Intracerebral Hemorrhage in a Child with Renal Artery Stenosis and COVID-19.

Pediatric intracerebral hemorrhage is a rare condition among children. We discuss the case of a 7-year-old Filipino male with generalized tonic seizures and diagnosed to have both SARS-CoV-2 infection and hypertension secondary to renal arterial stenosis. The occurrence of intracerebral hemorrhage in children, though commonly caused by arteriovenous malformations, may be secondary to an acute hypertensive episode. In this case, the presence of COVID-19 in the patient may have been contributory to the development of spontaneous intracerebral hemorrhage due to its direct endothelial effects, as well as its dysregulatory action on the renin-angiotensin-aldosterone system.

Reducing economic burden through split-shared care model for people living with uncontrolled type 2 diabetes and polypharmacy: a multi-center randomized controlled trial.

BACKGROUND: Interprofessional collaborative care such as a split-shared care model involving family physicians and community pharmacists can reduce the economic burden of diabetes management. This study aimed to evaluate the economic outcome of a split-shared care model between family physicians and community pharmacists within a pharmacy chain in managing people with uncontrolled type 2 diabetes and polypharmacy. METHOD: This was a multi-center, parallel arm, open label, randomized controlled trial comparing the direct and indirect economic outcomes of people who received collaborative care involving community pharmacists (intervention) versus those who received usual care without community pharmacist involvement (control). People with uncontrolled type 2 diabetes, defined as HbA1c > 7.0% and taking ≥ 5 chronic medications were included while people with missing baseline economic data (such as consultation costs, medication costs) were excluded. Direct medical costs were extracted from the institution's financial database while indirect costs were calculated from self-reported gross income and productivity loss, using Work Productivity Activity Impairment Global Health questionnaire. Separate generalized linear models with log link function and gamma distribution were used to analyze changes in direct and indirect medical costs. RESULTS: A total of 175 patients (intervention = 70, control = 105) completed the trial and were included for analysis. The mean age of the participants was 66.9 (9.2) years, with majority being male and Chinese. The direct medical costs were significantly lower in the intervention than the control group over 6 months (intervention: -US$70.51, control: -US$47.66, p < 0.001). Medication cost was the main driver in both groups. There were no significant changes in productivity loss and indirect costs in both groups. CONCLUSION: Implementation of split-shared visits with frontline community partners may reduce economic burden for patient with uncontrolled type 2 diabetes and polypharmacy. TRIAL REGISTRATION: Clinicaltrials.gov Reference Number: NCT03531944 (Date of registration: June 6, 2018).

Proteomic profiling of bronchoalveolar lavage fluid uncovers protein clusters linked to survival in idiopathic forms of interstitial lung disease.

Background: Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways. Results: Proteomic profiling successfully differentiated IIP from controls. k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity. Conclusions: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Epidemiologic Features of Recovery From SARS-CoV-2 Infection.

Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden. Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days. Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection. Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires. Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days. Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections. Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.

Skin cancer screening recommendations by U.S. cancer centers: Inconsistency with national guidelines.

OBJECTIVE: The incidence of melanoma has increased dramatically over the past four decades, while overall mortality has remained stable. This increase in incidence without a change in overall mortality may be due to overdiagnosis through skin cancer screening. Despite the USPSTF citing insufficient evidence for or against professional skin cancer screening in average-risk adults, U.S. skin cancer screening practices may be leading to overdiagnosis of skin cancers. METHODS: Two reviewers examined the online recommendations for skin cancer screening of 1113 U.S. cancer centers accredited by the Commission on Cancer, including 66 designated by the National Cancer Institute (NCI). Recommendations on skin cancer screening, such as age, frequency, and patient population (i.e. high-risk of developing skin cancer, "people of color") were documented. RESULTS: We found that 18% of centers (202) recommended professional screening in average-risk adults, 35.8% (399) advised regular self-examination, and only 3.4% (38) cited insufficient evidence for screening practices; 49% of NCI centers (32/66) recommended screening in high-risk adults compared to 13% of non-NCI centers (135/1047; p = 0.0004); 0.45% of centers (5) mentioned the potential harms of screening, while 3.5% (39) specifically recommended screening for people of color. CONCLUSION: Our study reveals that many U.S. cancer centers advise some form of skin cancer screening despite a lack of evidence for or against these practices. Few centers mentioned the potential harms of screening, including overdiagnosis. This indicates a need for stronger evidence for specific screening guidelines and for greater public awareness of the potential benefits and harms of routine skin cancer screening.

Dispensing of Glucagon-Like Peptide-1 Receptor Agonists to Adolescents and Young Adults, 2020-2023.

