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.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice.

PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease affecting 30% of the global population. In this article, we summarize current expert guidelines, review clinical practice implications, and provide insight into the utility of non-invasive tests (NITs). RECENT FINDINGS: The burden of MASLD is growing with the obesity epidemic, yet disease awareness and diagnosis is low. Patients can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), which can advance to liver fibrosis, cirrhosis, hepatic decompensation, and liver cancer. NITs help identify high-risk patients who may benefit from specialty referral and MASH-directed therapy. Global societies offer various recommendations for the screening and diagnosis of MASLD utilizing evidence-based, widely accessible methods such as serum indices, NITs, and liver biopsy. Several targeted steatotic liver disease (SLD) screening tools and novel therapies are under development.

Microangiopathic Hemolytic Anemia Is a Late and Fatal Complication of Gastric Signet Ring Cell Carcinoma: A Systematic Review and Case-Control Study.

BACKGROUND: Microangiopathic hemolytic anemia (MAHA) is a rare paraneoplastic syndrome that has been reported in patients with gastric signet ring cell carcinoma (SRCC). Clinical and prognostic features of MAHA in this setting have been poorly described. MATERIALS AND METHODS: We conducted a systematic review in 8 databases of gastric SRCC complicated by MAHA and performed a case-control study assessing factors associated with survival in patients with gastric SRCC and MAHA in our pooled cohort compared with age-, sex-, and stage-matched cases of gastric SRCC from the Surveillance, Epidemiology, and End Results (SEER) database. Descriptive analyses were performed and multivariable Cox-proportional hazards regression modeling was used to determine factors associated with overall survival. RESULTS: All identified patients (n = 47) were symptomatic at index presentation, commonly with back/bone pain, and dyspnea. Microangiopathic hemolytic anemia was the first manifestation of gastric SRCC in 94% of patients. Laboratory studies were notable for anemia (median 7.7 g/dL), thrombocytopenia (median 45.5 × 103/µL), and hyperbilirubinemia (median 2.3 mg/dL). All patients with MAHA had metastatic disease at presentation, most often to the bone, bone marrow, and lymph nodes. Median survival in patients with gastric SRCC and MAHA was significantly shorter than a matched SEER-derived cohort with metastatic gastric SRCC (7 weeks vs 28 weeks, P < .01). In multivariate analysis, patients with MAHA were at significantly increased risk of mortality (HR 3.28, 95% CI 2.11-5.12). CONCLUSION: Microangiopathic hemolytic anemia is a rare, late-stage complication of metastatic gastric SRCC and is associated with significantly decreased survival compared with metastatic gastric SRCC alone.

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.

Comparison of two-year treatment outcomes between subthreshold micropulse (577 nm) laser and aflibercept for diabetic macular edema.

PURPOSE: To compare two-year treatment outcomes of subthreshold micropulse (577 nm) laser and aflibercept for diabetic macular edema (DME). STUDY DESIGN: Retrospective case-control study. METHODS: A total 164 eyes in 164 DME patients treated with either micropulse laser (86 eyes) or intravitreal aflibercept monotherapy (78 eyes) were recruited. Main outcome measures included at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters' improvement from baseline at 6, 12 and 24 months. RESULTS: Rescue aflibercept was initiated in 24% of eyes in micropulse laser group. At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 5-letter visual acuity improvement than micropulse laser group (56% vs 38%, P = 0.044), however, this was not the case at 12-month (45% vs 49%, P = 0.584) and 24-month visits (49% vs 57%, P = 0.227). At 6-month visit the aflibercept group achieved a higher percentage of eyes with at least 10% improvement of central macular thickness (73% vs 49%, P = 0.005), but this was not the case at 12-month (73% vs 70%, P = 0.995) and 24-month visits (85% vs 84%, P = 0.872). CONCLUSION: Aflibercept achieved faster and higher rates of anatomical and functional improvement than micropulse laser in DME patients. Long term efficacy of treatment did not result in significant differences between aflibercept monotherapy and micropulse laser in DME patients. Primary treatment of micropulse laser with deferred rescue aflibercept might be the treatment option without reducing the chance of visual improvement in DME eyes.

