Recent Advances in Liver Transplantation for Hepatocellular Carcinoma.

OPINION STATEMENT: Liver transplantation for hepatocellular carcinoma (HCC) remains an evolving field. Major challenges HCC transplant patients face today include liver organ donor shortages and the need for both better pre-transplant bridging/downstaging therapies and post-transplant HCC recurrence treatment options. The advent of immunotherapy and the demonstrated efficacy of immune checkpoint inhibitors in multiple solid tumors including advanced/unresectable HCC hold promise in expanding both the neoadjuvant and adjuvant HCC transplant treatment regimen, though caution is needed with these immune modulating agents leading up to and following transplant. New options for pre-transplant HCC management will expand access to this curative option as well as ensure patients have adequate control of their HCC prior to transplant to maximize the utility of a liver donor. Machine perfusion has been an active area of investigation in recent years and could expand the organ donor pool, helping address current liver donor shortages. Finally, additional HCC biomarkers such as AFP-L3 and DCP have shown promise in improving risk stratification of HCC patients. Together, these three recent advancements will likely alter HCC transplant guidelines in the coming years.

Collaborative Innovations in Childhood Cancer Therapies.

The outcome for children with cancer has improved significantly over the past 60 years, with more than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States and Europe, with significant short- and long-term toxicity of treatment continuing to impact most children. While the past 15 years have witnessed dramatic scientific innovation for certain cancers in adult patients, pediatric cancer treatment innovation lags increasingly behind. To help bridge the adult-pediatric therapeutic development gap, collaborative efforts are essential among stakeholders within and outside the pediatric oncology community. Prioritizing collaboration in areas such as cancer characterization, target identification and validation, drug discovery, and approaches to currently "undruggable" targets is imperative to improving the outcomes for children with cancer.

Use of Lecanemab for Patients With Cardiovascular Disease: The Challenge of Uncertainty.

This Viewpoint discusses lecanemab use and the risk of cerebral macrohemorrhage for patients with mild cognitive impairment or early dementia.

Media Review: Empowered Sleep Apnea: A Handbook for Patients and the People Who Care About Them.

Empowered Sleep Apnea: A Handbook For Patients and the People Who Care About Them by Dr. David E. McCarty, MD, FAASM, and Dr. Ellen Stothard, PhD, published in 2022, is a book that focuses on empowering providers with the knowledge and resources to help patients take charge of their own health. The authors provide practical strategies for managing sleep apnea, including lifestyle modification, CPAP therapy, impact of other disorders, and troubleshooting common issues that arise. This book will be an invaluable resource for health care professionals starting their journey in sleep medicine. CITATION: Shah SB, Stahl S. Media review: Empowered Sleep Apnea: A Handbook for Patients and the People Who Care About Them. J Clin Sleep Med. 2024;20(4):669-670.

Comparison of invasive blood pressure monitoring vs. non-invasive blood pressure monitoring in critically ill children receiving vasoactive agents-a prospective observational study.

Objective: The primary aim of this study was to compare non-invasive blood pressure (NIBP) measurement using the automated oscillometric method with invasive blood pressure (IBP) measurement using peripheral arterial line insertion in critically ill children receiving vasoactive agents. Design: Single-centre, prospective cohort study. Setting: Tertiary care 15 bedded Pediatric ICU in Urban Indian city. Subjects: All critically ill children between the ages of 1 month to 16 years with shock on vasoactive medications and with IBP monitoring. Results: Forty children with 1,072 paired BP measurements were incorporated in the final analysis. Among all normotensive children (Total number of paired measurements = 623) receiving vasoactive agents, Bland-Altman analysis revealed an acceptable agreement between Invasive mean blood pressure (MBP) and non-invasive MBP with a bias of -2.10 mmHg (SD 11.35). The 95% limits of agreement were from -24.34 to 20.14 mmHg. In children with hypotension (Total number of paired measurements = 449), Bland-Altman analysis showed disagreement between Invasive MBP and non-invasive MBP i.e., a bias of -8.44 mmHg (SD 9.62). The 95% limits of agreement were from -27.29 to 10.41 mmHg. Conclusion: A limited agreement exists between invasive blood pressure (IBP) and non-invasive blood pressure (NIBP) measurements in critically ill children requiring vasoactive agents. This discrepancy can lead to either an underestimation or an overestimation of blood pressure. While NIBP can serve as a screening tool for hemodynamically stable children, those who are hemodynamically unstable and necessitate the initiation of vasoactive agents should undergo IBP monitoring.

Hazardous Alcohol Use Among Community-Dwelling Older Adults With Persistent or Recurrent Pain: Findings From the Health and Retirement Study.

