room performance of surgical residents. Development of standardized training curricula remains an urgent and important agenda, particularly for minimal invasive surgery. An innovative and progressive approach, borrowing experiences from the field of aviation, can provide the foundation for the next century of surgical training, ensuring the quality of the product. As the technology develops, the way we practice will continue to evolve, to the benefit of physicians and patients.

Role of potassium in acid secretion

Potassium (K+) ions are critical for the activation and catalytic cycle of the gastric H+,K+-ATPase, resulting in the secretion of hydrochloric acid into the parietal cell canaliculus. As both symptom, severity and esophageal mucosal damage in gastro-esophageal reflux disease (GERD) are related to the degree of acid exposure, K+ is a logical target for approaches to inhibit acid production.The probable K+ binding site on the gastric H+,K+-ATPase has recently been described and studies are elucidating how K+ activates the enzyme. K+ channels in the apical membrane of the parietal cell are implicated in the recycling of K+ and, to date, three potential K+ channels (KCNQ1, Kir2.1 and Kir4.1) have been identified. The channels represent theoretical sites for agents to control acid secretion but it will be difficult to develop selective blockers. An alternative strategy is to prevent K+ from activating gastric H+,K+-ATPase; the potassiumcompetitive acid blocker (P-CAB) class inhibits acidsecretion by binding at or near the K+ binding site.Ongoing research is further defining the role of K+ in the functioning of the gastric H+,K+-ATPase, as well as determining the clinical utility of agents directed toward this important cation.

Fully covered metal biliary stents: A review of the literature

Fully covered self-expandable metal stents(FCSEMS)represent the latest advancement of metal biliary stents used to endoscopically treat a variety of obstructive biliary pathology.A large stent diameter and synthetic covering over the tubular mesh prolong stent patency and reduce risk for tissue hyperplasia and tumor ingrowth.Additionally,FCSEMS can be easily removed.All these features address issues faced by plastic and uncovered metal stents.The purpose of this paper is to comprehensively review the application of FCSEMS in benign and malignant biliary strictures,biliary leak,and post-sphincterotomy bleeding.

Evolution in the treatment of metastatic colorectal carcinoma of the liver

Metastatic colorectal cancer to the liver is associated with a uniform poor prognosis without treatment. Advances in therapy over the past decades have now allowed surgical resections of the liver to occur with a low morbidity and mortality. Improvements in chemotherapy regimes have paralleled technical improvements and now allow a new group of patients to become eligible for surgical resection. This chapter will review the recent advances in surgical and chemotherapeutic regimes in metastatic colorectal cancer to the liver.

Insight into the biology of Macrophage Migration Inhibitory Factor （MIF） revealed by the cloning of its cell surface receptor

The recent cloning of MIF receptor fills an important gap in our understanding of the molecular biology and immunology of MIF. The MIF receptor, like MIF, does not fall into any established family of protein mediators, providing both new challenges and opportunities for the structural and functional analysis of MIF signal transduction.