Concordance between pathologists and between specimen types in detection of HER2-low breast carcinoma by immunohistochemistry.

CONTEXT: Recent clinical trials indicate that HER2-targeted therapy may benefit HER2-low breast cancer patients including HER2 score 1+ or 2+ and no gene amplification. Concordance between pathologists and between core biopsy and surgical excision in establishing HER2-low status was evaluated. DESIGN: 57 patients with HER2 negative breast cancer (IHC 0, 1+, or 2+, no gene amplification) by core biopsy were included. Core biopsy and representative tumor from corresponding surgical excision was immunostained for HER2. Original HER2 IHC scores were interpreted using 2018 guidelines. Three pathologists independently interpreted again under 2023 guidelines. Kappa statistic evaluated agreement of HER2 IHC scores. RESULTS: Applying 2023 guidelines, HER2 IHC scores were concordant among study pathologists in 46 of 57 (81 %) core biopsy and 50 of 57 (88 %) surgical resections. Kappa statistics were 0.78 and 0.85 (substantial agreement), for inter-pathologist agreement of core biopsy and surgical resections under 2023 guidelines; 0.55 (moderate agreement) for agreement between first interpretation by 2018 guidelines and second interpretation by 2023 guidelines; and 0.13 (slight agreement) for agreement in HER2 consensus scores between outside core and surgical resection and 0.49 (moderate agreement) for inside core and surgical resection. Low HER2 expression was found in 28 of 57 (49 %) core biopsy and in 25 of 57 (44 %) surgical excisions. CONCLUSIONS: Interobserver agreement among study pathologists was good in core biopsy and surgical excisions, applying updated 2023 guidelines. Intratumoral heterogeneity in protein expression and preanalytical factors may result in variable identification of HER2-low status in core biopsy and surgical excision specimens.

Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry.

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.

Early COVID-19 Attitudes and Behaviors and Their Associations With Later Infection: A Local Perspective From One U.S. City.

BACKGROUND: At the onset of the pandemic, there was poor public awareness and inaction in response to COVID-19; it is less known whether this translated to subsequent infections. OBJECTIVES: To explore whether adults who perceived COVID-19 as less of a threat and who were not taking early actions were more likely to become infected over the following year. RESEARCH DESIGN: Survey data from the ongoing (COVID-19 & Chronic Conditions (C3) anonymized for review) cohort study. PARTICIPANTS: Six hundred forty-two adults with a mean age of 63 and ≥1 chronic condition. MEASURES: Self-reported attitudes and behaviors regarding COVID-19 were assessed from March 13 to April 3, 2020, and COVID-19 infection status was captured between May 2020 and January 2021. Bivariate and multivariable analyses examined associations between early perceptions and behaviors with later infection. RESULTS: Approximately 7% reported infection with COVID-19 (N = 46). Adults who perceived the threat of COVID-19 less seriously at the initial outbreak were more likely to test positive over the following year [odds ratio (OR): 0.81, CI: 0.70-0.94; P = 0.006]. Those who were less likely to believe their actions would affect whether they would become infected were more likely to test positive (OR: 0.87, CI: 0.77-0.99; P = 0.03), as were adults who reported not changing their routines (OR: 0.45; CI: 0.24-0.85; P = 0.01). CONCLUSIONS: Adults with delayed responses in acknowledging the threat of COVID-19 and in changing behaviors were more likely to contract the virus. This investigation provides insight into the consequences of inadequate public understanding and response to COVID-19, and it highlights the importance of promoting early awareness among high-risk groups during public health crises.