Gallbladder Disorders: A Comprehensive Review.

Gallbladder disorders encompass a wide breadth of diseases that vary in severity. We present a comprehensive review of literature for the clinical presentation, pathophysiology, diagnostic evaluation, and management of cholelithiasis-related disease, acute acalculous cholecystitis, functional gallbladder disorder, gallbladder polyps, gallbladder hydrops, porcelain gallbladder, and gallbladder cancer.

Suitability for Kidney Transplantation in AL Amyloidosis: A Survey Study of Transplant and Amyloidosis Physicians.

Background: Historically, kidney transplantation has been considered inappropriate for most patients with AL amyloidosis-associated kidney failure because of concerns about recurrent disease in the allograft and poor long-term survival. With improvements in rates and durability of hematologic responses and survival that have accompanied treatment advances, a greater proportion of patients with AL amyloidosis may be suitable for kidney transplantation. However, there are no widely accepted criteria for kidney transplant eligibility for this patient population. Methods: We administered surveys electronically to transplant nephrologists and amyloidosis experts at a geographically diverse set of academic medical centers in the United States. Questions were designed to elucidate views about suitability and timing of kidney transplantation for patients with AL amyloidosis-associated kidney failure. Results: The survey was completed by 20 (65%) of invited amyloidosis experts and 20 (29%) of invited transplant physicians. Respondents indicated that, for patients with AL amyloidosis, most transplant nephrologists have limited experience with both determining eligibility for and providing care after kidney transplantation. Most transplant nephrologists and amyloidosis experts viewed anticipated patient survival as the most important determinant of suitability for kidney transplantation. Compared with transplant program respondents, amyloidosis program respondents reported a higher degree of confidence in determining suitability for kidney transplantation, were comfortable proceeding with kidney transplantation earlier after patients attained a hematologic response, and were less concerned about extrarenal amyloid involvement as a barrier to kidney transplantation. In both groups, most respondents indicated that there is a lack of consensus between amyloidosis and kidney transplant physicians about criteria for determining suitability for kidney transplantation. Conclusion: Views about criteria for kidney transplantation for patients with AL amyloidosis-associated kidney failure differed between amyloidosis and transplant nephrology program respondents, with amyloidosis specialists generally favoring a less-restrictive approach to transplant eligibility. The findings suggest a need for consensus building across specialties.

Endoscopic vitreoretinal surgery: Review of current applications and future trends.

Endoscopy provides unique optical properties to circumvent anterior segment opacities and visualize difficult-to-access anatomical regions, including retroirideal, retrolental, ciliary body, and anterior retinal structures. We summarize the basic principles and utilization of endoscopic vitreoretinal surgery, along with recent technological advances in the field base on a structured literature search in Pubmed, Embase, and Google Scholar database up to February, 2020. Endoscopy has been used in the management of retinal detachment, ischemic retinopathies with neovascular glaucoma, severe ocular trauma, endophthalmitis, lens-related disorders in the posterior segment, pediatric vitreoretinal diseases, and implantation of retinal prostheses. Ongoing development of endoscopic technology aims to provide higher resolution images with endoscopes of smaller diameter. New surgical techniques supported by the adoption of endoscopy are available to manage challenging surgical scenarios. Endoscopy can be a useful adjunct to microscope wide-angle viewing systems in the management of complex vitreoretinal diseases.

Unilateral versus bilateral hilar stents for the treatment of cholangiocarcinoma: a multicenter international study.

