Impact of frailty on endoscopic retrograde cholangiopancreatography outcomes in nonagenarians:A United States national experience

BACKGROUND Endoscopic retrograde cholangiopancreatography(ERCP)is an essential therapeutic tool for biliary and pancreatic diseases.Frail and elderly patients,especially those aged≥90 years are generally considered a higher-risk population for ERCP-related complications.AIM To investigate outcomes of ERCP in the Non-agenarian population(≥90 years)concerning Frailty.METHODS This is a cohort study using the 2018-2020 National Readmission Database.Patients aged≥90 were identified who underwent ERCP,using the international classification of diseases-10 code with clinical modification.Johns Hopkins’s adjusted clinical groups frailty indicator was used to classify patients as frail and non-frail.The primary outcome was mortality,and the secondary outcomes were morbidity and the 30 d readmission rate related to ERCP.We used univariate and multivariate regression models for analysis.RESULTS A total of 9448 patients were admitted for any indications of ERCP.Frail and non-frail patients were 3445(36.46%)and 6003(63.53%)respectively.Indications for ERCP were Choledocholithiasis(74.84%),Biliary pancreatitis(9.19%),Pancreatico-biliary cancer(7.6%),Biliary stricture(4.84%),and Cholangitis(1.51%).Mortality rates were higher in frail group[adjusted odds ratio(aOR)=1.68,P=0.02].The Intra-procedural complications were insigni-ficant between the two groups which included bleeding(aOR=0.72,P=0.67),accidental punctures/lacerations(aOR=0.77,P=0.5),and mechanical ventilation rates(aOR=1.19,P=0.6).Post-ERCP complication rate was similar for bleeding(aOR=0.72,P=0.41)and post-ERCP pancreatitis(aOR=1.4,P=0.44).Frail patients had a longer length of stay(6.7 d vs 5.5 d)and higher mean total charges of hospitalization($78807 vs$71392)compared to controls(P<0.001).The 30 d all-cause readmission rates between frail and non-frail patients were similar(P=0.96).CONCLUSION There was a significantly higher mortality risk and healthcare burden amongst nonagenarian frail patients undergoing ERCP compared to non-frail.Larger studies are warranted to investigate and mitigate modifiable risk factors.

Mitigating the Prevalence of Diabetic Retinopathy in the United States: Utilization of the Chronic Care Model as a Public Health Framework

As the prevalence of diabetic retinopathy continues to be on the rise, the Chronic Care Model (CCM) offers a transformative, patient-focused approach for efficient diabetic retinopathy care, emphasizing the need for urgent and innovative strategies in the United States. The model integrates community resources, healthcare organizations, self-management support, delivery system design, decision support, and clinical information systems. Addressing challenges and solutions, the model emphasizes proactive and preventive measures, collaborative multidisciplinary care, technological integration, and overcoming resistance to change. This paper proposes the utilization of the Chronic Care Model (CCM) as a possible public health framework for comprehensive management of diabetic retinopathy in the United States. Implementing the CCM offers a comprehensive approach to diabetic retinopathy care, addressing both individual and systemic factors, essential for improving public health outcomes.

Significant risk factors for intensive care unit-acquired weakness:A processing strategy based on repeated machine learning

BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.

Impact of microplastics and nanoplastics on liver health:Current understanding and future research directions

With continuous population and economic growth in the 21st century,plastic pollution is a major global issue.However,the health concern of microplastics/nanoplastics(MPs/NPs)decomposed from plastic wastes has drawn public attention only in the recent decade.This article summarizes recent works dedicated to understanding the impact of MPs/NPs on the liver-the largest digestive organ,which is one of the primary routes that MPs/NPs enter human bodies.The interrelated mechanisms including oxidative stress,hepatocyte energy re-distribution,cell death and autophagy,as well as immune responses and inflammation,were also featured.In addition,the disturbance of microbiome and gut-liver axis,and the association with clinical diseases such as metabolic dysfunction-associated fatty liver disease,steatohepatitis,liver fibrosis,and cirrhosis were briefly discussed.Finally,we discussed potential directions in regard to this trending topic,highlighted current challenges in research,and proposed possible solutions.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Inferior outcomes of liver transplantation for hepatocellular carcinoma during early-COVID-19 pandemic in the United States