BACKGROUND: Although pain and alcohol use are highly prevalent and associated with deleterious health outcomes among older adults, a paucity of literature has examined hazardous drinking among older adults with pain. We aimed to examine the prevalence of hazardous drinking among a nationally representative sample of older adults with persistent or recurrent pain. METHODS: We conducted cross-sectional analyses of data collected from the 2018 wave of the Health and Retirement Study. Participants included 1  549 community-dwelling adults aged ≥65 with persistent or recurrent pain (ie, clinically significant pain present at 2 consecutive survey waves). RESULTS: More than one-quarter of older adults with persistent or recurrent pain reported regular alcohol use (≥weekly), nearly half of whom reported hazardous patterns of drinking. Specifically, 32% reported excessive drinking (ie, >2 drinks per day for older men; >1 drink per day for older women), and 22% reported binge drinking (ie, ≥4 drinks on one occasion). Exploratory analyses revealed a high prevalence of hazardous drinking among the subsample of older adults who used opioids (47%). CONCLUSIONS: Hazardous alcohol use-including both excessive and binge drinking-is common among older adults with persistent or recurrent pain, including those who take opioids. Given that hazardous drinking can complicate pain management and increase the risk for adverse opioid effects (eg, overdose), the current findings underscore the importance of assessing and addressing hazardous patterns of alcohol use among older adults with persistent or recurrent pain.

The survival and clinical performance of anterior composite resin restorations and posterior indirect and cast restorations used to treat generalised tooth wear.

Objective To evaluate the survival and clinical performance of restorative materials used in the rehabilitation of generalised severe tooth wear within a UK NHS postgraduate teaching hospital.Methods The clinical performance of 527 restorations on 20 patients with generalised severe tooth wear was reviewed after a mean period of five years. Anterior teeth were restored with direct composite resin and posterior teeth with indirect restorations. The study used the modified United States Public Health Service criteria for restoration assessment. Survival of the restorations was analysed using Kaplan-Meier survival curves, the log-rank test and the Cox proportional hazards regression analysis.Results The sample included 20 participants: 13 men and 7 women, with a median age of 51.8 years (range: 33-73 years). The median survival time for all restorations was 11.3 years when major failures were considered and 5.9 years for restorations when all types of failure were considered. A median survival time of 5.9 years for composite resin restorations and over seven years for cast restorations was found when considering all failures. Composite resin restorations commonly failed as a result of fracture, wear and marginal discolouration. Factors significantly influencing restoration survival were the material used, aetiology, incisal relationship and tooth location. The biological complications associated with this treatment regime were rare. Patient satisfaction remained generally high, with greatest dissatisfaction related to treatment time.Conclusions The use of anterior composite resin with posterior indirect restorations to treat generalised severe tooth wear is a viable treatment modality with very few major complications.

Enhanced External Counterpulsation Improves Cognitive Function of Persons With Long COVID.

OBJECTIVE: The aim of this study is to determine the effects of enhanced external counterpulsation (EECP) in patients with long COVID and objectively assessed cognitive impairment. DESIGN: A retrospective evaluation of long COVID patients referred for EECP, with cognitive sequela, and having completed an objective digital assessment before and after therapy. Patients had either cognitive impairment or no cognitive impairment at baseline. We assessed changes in composite score using multifactor analysis of variance. Multiple linear and logistic regression analyses were conducted to evaluate several independent variables. RESULTS: Eighty long COVID patients (38 cognitive impairment vs. 42 no cognitive impairment) were included for analyses. All baseline characteristics were well matched. There was significant improvement in composite score post EECP in those with objective cognitive impairment at baseline. There were no notable documented safety concerns. CONCLUSIONS: This is the first study showing that EECP led to significant improvement in cognitive functioning of long COVID patients with objectively defined cognitive impairment. Although a lack of a negative control group is a limitation of this study, EECP seems to be highly safe and effective with the potential for widespread application.

2023 Update in ambulatory general internal medicine.

The practice of outpatient medicine is demanding, encompasses a wide scope of practice, and leaves little time for internists to stay up to date with the current literature. This article reviews 5 studies published in 2022 and 2023 that have the potential to change the practice of outpatient medicine. Topics covered include chronic kidney disease, secondary cardiovascular disease, kidney stones, obesity, and lipid management.

Large discordance between creatinine-based and cystatin C-based estimated glomerular filtration rates is associated with falls, hospitalizations, and death in older adults.