BACKGROUND: Endoscopic placement of hilar stents is an accepted palliative therapy for patients with advanced, unresectable cholangiocarcinoma. However, whether unilateral versus bilateral stent placement provides optimal relief continues to be a subject of debate. The aim of this study was to compare the technical and clinical outcomes in patients with inoperable cholangiocarcinoma who received unilateral or bilateral self-expanding metal stents (SEMS). METHODS: We conducted a multicenter, international retrospective study of 187 patients with cholangiocarcinoma who received unilateral or bilateral SEMS. Outcomes included, but were not limited to, technical success, clinical success, adverse events, stent occlusion, and survival time. Results were further stratified based on the Bismuth classification. RESULTS: Fifty patients received unilateral stents and 137 patients received bilateral stents. All patients achieved technical success. The clinical success rates were 86% for unilateral stents and 82.5% for bilateral stents (P>0.99). Clinical success was not statistically different for either group when stratified by the Bismuth classification (P=0.62 and P=0.72 respectively). There were significantly more adverse events in the bilateral stents group (11.7% vs. 0%, P=0.007). There was no greater risk of stent occlusion when bilateral stents were used (unadjusted P=0.71, adjusted P=0.81). There was a greater risk of death for patients who received bilateral SEMS (hazard ratio 1.78, 95% confidence interval 1.09-2.89; P=0.02). CONCLUSIONS: Unilateral and bilateral drainage had similar technical and clinical success rates. However, bilateral stents had a higher risk of death and more adverse events. Therefore, unilateral SEMS placement is sufficient for relief of biliary obstruction secondary to cholangiocarcinoma.

[Aborder les soins préventifs chez les aînés].

OBJECTIF: Guider les médecins de famille dans l'élaboration de plans de dépistage et de traitements préventifs à l'intention de leurs patients âgés. SOURCES DE L'INFORMATION: Une recension a été effectuée dans la base de données MEDLINE pour trouver des lignes directrices canadiennes sur les soins de santé primaires et les personnes âgées; des lignes directrices, des méta-analyses, des guides de pratique clinique ou des révisions systématiques portant sur le dépistage de masse chez les 80 ans et plus et les aînés fragiles, se limitant à ceux publiés entre 2006 et juillet 2016; et des articles sur les services de santé préventifs à l'intention des aînés et présentant un intérêt pour la pratique familiale ou les médecins de famille, limités à ceux publiés en anglais entre 2012 et juillet 2016. MESSAGE PRINCIPAL: L'estimation de l'espérance de vie n'est pas une science facile ou précise, mais la fragilité est un concept émergent susceptible d'être utile à cet égard. Le Groupe d'étude canadien sur les soins de santé préventifs propose des lignes directrices sur le dépistage du cancer, mais elles sont moins précises en ce qui concerne les patients de plus de 74 ans et il faut donc individualiser les plans de prise en charge. L'estimation des années de vie qui restent aide à orienter vos recommandations concernant les plans de dépistage et de traitements préventifs. Les risques augmentent souvent proportionnellement avec la fragilité et la comorbidité. D'autre part, les bienfaits diminuent souvent à mesure que l'espérance de vie raccourcit. Les plans de prise en charge préventive devraient tenir compte des points de vue du patient et être convenus d'un commun accord. Un moyen mnémonique pour se rappeler des principaux domaines de prévention en soins primaires - CCMF, abréviation pour cancer, cardiovasculaire, mauvais équilibre, chute et ostéoporose, fiche de vaccinations préventives - pourrait se révéler utile. CONCLUSION: Les médecins de famille pourraient trouver utile de tenir compte des éléments suivants lorsqu'ils envisagent une intervention en soins préventifs : l'âge, l'espérance de vie (incluant le concept de la fragilité), la comorbidité et l'état fonctionnel, les risques et les bienfaits du dépistage ou du traitement, de même que les valeurs et les préférences du patient.

Approach to preventive care in the elderly.

OBJECTIVE: To guide family physicians in creating preventive screening and treatment plans for their elderly patients. SOURCES OF INFORMATION: The MEDLINE database was searched for Canadian guidelines on primary health care and the elderly; guidelines or meta-analyses or practice guidelines or systematic reviews related to mass screening in those aged 80 and older and the frail elderly, limited to between 2006 and July 2016; and articles on preventive health services for the elderly related to family practice or family physicians, limited to English-language publications between 2012 and July 2016. MAIN MESSAGE: Estimating life expectancy is not an easy or precise science, but frailty is an emerging concept that can help with this. The Canadian Task Force on Preventive Health Care offers cancer screening guidelines, but they are less clear for patients older than 74 years and management plans need to be individualized. Estimating remaining years of life helps guide your recommendations for preventive screening and treatment plans. Risks often increase along with an increase in frailty and comorbidity. Conversely, benefits often diminish as life expectancy decreases. Preventive management plans should take into account the patient's perspective and be mutually agreed upon. A mnemonic device for key primary care preventive areas-CCFP, short for cancer, cardiovascular disease, falls and osteoporosis, and preventive immunizations-might be useful. CONCLUSION: Family physicians might find addressing the following areas helpful when considering a preventive health intervention: age, life expectancy (including concept of frailty), comorbidities and functional status, risks and benefits of screening or treatment, and values and preferences of the patient.

Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome.

Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson-Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.

Muir-Torre Syndrome in a Middle-Aged Chinese Patient with Sebaceous Carcinoma of the Eyelid.

Muir-Torre syndrome is a rare, autosomal dominant condition characterized by the presence of a skin tumor of sebaceous differentiation and visceral malignancies. We reviewed the case of a 46-year-old Chinese man who had a bleeding mass over the right upper eyelid. He had a history of colon cancer and a family history satisfying the Amsterdam criteria for hereditary non-polyposis colorectal cancer syndrome with germline mutation in the MutS homolog-2 gene. The eyelid lesion was excised completely and submitted for histopathologic examination which showed sebaceous carcinoma. Frozen section and conjunctival map biopsy showed no residual malignancy or local metastasis. Post-operative positron-emission tomography with combined computed tomography did not reveal any residual or visceral malignancy. He had no recurrence in the 32-month follow-up period. We should consider Muir-Torre syndrome in patients with sebaceous carcinoma, especially in the presence of personal and/or family history of visceral malignancies.

Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2.

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated ß-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

Medical Problems Referred to a Care of the Elderly Physician: Insight for Future Geriatrics CME.

PURPOSE: Family physicians provide the majority of elderly patient care in Canada. Many experience significant challenges in serving this cohort. This study aimed to examine the medical problems of patients referred to a care of the elderly physician, to better understand the geriatric continuing medical education (CME) needs of family doctors. METHODS: A retrospective chart review of patients assessed at an urban outpatient seniors' clinic between 2003 and 2008 was conducted. Data from 104 charts were analyzed and survey follow-up with 28 of the referring family physicians was undertaken. Main outcomes include the type and frequency of medical problems actually referred to a care of the elderly physician. Clarification of future geriatric CME topics of need was also assessed. RESULTS: Preventive care issues were addressed with 67 patients. Twenty-four required discussion of advance directives. The most common medical problems encountered were osteoarthritis (42), hypertension (34), osteoporosis (32), and depression or anxiety (23). Other common problems encountered that have not been highly cited as being a target of CME included musculoskeletal and joint pain (41), diabetes (23), neck and back pain (20), obesity (11), insomnia (11), and neuropathic, fibromyalgia and "leg cramps" pain (10). The referring family physicians surveyed agreed that these were topics of need for future CME. CONCLUSIONS: The findings support geriatric CME for the common medical problems encountered. Chronic pain, diabetes, obesity and insomnia continue to be important unresolved issues previously unacknowledged by physicians as CME topics of need. Future CME focusing more on process of geriatric care may also be relevant.

Crystal structures of the human histone H4K20 methyltransferases SUV420H1 and SUV420H2.

SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. In this study, we present the high-resolution crystal structures of human SUV420H1 and SUV420H2 in complex with SAM, and report their substrate specificity. Both methyltransferases have a unique N-terminal domain and Zn-binding post-SET domain, and prefer the monomethylated histone H4K20 as a substrate in vitro. No histone H4K20 trimethylation activity was detected by our radioactivity-based assay for either enzyme, consistent with the presence of a conserved serine residue that forms a hydrogen bond with the target lysine side-chain and limits the methylation level.

Crystal structures of the Tudor domains of human PHF20 reveal novel structural variations on the Royal Family of proteins.

The human PHD finger protein 20 (PHF20) is a putative transcription factor. While little is known about its cognate cellular role, antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula. PHF20 comprises two N-terminal Tudor domains, a central C2H2-link zinc finger domain and a C-terminal zinc-binding PHD domain, and is a component of some MLL methyltransferase complexes. Here, we report the crystal structures of the N-terminal Tudor domains of PHF20 and highlight the novel structural features of each domain. We also confirm previous studies suggesting that the second Tudor domain of PHF20 exhibits preference for dimethylated histone substrates.