Association of polygenic risk score with response to deep brain stimulation in Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment option for select patients with Parkinson's Disease (PD). However, response to DBS varies, therefore, the ability to predict who will have better outcomes can aid patient selection. Some PD-related monogenic mutations have been reported among factors that influence response to DBS. However, monogenic disease accounts for only a minority of patients with PD. The polygenic risk score (PRS) is an indication of cumulative genetic risk for disease. The PRS in PD has also been correlated with age of onset and symptom progression, but it is unknown whether correlations exist between PRS and DBS response. Here, we performed a pilot study to look for any such correlation. METHODS: We performed a retrospective analysis of 33 PD patients from the NIH PD Clinic and 13 patients from the Parkinson's Progression Markers Initiative database who had genetic testing and underwent bilateral subthalamic nucleus DBS surgery and clinical follow-up. A PD-specific PRS was calculated for all 46 patients based on the 90 susceptibility variants identified in the latest PD genome-wide association study. We tested associations between PRS and pre- and post-surgery motor and cognitive measures using multiple regression analysis for up to two years after surgery. RESULTS: Changes in scores on the Beck Depression Inventory (BDI) were not correlated with PRS when derived from all susceptibility variants, however, when removing pathogenic and high-risk carriers from the calculation, higher PRS was significantly associated with greater reduction in BDI score at 3 months and with similar trend 24 months after DBS. PRS was not a significant predictor of Unified Parkinson's Disease Rating Scale, Dementia Rating Scale, or phenomic and semantic fluency outcomes at 3- and 24-months after DBS surgery. CONCLUSIONS: This exploratory study suggests that PRS may predict degree of improvement in depressive symptoms after DBS, though was not predictive of motor and other cognitive outcomes after DBS. Additionally, PRS may be most relevant in predicting DBS outcomes in patients lacking pathogenic or high-risk PD variants. However, this was a small preliminary study and response to DBS treatment is multifactorial, therefore, more standardized high-powered studies are needed.

Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.

PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease.

The impact of underrepresented minority or marginalized identity status on training outcomes of MD-PhD students.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine.

Association between medication regimen complexity and glycemic control among patients with type 2 diabetes.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and comorbid conditions require patients to take complex medication regimens. Greater regimen complexity has been associated with poorer T2DM management; however, the relationship between overall regimen complexity and glycemic control is unclear. OBJECTIVES: Our objectives were: (1) to examine associations between regimen complexity (with the Medication Regimen Complexity Index [MRCI]) and glycemic control (A1C), and (2) to compare overall MRCI with other measures of regimen complexity (overall and diabetes-specific medication count) and diabetes-specific MRCI. METHODS: This was a secondary data analysis of cross-sectional data from a parent trial. Participants were patients with T2DM taking at least 3 chronic medications followed in safety net clinics in the Chicago area. The MRCI measures complexity based on dosing frequency, route of administration, and special instructions for prescribed medications. MRCI scores were created for overall regimens and diabetes-specific medications. Sociodemographics and outpatient visit utilization were included in models as covariates. Linear regression was used to examine the associations between variables of interest and hemoglobin A1C. RESULTS: Participants (N = 432) had a mean age of 56.9 years, most were female (66.0%), and Hispanic or Latino (73.3%). Regimen complexity was high based on overall medications (mean = 6.6 medications, SD: 3.09) and MRCI (mean = 21.4, SD: 11.3). Higher diabetes-specific MRCI was associated with higher A1C in bivariate and multivariable models. In multivariable models, overall MRCI greater than 14, fewer outpatient health care visits, male gender, and absence of health insurance were independently associated with higher A1C. The variance in A1C explained by MRCI was higher compared to medication count for overall and diabetes-specific regimen complexity. CONCLUSIONS: More complex regimens are associated with worse A1C and measuring complexity with MRCI may have advantages. Deprescribing, increasing insurance coverage, and promoting engagement in health care may improve A1C among underserved populations with complex regimens.

Immunohistochemical Markers for Distinguishing Metastatic Breast Carcinoma from Other Common Malignancies: Update and Revisit.

Due to the high prevalence of breast cancer in the female, a metastasis from primary breast cancer is usually considered in the differential diagnosis of metastatic carcinoma in the female patient, even for those without a history of breast cancer, as some breast cancers are first diagnosed as metastases. Immunohistochemical analysis for breast cancer markers is the most common way to determine breast cancer origin besides clinical history and histology. In this review, we (1) summarize the commonly used and the newly identified breast cancer markers, including GCDFP-15, mammaglobin, GATA3, SOX10, and TRPS1; (2) point out the strengths and weaknesses of using these markers for breast cancers with luminal/epithelial or basal/myoepithelial differentiation; and (3) recommend diagnostic panels to differentiate breast carcinoma from carcinoma with similar morphology of other origins.

α-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease.

BACKGROUND: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. OBJECTIVE: This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. METHODS: α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. RESULTS: α-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. CONCLUSIONS: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society.

The Relationship of Breast Density and Positive Lumpectomy Margins.