BACKGROUND Early in the coronavirus disease 2019(COVID-19)pandemic,there was a significant impact on routine medical care in the United States,including in fields of transplantation and oncology.AIM To analyze the impact and outcomes of early COVID-19 pandemic on liver transplantation(LT)for hepatocellular carcinoma(HCC)in the United States.METHODS WHO declared COVID-19 as a pandemic on March 11,2020.We retrospectively analyzed data from the United Network for Organ Sharing(UNOS)database regarding adult LT with confirmed HCC on explant in 2019 and 2020.We defined pre-COVID period from March 11 to September 11,2019,and early-COVID period as from March 11 to September 11,2020.RESULTS Overall,23.5%fewer LT for HCC were performed during the COVID period(518 vs 675,P<0.05).This decrease was most pronounced in the months of March-April 2020 with a rebound in numbers seen from May-July 2020.Among LT recipients for HCC,concurrent diagnosis of non-alcoholic steatohepatitis significantly increased(23 vs 16%)and alcoholic liver disease(ALD)significantly decreased(18 vs 22%)during the COVID period.Recipient age,gender,BMI,and MELD score were statistically similar between two groups,while waiting list time decreased during the COVID period(279 days vs 300 days,P=0.041).Among pathological characteristics of HCC,vascular invasion was more prominent during COVID period(P<0.01),while other features were the same.While the donor age and other characteristics remained same,the distance between donor and recipient hospitals was significantly increased(P<0.01)and donor risk index was significantly higher(1.68 vs 1.59,P<0.01)during COVID period.Among outcomes,90-day overall and graft survival were the same,but 180-day overall and graft were significantly inferior during COVID period(94.7 vs 97.0%,P=0.048).On multivariable Coxhazard regression analysis,COVID period emerged as a significant risk factor of post-transplant mortality(Hazard ratio 1.85;95%CI:1.28-2.68,P=0.001).CONCLUSION During COVID period,there was a significant decrease in LTs performed for HCC.While early postoperative outcomes of LT for HCC were same,the overall and graft survival of LTs for HCC after 180 days were significantly inferior.

Peptic ulcer disease in non-alcoholic fatty liver disease hospitalizations:A new challenge on the horizon in the United States

BACKGROUND Peptic ulcer disease(PUD)is frequently seen in patients with liver cirrhosis.However,current literature lacks data on PUD in non-alcoholic fatty liver disease(NAFLD)hospitalizations.AIM To identify trends and clinical outcomes of PUD in NAFLD hospitalizations in the United States.METHODS The National Inpatient Sample was utilized to identify all adult(≥18 years old)NAFLD hospitalizations with PUD in the United States from 2009-2019.Hospitalization trends and outcomes were highlighted.Furthermore,a control group of adult PUD hospitalizations without NAFLD was also identified for a comparative analysis to assess the influence of NAFLD on PUD.RESULTS The total number of NAFLD hospitalizations with PUD increased from 3745 in 2009 to 3805 in 2019.We noted an increase in the mean age for the study population from 56 years in 2009 to 63 years in 2019(P<0.001).Racial differences were also prevalent as NAFLD hospitalizations with PUD increased for Whites and Hispanics,while a decline was observed for Blacks and Asians.The all-cause inpatient mortality for NAFLD hospitalizations with PUD increased from 2%in 2009 to 5%in 2019(P<0.001).However,rates of Helicobacter pylori(H.pylori)infection and upper endoscopy decreased from 5%in 2009 to 1%in 2019(P<0.001)and from 60%in 2009 to 19%in 2019(P<0.001),respectively.Interestingly,despite a significantly higher comorbidity burden,we observed lower inpatient mortality(2%vs 3%,P=0.0004),mean length of stay(LOS)(11.6 vs 12.1 d,P<0.001),and mean total healthcare cost(THC)($178598 vs$184727,P<0.001)for NAFLD hospitalizations with PUD compared to non-NAFLD PUD hospitalizations.Perforation of the gastrointestinal tract,coagulopathy,alcohol abuse,malnutrition,and fluid and electrolyte disorders were identified to be independent predictors of inpatient mortality for NAFLD hospitalizations with PUD.CONCLUSION Inpatient mortality for NAFLD hospitalizations with PUD increased for the study period.However,there was a significant decline in the rates of H.pylori infection and upper endoscopy for NAFLD hospitalizations with PUD.After a comparative analysis,NAFLD hospitalizations with PUD had lower inpatient mortality,mean LOS,and mean THC compared to the non-NAFLD cohort.