BACKGROUND: Estimated glomerular filtration rate (eGFR) calculated using creatinine and cystatin C often differ in older adults. We hypothesized that older adults with cystatin-based eGFR (eGFRcys) values significantly lower than creatinine-based eGFR (eGFRcr) values may have higher risk for aging-related adverse outcomes, independent of kidney function. METHODS: We conducted a longitudinal cohort study of adults ≥65 years old from the Health and Retirement Study, a cohort of older American adults, to determine the relationship between eGFR discordance and aging-related adverse outcomes. We calculated eGFRcr and eGFRcys using baseline creatinine and cystatin C measurements. A large eGFR discordance was defined as eGFRcys >30% lower than eGFRcr. We assessed four aging-related adverse outcomes over a two-year follow-up: falls, hip fractures, hospitalizations, and death. We fit separate multivariable regression models to determine the association between having a large eGFR discordance and each outcome adjusting for confounders including kidney function. RESULTS: Of 5574 older adults, 1683 (30%) had a large eGFR discordance. Those with a large eGFR discordance were more likely to be older, female, and White. The prevalence of a large eGFR discordance increased with age, from 20% among those 65-69 years to 44% among those 80 years and older. Over a two-year follow-up, there were 305 deaths (5.5%), 2013 falls (39.2%), 69 hip fractures (1.3%), and 1649 hospitalizations (32.2%). In adjusted analyses, large eGFR discordance was associated with a higher hazard ratio for death (HR 1.43, 95% CI 1.12-1.82) and significantly higher odds of falls (odds ratio [OR] 1.32, 95% CI 1.16-1.51) and hospitalizations (OR 1.32, 95% CI 1.15-1.51). A large eGFR discordance was not associated with hip fractures. CONCLUSION: In a large, nationally representative cohort of older adults, prevalence of eGFR discordance increased with age and was associated with higher risk of falls, hospitalization, and death, independent of kidney function.

The Heterogeneous Effect of Atrial Fibrillation Screening: A Secondary Analysis of the VITAL-AF Trial.

Background: One-time screening trials for atrial fibrillation (AF) have produced mixed results; however, it is unclear if there is a subset of individuals for whom screening would be effective. Identifying such a subgroup would support targeted screening. Methods: We conducted a secondary analysis of VITAL-AF, a randomized trial of one-time, single-lead ECG screening during primary care visits. We tested two approaches to identify a subgroup where screening is effective. First, we developed an effect-based model for heterogeneous screening effects using a T-learner. Specifically, we separately predicted the likelihood of AF diagnosis under screening and usual care conditions using LASSO, a penalized regression method. The difference between these probabilities was the predicted screening effect. Second, we used the CHARGE-AF score, a validated AF risk model, to test for a heterogeneous screening effect. We used interaction testing to determine if observed AF diagnosis rates in the screening and usual care groups differed when stratified by decile of the predicted screening effect and predicted AF risk. Results: Baseline characteristics were similar between the screening (n=15187) and usual care (n=15078) groups (mean age 74 years, 59% female). On average, screening did not significantly increase the AF diagnosis rate (2.55 vs. 2.30 per 100 person-years, rate difference 0.24, 95%CI -0.18 to 0.67). In the effect-based analysis, in the highest decile of predicted screening efficacy (n=3026), AF diagnosis rates were higher in the screening group (6.50 vs. 3.06 per 100 person-years, rate difference 3.45, 95%CI 1.62 to 5.28). In this group, the mean age was 84 years, 68% were female, and 55% had vascular disease. The risk-based analysis did not identify a subgroup where screening was more effective. Predicted screening effectiveness and predicted baseline AF risk were poorly correlated and demonstrated a U-shaped relationship (Spearman coefficient 0.13). Conclusions: In a secondary analysis of the VITAL-AF trial, we identified a small subgroup where one-time screening was associated with increased AF diagnoses using an effect-based approach. In this study, predicted AF risk was a poor proxy for predicted screening efficacy. These data caution against the assumption that high AF risk is necessarily correlated with high screening efficacy.

Estimating Vitamin K Antagonist Anticoagulation Benefit in People With Atrial Fibrillation Accounting for Competing Risks: Evidence From 12 Randomized Trials.