This study uses data from US retail pharmacies to assess national GLP-1RA dispensing to adolescents and young adults from 2020-2023.

The Glycemia Risk Index Predicts Performance of Diabetes Self-Management Habits in Youth With Type 1 Diabetes Mellitus.

BACKGROUND: The Glycemia Risk Index (GRI) was developed in adults with diabetes and is a validated metric of quality of glycemia. Little is known about the relationship between GRI and type 1 diabetes (T1D) self-management habits, a validated assessment of youths' engagement in habits associated with glycemic outcomes. METHOD: We retrospectively examined the relationship between GRI and T1D self-management habits in youth with T1D who received care from a Midwest pediatric diabetes clinic network. The GRI was calculated using seven days of continuous glucose monitor (CGM) data, and T1D self-management habits were assessed ±seven days from the GRI score. A mixed-effects Poisson regression model was used to evaluate the total number of habits youth engaged in with GRI, glycated hemoglobin A1c (HbA1c), age, race, ethnicity, and insurance type as fixed effects and participant ID as a random effect to account for multiple clinic visits per individual. RESULTS: The cohort included 1182 youth aged 2.5 to 18.0 years (mean = 13.8, SD = 3.5) comprising 50.8% male, 84.6% non-Hispanic White, and 64.8% commercial insurance users across a total of 6029 clinic visits. Glycemia Risk Index scores decreased as total number of habits performed increased, suggesting youth who performed more self-management habits achieved a higher quality of glycemia. CONCLUSIONS: In youth using CGMs, GRI may serve as an easily obtainable metric to help identify youth with above target glycemia, and engagement/disengagement in the T1D self-management habits may inform clinicians with suitable interventions for improving glycemic outcomes.

Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells. METHODS: We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest. RESULTS: Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers. CONCLUSIONS: Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies.

A Primary Care-Based Weight Navigation Program.

Importance: Evidence-based weight management treatments (WMTs) are underused; strategies are needed to increase WMT use and patients' weight loss. Objective: To evaluate the association of a primary care-based weight navigation program (WNP) with WMT use and weight loss. Design, Setting, and Participants: This cohort study comprised a retrospective evaluation of a quality improvement program conducted from October 1, 2020, to September 30, 2021. Data analysis was performed from August 2, 2022, to March 7, 2024. Adults with obesity and 1 or more weight-related condition from intervention and control sites in a large academic health system in the Midwestern US were propensity matched on sociodemographic and clinical factors. Exposure: WNP, in which American Board of Obesity Medicine-certified primary care physicians offered weight-focused visits and guided patients' selection of preference-sensitive WMTs. Main Outcomes and Measures: Primary outcomes were feasibility measures, including rates of referral to and engagement in the WNP. Secondary outcomes were mean weight loss, percentage of patients achieving 5% or more and 10% or more weight loss, referral to WMTs, and number of antiobesity medication prescriptions at 12 months. Results: Of 264 patients, 181 (68.6%) were female and mean (SD) age was 49.5 (13.0) years; there were no significant differences in demographic characteristics between WNP patients (n = 132) and matched controls (n = 132). Of 1159 WNP-eligible patients, 219 (18.9%) were referred to the WNP and 132 (11.4%) completed a visit. In a difference-in-differences analysis, WNP patients lost 4.9 kg more than matched controls (95% CI, 2.11-7.76; P < .001), had 4.4% greater weight loss (95% CI, 2.2%-6.4%; P < .001), and were more likely to achieve 5% or more weight loss (odds ratio [OR], 2.90; 95% CI, 1.54-5.58); average marginal effects, 21.2%; 95% CI, 8.8%-33.6%) and 10% or more weight loss (OR, 7.19; 95% CI, 2.55-25.9; average marginal effects, 17.4%; 95% CI, 8.7%-26.2%). Patients in the WNP group were referred at higher rates to WMTs, including bariatric surgery (18.9% vs 9.1%; P = .02), a low-calorie meal replacement program (16.7% vs 3.8%; P < .001), and a Mediterranean-style diet and activity program (10.6% vs 1.5%; P = .002). There were no between-group differences in antiobesity medication prescribing. Conclusions and Relevance: The findings of this cohort study suggest that WNP is feasible and associated with greater WMT use and weight loss than matched controls. The WNP warrants evaluation in a large-scale trial.

Associations between periodontitis and serum anti-malondialdehyde-acetaldehyde antibody concentrations in rheumatoid arthritis: A case-control study.