Real-world clinical effectiveness of sorafenib among patients with unresectable hepatocellular carcinoma at two centers in the United States

BACKGROUND In the United States,sorafenib monotherapy was approved in 2007 for first-line(1L)treatment of patients with unresectable hepatocellular carcinoma(uHCC).As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines,it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners’decisions for better patient care.AIM To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings.METHODS A retrospective observational study was conducted among adult patients(≥18 years)in the United States initiating sorafenib monotherapy as 1L systemic therapy for uHCC with Eastern Cooperative Oncology Group status of 0 or 1 between January 2016 and December 2019 at City of Hope and Advent Health.Data were extracted by trained abstractionists from individual patients’electronic health records and captured in electronic case report forms.Institutional Review Board approvals were obtained prior to study initiation.Data were captured from the time of sorafenib initiation until death or the end of follow-up.All data were de-identified prior to analyses.Clinical outcomes assessed included provider-reported best response,progression-free survival(PFS),and overall survival(OS).PFS and OS were estimated using Kaplan-Meier methods.RESULTS Among 134 uHCC patients treated with 1L sorafenib,majority were male(75%),and most were Caucasian(62%)or Asian(19%).Median patient age was 64 years.The most common etiologies of liver disease were hepatitis C(54%),alcohol-related liver disease(16%),and hepatitis B(11%).Most patients were reported to have Barcelona Clinic Liver Cancer stage B(19%)or stage C(70%)disease.Of 134 patients,110(82%)were reported to have discontinued treatment or died during follow-up.Primary reasons for sorafenib discontinuation were reported as progression(35%)and toxicity(30%).Best overall response was reported for 124 patients,of which 7.3%reported complete or partial response.Median time to treatment discontinuation was 2.3 mo.Overall,103 patients(77%)had disease progression or died during sorafenib therapy.Median PFS was estimated to be 2.9 mo.At the end of follow-up,82 patients(61%)were deceased.Median OS was 8.5 mo.CONCLUSION Newer therapeutic options that have reported higher PFS and OS in real-world clinical practice should be considered to enhance patient outcomes.

Use of machine learning models for the prognostication of liver transplantation: A systematic review

BACKGROUND Liver transplantation(LT)is a life-saving intervention for patients with end-stage liver disease.However,the equitable allocation of scarce donor organs remains a formidable challenge.Prognostic tools are pivotal in identifying the most suitable transplant candidates.Traditionally,scoring systems like the model for end-stage liver disease have been instrumental in this process.Nevertheless,the landscape of prognostication is undergoing a transformation with the integration of machine learning(ML)and artificial intelligence models.AIM To assess the utility of ML models in prognostication for LT,comparing their performance and reliability to established traditional scoring systems.METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines,we conducted a thorough and standardized literature search using the PubMed/MEDLINE database.Our search imposed no restrictions on publication year,age,or gender.Exclusion criteria encompassed non-English studies,review articles,case reports,conference papers,studies with missing data,or those exhibiting evident methodological flaws.RESULTS Our search yielded a total of 64 articles,with 23 meeting the inclusion criteria.Among the selected studies,60.8%originated from the United States and China combined.Only one pediatric study met the criteria.Notably,91%of the studies were published within the past five years.ML models consistently demonstrated satisfactory to excellent area under the receiver operating characteristic curve values(ranging from 0.6 to 1)across all studies,surpassing the performance of traditional scoring systems.Random forest exhibited superior predictive capabilities for 90-d mortality following LT,sepsis,and acute kidney injury(AKI).In contrast,gradient boosting excelled in predicting the risk of graft-versus-host disease,pneumonia,and AKI.CONCLUSION This study underscores the potential of ML models in guiding decisions related to allograft allocation and LT,marking a significant evolution in the field of prognostication.

Incidence of sports-related sternoclavicular joint dislocations in the United States over the last two decades