BACKGROUND: Patients with atrial fibrillation have a high mortality rate that is only partially attributable to vascular outcomes. The competing risk of death may affect the expected anticoagulant benefit. We determined if competing risks materially affect the guideline-endorsed estimate of anticoagulant benefit. METHODS: We conducted a secondary analysis of 12 randomized controlled trials that randomized patients with atrial fibrillation to vitamin K antagonists (VKAs) or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of VKAs to prevent stroke or systemic embolism using 2 methods-first using a guideline-endorsed model (CHA2DS2-VASc) and then again using a competing risk model that uses the same inputs as CHA2DS2-VASc but accounts for the competing risk of death and allows for nonlinear growth in benefit. We compared the absolute and relative differences in estimated benefit and whether the differences varied by life expectancy. RESULTS: A total of 7933 participants (median age, 73 years, 36% women) had a median life expectancy of 8 years (interquartile range, 6-12), determined by comorbidity-adjusted life tables and 43% were randomized to VKAs. The CHA2DS2-VASc model estimated a larger ARR than the competing risk model (median ARR at 3 years, 6.9% [interquartile range, 4.7%-10.0%] versus 5.2% [interquartile range, 3.5%-7.4%]; P<0.001). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA2DS2-VASc model - competing risk model 3-year risk) was -1.3% (95% CI, -1.3% to -1.2%); for those with life expectancies in the lowest decile, 3-year ARR difference was 4.7% (95% CI, 4.5%-5.0%). CONCLUSIONS: VKA anticoagulants were exceptionally effective at reducing stroke risk. However, VKA benefits were misestimated with CHA2DS2-VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced when life expectancy was low and when the benefit was estimated over a multiyear horizon.

Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. METHODS: This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm2/m2 for women and <55 cm2/m2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. RESULTS: Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. CONCLUSIONS: CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.

Affimer reagents enable targeted delivery of therapeutic agents and RNA via virus-like particles.

Monoclonal antibodies have revolutionized therapies, but non-immunoglobulin scaffolds are becoming compelling alternatives owing to their adaptability. Their ability to be labeled with imaging or cytotoxic compounds and to create multimeric proteins is an attractive strategy for therapeutics. Focusing on HER2, a frequently overexpressed receptor in breast cancer, this study addresses some limitations of conventional targeting moieties by harnessing the potential of these scaffolds. HER2-binding Affimers were isolated and characterized, demonstrating potency as binding reagents and efficient internalization by HER2-overexpressing cells. Affimers conjugated with cytotoxic agent achieved dose-dependent reductions in cell viability within HER2-overexpressing cell lines. Bispecific Affimers, targeting HER2 and virus-like particles, facilitated efficient internalization of virus-like particles carrying enhanced green fluorescent protein (eGFP)-encoding RNA, leading to protein expression. Anti-HER2 affibody or designed ankyrin repeat protein (DARPin) fusion constructs with the anti-VLP Affimer further underscore the adaptability of this approach. This study demonstrates the versatility of scaffolds for precise delivery of cargos into cells, advancing biotechnology and therapeutic research.

Arthroscopic Releases and Hindfoot Fusion for Spastic Equinovarus Foot Deformities, An All-Inside Technique.

Neurologic foot contractures pose a challenging situation for orthopaedic surgeons. These deformities are long-standing problems for patients with acute brain injuries, ultimately affecting their quality of life. We report our experience with using arthroscopic assisted, minimally invasive contracture tenotomies paired with a tibio-talo-calcaneal arthrodesis to achieve improved alignment and functional reconstruction of spastic equinovarus foot deformities.

Do Anticoagulants Preserve Function and Quality of Life in Older Adults with Atrial Fibrillation?

Anticoagulants in Older Adults with Atrial FibrillationAn 82-year-old woman with hypertension and diabetes is seen in the clinic for newly diagnosed atrial fibrillation. She uses a walker and fell twice last year. She completes activities of daily living independently. Should she be prescribed an anticoagulant?

Enhanced external counterpulsation for management of symptoms associated with long COVID.

Study objective: Enhanced external counterpulsation (EECP) as a possible therapy for Long COVID. Design: Retrospective analysis of a contemporary, consecutive patient cohort. Setting: 7 outpatient treatment centers. Participants: Long COVID patients. Intervention: 15-35 EECP treatments. Main outcome measures: The change from baseline in 1) Patient Reported Outcome Measurement Information System (PROMIS) Fatigue; 2) Seattle Angina Questionnaire (SAQ); 3) Duke Activity Status Index (DASI); 4) 6-Minute Walk Test (6MWT); 5) Canadian Cardiovascular Society (CCS) Angina Grade; 6) Rose Dyspnea Scale (RDS); and 7) Patient Health Questionnaire (PHQ-9). Results: Compared to baseline, the PROMIS Fatigue, SAQ, DASI, and 6MWT improved by 4.63 ± 3.42 (p < 0.001), 21.44 ± 16.54 (p < 0.001), 18.08 ± 13.82 (p < 0.001), and 200.00 ± 180.14 (p = 0.002), respectively. CCS and RDS improved in 63% and 44% of patients, respectively. All patients unable to work prior to EECP were able to return post-therapy. Conclusions and relevance: EECP significantly improved validated fatigue and cardiovascular-related markers in patients with Long COVID.