BACKGROUND: Malondialdehyde-acetaldehyde (MAA) adducts lead to generation of anti-MAA autoantibodies and have been independently identified in inflamed periodontal and rheumatoid arthritis (RA) tissues. This study evaluates serum samples from RA cases and osteoarthritis (OA) controls to quantify associations between periodontal clinical measures, alveolar bone loss (ABL), and anti-Porphyromonas gingivalis, anti-Prevotella intermedia, and anti-Fusobacterium nucleatum antibody concentrations with anti-MAA antibody concentrations. METHODS: Participants (n = 284 RA cases, n = 330 OA controls) underwent periodontal clinical assessments and ABL measurements. Serum immunoglobulin (Ig) A, IgG, and IgM anti-MAA and serum IgG antibacterial antibody concentrations were quantified by enzyme-linked immunosorbent assay (ELISA). Analyses utilized simple linear regression and multivariable adjusted models. RESULTS: No significant associations of periodontal clinical measures with serum anti-MAA were found. Moderate (p = 0.038 and p = 0.036, respectively) and high ABL (p = 0.012 and p = 0.014, respectively) in RA cases (but not in OA) were positively associated with IgG and IgM anti-MAA. Anti-P. gingivalis and anti-P. intermedia antibody concentrations were positively associated with IgA (p = 0.001 for both), IgG (p = 0.007 and p = 0.034, respectively), and IgM anti-MAA antibody concentrations (p < 0.001 and p = 0.020, respectively), while anti-F. nucleatum was positively associated with IgG anti-MAA (p = 0.042), findings that were similar across groups. CONCLUSIONS: A positive association was demonstrated between ABL and serum IgG and IgM anti-MAA antibody concentrations that was unique to RA and not observed in OA. Serum anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations displayed significant associations with anti-MAA antibody in both groups. These findings suggest MAA may play a role in the interrelationship between the periodontium and RA.

Screening for diabetes distress and depression in routine clinical care for youth with type 1 diabetes.

OBJECTIVE: The purpose of this study is to examine diabetes distress as a potential mediator of the relationship between depression symptoms and diabetes outcomes, including hemoglobin A1c (hemoglobin A1c [HbA1c]) and diabetes management behaviors in a clinical sample of adolescents and young adults. METHODS: In a pediatric diabetes clinic, 716 youth (ages 12-21 years) completed measures of diabetes distress (Problem Areas in Diabetes-Teen [PAID-T]), a single-item of diabetes distress, and depression (Patient Health Questionnaire [PHQ-9]) as part of standard care. Electronic health records were extracted for the "Six Habits" and glycemic management (HbA1c). RESULTS: Overall, 3.6% (n = 26) of adolescents had clinically elevated diabetes distress and depression symptoms, 5.0% had diabetes distress alone, 8.7% had depression symptoms alone, and 82.7% had neither clinical elevation of diabetes distress nor depression symptoms. Results of mediation analysis demonstrated diabetes distress (both full and single-item measures) fully mediated the relationship between depression symptoms and HbA1c (p < .001). Also, mediation analysis results showcase incomplete mediation of the effect of the Six Habits score on HbA1c appears by PAID-T Diabetes Distress. CONCLUSIONS: In a clinical sample of youth with type 1 diabetes, both depressive symptoms and diabetes distress are associated with HbA1c. Furthermore, diabetes distress fully mediates the relationship between depressive symptoms and HbA1c. As part of standard clinical care, the single-item screener for diabetes distress captured similar results as the full-scaled PAID-T. With limited clinical resources, providers may consider focusing assessment and interventions on the psychological factor of diabetes distress within the diabetes clinic to maximize the impact on glycemic control and consider the use of single-item screening to identify distress.

Outcomes of atypical lobular hyperplasia managed by active surveillance or immediate surgery.

BACKGROUND: Atypical lobular hyperplasia (ALH) is typically diagnosed via needle core biopsy (NCB) and is commonly removed surgically in light of upgrade to malignancy rates of 1%-5%. As studies on radiographic outcomes of ALH managed by active surveillance (AS) are limited, we investigated the upgrade rates of surgically excised ALH as well as radiographic progression during AS. METHODS: In this retrospective study, 125 patients with 127 ALH lesions diagnosed via NCB at Weill Cornell Medicine from 2015 to 2021 were included. The upgrade rate to cancer was determined for patients who had surgical management ≤6 months after biopsy. Among patients with ALH managed by AS, we investigated radiographic progression on 6-month interval imaging. RESULTS: Of 127 ALH lesions, 75% (n = 95) were immediately excised and 25% (n = 32) were observed under AS. The upgrade rate of immediately excised ALH was 2.1% (n = 2; invasive ductal carcinoma [IDC], T1N0 and IDC, and T1Nx). In the AS cohort, no ALH lesions progressed radiographically during the follow-up period of 22.5 months (median), with all remaining stable (50%, n = 16), resolving (47%, n = 15), or decreasing in size (3%, n = 1). CONCLUSIONS: In this study, NCB-diagnosed ALH had a low upgrade to malignancy rate (2.1%), and no ALH lesions managed by AS progressed radiographically during the follow-up period of 22.5 months. These results support AS as the favorable option for patients with pure ALH on biopsy, with surgical excision for lesions that progress on surveillance.