BACKGROUND Epidemiological understanding of acute sternoclavicular(SC)dislocations secondary to sports across the United States is poorly defined.AIM To identify and assess epidemiological trends of SC dislocations occurring secondary to sports-related mechanisms across United States over the past two decades.METHODS This cross-sectional,descriptive epidemiological study evaluates epidemiological trends of SC dislocations from sports that present to emergency departments(EDs)across the United States.Data were obtained from the National Electronic Injury Surveillance System database spanning two decades.Data on incidence,patient demographics,mechanisms of injury,dislocation types,incident locales,and patient dispositions were collected.RESULTS 1622 SC dislocations occurred nationwide from 2001 to 2020[incidence=0.262/1000000 people,confidence interval(CI)=0.250-0.275],comprising 0.1%of shoulder/upper trunk dislocations.Most patients were male(91%,n=1480)and aged 5-17(61%,n=982).Football,wrestling,and biking were the most frequently implicated sports,with contact sports responsible for 59%of athletic injuries(n=961).Recreational vehicle-related sports injuries,such as all-terrain vehicles,dirt bikes,and mopeds accounted for 7.8%of all injuries(n=126),with dirt bikes specifically comprising 3.7%(n=61).Ultimately,82%were discharged from the ED(n=1337),12%were admitted(n=194),and 6%were transferred(n=90).All recorded posterior dislocations were admitted or transferred from the ED.Patients sustaining SC dislocations from contact sports had a significantly increased risk of hospital admission or transfer rather than discharge from the ED as compared to patients whose injuries were from non-contact sports(incidence rate ratio=1.46,CI:=1.32-1.61,P<0.001).CONCLUSION SC dislocations from sports continue to be rare with a stably low incidence over the past two decades,likely comprising a smaller proportion of shoulder dislocations than previously thought.Contact sports are a frequent source of injury,especially among school-aged and teenage males.Most patients are discharged directly from the ED;however,a substantial number are hospitalized,many of which had documented posterior dislocations.Ultimately,understanding the epidemiology and mechanism-related trends of acute SC dislocations is important given the potential severity of these injuries,concentration in a specific population,and uncertainty linked to rare presentation.

Disparities in esophageal cancer incidence and esophageal adenocarcinoma mortality in the United States over the last 25-40 years

BACKGROUND Esophageal carcinoma presents as 2 types,esophageal adenocarcinoma(EAC)and esophageal squamous cell carcinoma(ESCC)with the frequency of both changing in the United States(US).AIM To investigate EAC/ESCC incidence time trends among the 3 main US racial groups and investigate trends in US EAC survival by ethnicity.METHODS Twenty-five years(1992-2016)of data from SEER 13 program was analyzed to compare incidence trends in EAC and ESCC between non-Hispanic whites(nHW),non-Hispanic Blacks(nHB)and Hispanics(Hisp)using SEERStat®.In addition,SEER 18 data,from 1975-2015,on EAC in the US was analyzed to evaluate racial disparities in incidence and survival using SEERStat®and Ederer II method.RESULTS In the 3 major US ethnic groups,age-adjusted incidence of ESCC has declined while EAC has continued to rise from 1992-2016.Of note,in Hisp,the EAC incidence rate increased while ESCC decreased from 1992 to 2016,resulting in EAC as the predominant esophageal cancer subtype in this group since 2011,joining nHW.Furthermore,although ESCC remains the predominant tumor in nHB,the difference between ESCC and EAC has narrowed dramatically over 25 years.EAC survival probabilities were worse in all minority groups compared to nHw.CONCLUSION Hisp have joined nHW as US ethnic groups more likely to have EAC than ESCC.Of note,EAC incidence in nHB is increasing at the highest rate nationally.Despite lower EAC incidence in all minority groups compared to nHW,these populations have decreased survival compared to nHW.

Off-farm employment,agriculture production activities,and household dietary diversity in environmentally and economically vulnerable areas of Asia

Access to off-farm employment has been expected to be a critical approach to ending hunger and all forms of malnutrition,two important targets of achieving Zero Hunger.This study aims to investigate the role of off-farm employment in improving dietary diversity through substitution effect and complementary effect with agricultural production activities and income effect.This study adopts Poisson/Tobit/Probit/OLS regressions and the instrument variable method based on the primary survey data collected among 1,282 households at 12 sites in environmentally and economically vulnerable areas of China,Nepal,Cambodia,Thailand,and Myanmar in 2019.The results show that off-farm employment is positively associated with household dietary diversity and the consumption of flesh meat,fish and other aquatic animals,fruits,and milk and dairy products,which are rich in protein and micronutrients.The results of mechanism analysis show that off-farm employment contributes to household dietary diversity by improving crop diversity,especially for poor households,boosting the probability of livestock raising for households with the middle one-third disposal income,and increasing household income.The positive association between off-farm employment and household dietary diversity is much higher for households with the bottom one-third disposal income,low illiteracy,and from upper-middle income countries.These findings imply that off-farm employment does play a vital role in achieving multiple benefits of poverty alleviation,malnutrition reduction,and agrobiodiversity conservation in environmentally and economically vulnerable areas.However,it may enlarge the gaps in dietary diversity between households with low human capital and from low and lower-middle income countries and those with high human capital and from middle-high countries.

Knowledge, Attitudes, and Practice of Patient Teaching among Nurses in Primary Health Care, United Arab Emirates

Patient education is defined as the process of influencing a patient’s behavior and helping them make the necessary changes to their knowledge, attitudes, and skills to maintain or improve their health. It is a crucial part of patient care, and the EHS ambulatory care healthcare system is giving patient education more importance. Many experts claim that nurses still have difficulties providing patient education because of a range of factors, which include a lack of expertise and numerous other obstacles. Moreover, there isn’t any published research that studies nurses’ attitudes, knowledge, and patient-teaching practices in primary healthcare in the United Arab Emirates. The research project aims to investigate the knowledge, attitude, and practice of patient teaching among nurses in primary health care centers to better understand how nurse knowledge and attitudes may affect nurse-performed patient education. The target population is nurses working in primary healthcare centers in Sharjah, Ajman, Dubai, Ras Al-Khaimah, Fujairah, and Umm Al Quwain. However, the sample size is 300 using a random cluster sampling technique. The participants were encouraged to take part in the study (KAPPTNQ) through an online survey. The study concludes that the majority of nurses are knowledgeable about patient education;a large proportion of the nurses have a positive attitude toward patient education;and the majority of the nurses have a positive practice of patient education. However, the major challenges nurses encounter with patients’ health teaching include language barriers, inadequate communication, ineffective time management, and cultural impacts on patient health education. .

Acute exacerbation of interstitial lung disease in the intensive care unit:Principles of diagnostic evaluation and management

Interstitial lung disease(ILD)is typically managed on an outpatient basis.Critical care physicians manage patients with ILD in the setting of an acute exacerbation(ILD flare)causing severe hypoxia.The principles of management of acute exacerbation of ILD are different from those used to manage patients with acute respiratory distress syndrome from sepsis,etc.Selected patients may be candidates for aggressive measures like extracorporeal membrane oxygenation and lung transplantation,while almost all patients will benefit from early palliative care.This review focused on the types of ILD,diagnosis,and management pathways for this challenging condition.

Analysis of the effects of donor and recipient hepatitis C infection on kidney transplant outcomes in the United States

BACKGROUND As Hepatitis C virus infection(HCV+)rates in kidney donors and transplant recipients rise,direct-acting antivirals(DAA)may affect outcomes.AIM To analyze the effects of HCV+in donors,recipients,or both,on deceased-donor(DD)kidney transplantation(KT)outcomes,and the impact of DAAs on those effects.METHODS The Organ Procurement and Transplantation Network data of adult first solitary DD-KT recipients 1994-2019 were allocated into four groups by donor and recipient HCV+status.We performed patient survival(PS)and death-censored graft survival(DCGS)pairwise comparisons after propensity score matching to assess the effects of HCV+in donors and/or recipients,stratifying our study by DAA era to evaluate potential effect modification.RESULTS Pre-DAA,for HCV+recipients,receiving an HCV+kidney was associated with 1.28-fold higher mortality(HR 1.151.281.42)and 1.22-fold higher death-censored graft failure(HR 1.081.221.39)compared to receiving an HCV-kidney and the absolute risk difference was 3.3%(95%CI:1.8%-4.7%)for PS and 3.1%(95%CI:1.2%-5%)for DCGS at 3 years.The HCV dual-infection(donor plus recipient)group had worse PS(0.56-fold)and DCGS(0.71-fold)than the dual-uninfected.Donor HCV+derived worse post-transplant outcomes than recipient HCV+(PS 0.36-fold,DCGS 0.34-fold).In the DAA era,the risk associated with HCV+in donors and/or recipients was no longer statistically significant,except for impaired PS in the dual-infected vs dual-uninfected(0.43-fold).CONCLUSION Prior to DAA introduction,donor HCV+negatively influenced kidney transplant outcomes in all recipients,while recipient infection only relatively impaired outcomes for uninfected donors.These adverse effects disappeared with the introduction of DAA.