Utilizing the Glucose and Insulin Response Shape of an Oral Glucose Tolerance Test to Predict Dysglycemia in Children with Overweight and Obesity, Ages 8-18 Years.

Common dysglycemia measurements including fasting plasma glucose (FPG), oral glucose tolerance test (OGTT)-derived 2 h plasma glucose, and hemoglobin A1c (HbA1c) have limitations for children. Dynamic OGTT glucose and insulin responses may better reflect underlying physiology. This analysis assessed glucose and insulin curve shapes utilizing classifications-biphasic, monophasic, or monotonically increasing-and functional principal components (FPCs) to predict future dysglycemia. The prospective cohort included 671 participants with no previous diabetes diagnosis (BMI percentile ≥ 85th, 8-18 years old); 193 returned for follow-up (median 14.5 months). Blood was collected every 30 min during the 2 h OGTT. Functional data analysis was performed on curves summarizing glucose and insulin responses. FPCs described variation in curve height (FPC1), time of peak (FPC2), and oscillation (FPC3). At baseline, both glucose and insulin FPC1 were significantly correlated with BMI percentile (Spearman correlation r = 0.22 and 0.48), triglycerides (r = 0.30 and 0.39), and HbA1c (r = 0.25 and 0.17). In longitudinal logistic regression analyses, glucose and insulin FPCs predicted future dysglycemia (AUC = 0.80) better than shape classifications (AUC = 0.69), HbA1c (AUC = 0.72), or FPG (AUC = 0.50). Further research should evaluate the utility of FPCs to predict metabolic diseases.

Cutaneous Hydrophilic Polymer Embolism: An Important and Overlooked Clinical Entity.

ABSTRACT: Hydrophilic polymer embolism from vascular medical devices is an underrecognized clinical entity that can cause deleterious end-organ ischemia and culminate in mortality. This is concerning as we are in the era where minimally invasive procedures are commonplace. Diagnosis is often made retrospectively after obtaining histopathological tissue samples showing endoluminal, cerebriform, amorphous, anucleate, basophilic, nonrefractile, nonpolarizable foreign body material. We detail 2 more cases of cutaneous hydrophilic polymer embolism to underscore its salient clinicopathological features and increase awareness of this important iatrogenic entity.

Overview of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Its Treatment.

Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.

Association Between Psychosocial Acuity and Glycemic Control in a Pediatric Type 1 Diabetes Clinic.

PURPOSE: The purpose of this study was to describe the frequency of psychosocial risk and its associations with glycemic levels in youth with type 1 diabetes (T1D) seen by social work staff during regular clinical care. METHODS: A retrospective longitudinal analysis of observational clinical data was conducted. Individuals (1-26 years) with known T1D who were seen at a pediatric diabetes clinic in a US academic medical center between 2014 and 2021 were included. Variables included psychosocial acuity, A1C, and demographic characteristics. Chi-square tests, Wilcoxon rank sum tests, and mixed linear regressions were used to examine associations between demographic variables, psychosocial acuity, and A1C. RESULTS: Of 966 patients, 513 (53.1%) were male, 76 (7.9%) were non-Hispanic Black, and 804 (83.2%) were non-Hispanic White. There was a mean of 6.9 annual social work encounters per patient, with 3 psychosocial domains measured at each visit. Results showed that as psychosocial acuity level increased, glycemic control decreased. There were significant differences in A1C according to race/ethnicity, insurance, age, and psychosocial acuity. CONCLUSIONS: In a real-world clinical population, psychosocial acuity was associated with glycemic control. Presenting for psychosocial issues in their diabetes clinic was associated with reduced glycemic control among youth with T1D. There is an opportunity to connect pediatric patients with appropriate mental health services and psychosocial supports.

Multimodal Integrative Genomics and Pathology Analyses in Neoadjuvant Nivolumab Treatment for Intermediate and Locally Advanced Hepatocellular Carcinoma.

Introduction: Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods: In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results: Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion: Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness.

Demographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study.

This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.

The Alopecia Areata Severity and Morbidity Index (ASAMI) Study: Results From a Global Expert Consensus Exercise on Determinants of Alopecia Areata Severity.

Importance: Current measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact. Objective: To explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI). Evidence Review: A total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022. Findings: Of all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss. Conclusions and Relevance: This eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.