A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

Noncoding RNAs instruct the Cas9 nuclease to site speifillyl cleave DNA in the CRISPR/Cas9 system.Despite the high incidence of hepatocellular carcinoma(HCC),the patient's outcome is poor.As a result of the emergence of therapeutic resistance in HCC patients,dlinicians have faced difficulties in treating such tumor.In addition,CRISPR/Cas9 screens were used to identify genes that improve the dlinical response of HCC patients.It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer,with a particular emphasis on HCC as part of the current state of knowledge.Thus,in order to locate recent developments in oncology research,we examined both the Scopus database and the PubMed database.The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs.Drug resistance can be overcome with the help of the CRISPR/Cas9 system.HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening although this method is not without limitations.It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy.CRISPR and its applications to tumor research,particularly in HCC,are examined in this study through a review of the literature.

Management of monogenic diabetes in pregnancy:A narrative review

Pregnancy in women with monogenic diabetes is potentially complex,with significant implications for both maternal and fetal health.Among these,maturity-onset diabetes of the young(MODY)stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice.Each subtype of MODY requires a distinct approach tailored to the pregnancy,diverging from management strategies in non-pregnant individuals.Glucokinase MODY(GCK-MODY)typically does not require treatment outside of pregnancy,but special considerations arise when a woman with GCK-MODY becomes pregnant.The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus.During pregnancy,the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha(HNF1A)-MODY and HNF4A-MODY depends on the mother’s specific circumstances and the available expertise.Management of other rarer MODY subtypes is individu-alized,with decisions made on a case-by-case basis.Therefore,a collaborative approach involving expert diabetes and obstetric teams is crucial for the compre-hensive management of MODY pregnancies.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases in children and adolescents.NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis(NASH),wherein hepatocellular inflammation and/or fibrosis coexist with steatosis.Circulating microRNA(miRNA)levels have been suggested to be altered in NAFLD,but the extent to which miRNA are related to NAFLD features remains unknown.This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents.AIM To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD.METHODS This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study.Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD.Plasma samples were collected during surgery for miRNA profiling.A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform.We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age,sex,race,and other key covariates.Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD.RESULTS We identified 16 upregulated plasma miRNAs,including miR-193a-5p and miR-193b-5p,and 22 downregulated plasma miRNAs,including miR-1282 and miR-6734-5p,in adolescents with NAFLD.Moreover,52,16,15,and 9 plasma miRNAs were associated with NASH,fibrosis,ballooning degeneration,and lobular inflammation,respectively.Collectively,16 miRNAs were associated with two or more histological features of NAFLD.Among those miRNAs,miR-411-5p was downregulated in NASH,ballooning,and fibrosis,while miR-122-5p,miR-1343-5p,miR-193a-5p,miR-193b-5p,and miR-7845-5p were consistently and positively associated with all histological features of NAFLD.Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression,while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B.CONCLUSION Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity.Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

Diagnostic challenges and individualized treatment of cervical adenocarcinoma metastases to the breast:A case report

BACKGROUND Cervical cancer is a rare primary tumor resulting in metastases to the breast with few cases reported in literature.Breast metastases are associated with poor prognosis.The following case highlights the diagnostic challenges associated with metastatic cervical cancer to the breast along with individualized treatment.CASE SUMMARY A 44-year-old G7P5025 with no significant past medical or surgical history presented with heavy vaginal to an outside emergency department where an exam and a pelvic magnetic resonance imaging showed a 4.5 cm heterogenous lobulated cervical mass involving upper two thirds of vagina,parametria and lymph node metastases.Cervical biopsies confirmed high grade adenocarcinoma with mucinous features.A positron emission tomography/computed tomography(PET/CT)did not show evidence of metastatic disease.She received concurrent cisplatin with external beam radiation therapy.Follow up PET/CT scan three months later showed no suspicious fluorodeoxyglucose uptake in the cervix and no evidence of metastatic disease.Patient was lost to follow up for six months.She was re-imaged on re-presentation and found to have widely metastatic disease including breast disease.Breast biopsy confirmed programmed death-ligand 1 positive metastatic cervical cancer.The patient received six cycles of carboplatin and paclitaxel with pembrolizumab.Restaging imaging demonstrated response.Patient continued on pembrolizumab with disease control.CONCLUSION Metastatic cervical cancer to the breast is uncommon with nonspecific clinical findings that can make diagnosis challenging.Clinical history and immunohistochemical evaluation of breast lesion,and comparison to primary tumor can support diagnosis of metastatic cervical cancer to the breast.Overall,the prognosis is poor,but immunotherapy can be considered in select patients and may result in good disease response.