BACKGROUND: A positive lumpectomy margin after breast-conserving surgery (BCS) is a significant predictor for ipsilateral cancer recurrence. The MarginProbe, a Food and Drug Administration (FDA)-approved device for intraoperative assessment of lumpectomy margins, is associated with a reduction in re-excision surgery. This study aimed to evaluate the relationship of mammographic breast density (MBD) and clinicopathologic characteristics with margin status in women undergoing BCS with the MarginProbe. METHODS: The institutional database was queried for patients with breast cancer who had BCS with the MarginProbe from 2013 to 2017. Clinicopathologic characteristics were collected. The study defined MBD as less dense (Breast Imaging Reporting and Data System [BI-RADS] A and B) and more dense (BI-RADS C and D). A positive margin was defined as smaller than 1 mm. Pearson Chi square and uni- and multivariate logistic regression were performed. RESULTS: Of 1734 patients, 341 met the study criteria. The median patient age was 63 years. The patients with higher mammographic density were younger (p < 0.0001) and had a lower body mass index (BMI) (p < 0.0001). The patients with higher MBD were more likely to present with a palpable mass (p = 0.0360). Of the 341 patients, 135 (39.6%) had one or more positive margins on the main specimen, and 101 (74.8%) were converted to final negative margins after the MarginProbe directed re-excisions. Positive final margins were associated with larger tumor size (p = 0.0242) and more advanced stage of disease at diagnosis (p = 0.0255). CONCLUSIONS: In this study of patients undergoing BCS, breast density was not correlated with the likelihood of a positive margin. The presence of positive final lumpectomy margins was associated with older age and more extensive disease.

Impact of biomarkers and genetic profiling on breast cancer prognostication: A comparative analysis of the 8th edition of breast cancer staging system.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging guidelines combine traditional TNM system with biomarkers to reflect our current understanding of tumor biology and targeted therapy. In this study, we investigated the impact of the TNM + Biomarkers staging system and the additive value of Oncotype Dx™ genomic profile recurrence score (RS) (TNM + Biomarkers+RS <11) for the staging of breast cancer (BC) using data from two tertiary referral cancer centers. Compared to TNM alone, the TNM + Biomarkers system changed the stage group in 32.7% of BCs (27% downstage, 5.7% upstage). Most (98.3%) of the downstaged BCs were estrogen receptor (ER)+/progesterone receptor (PR)+, whereas 78% of the upstaged BCs were ER-/PR-/human epidermal growth factor receptor 2 (HER2)-. Compared to TNM + Biomarkers staging, the addition of genetic profile data (TNM + Biomarker+RS <11) downstaged only <1% BCs. Our analysis suggests that for T1-T2N0 ER+/HER2- BCs, Oncotype Dx™ RS <11 provides added value as a staging parameter only in a very small group of cases compared to TNM + Biomarkers alone.

Ultrasound and Histopathologic Correlation of Ovarian Cystadenofibromas: Diagnostic Value of the "Shadow Sign".

OBJECTIVES: Cystadenofibromas (CAFs) are rare benign ovarian tumors without a widely accepted ultrasound (US) pattern. They are usually described by as thin-walled, unilocular or multilocular, and at times septated cysts with scant blood flow and no solid components. We describe a unique US feature, the "shadow sign," seen in prospectively diagnosed benign CAFs. We also provide the histopathologic basis for this typical US appearance. METHODS: Ultrasound (US) examinations were performed in our obstetric and gynecologic US unit. Pathologic examinations were performed by a dedicated gynecologic pathology team. The US and pathology department's database was searched for the diagnosis of a CAF between 2010 and 2017. RESULTS: We identified 20 patients who underwent transvaginal US examinations with a sole US diagnosis of a CAF, and the tumors were surgically removed. The common US feature across the 20 cases was the presence of hyperechoic avascular shadowing nodules. The correlating histologic features were unilocular or multilocular cysts with a smooth internal wall surface lined by a simple epithelium and occasional robust polypoid fibrous stroma. CONCLUSIONS: This US marker helps in differentiating CAFs from borderline ovarian tumors, which do not show this US feature. We hope that recognizing the suggested shadow sign as an additional descriptor of CAFs will lead to minimizing their unnecessary removal and eliminating additional and unnecessary imaging by computed tomography and magnetic resonance imaging.

A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects.

OBJECTIVES: The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects. METHODS: Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study. RESULTS: Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for Cmax for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC0-inf were 0.96, 1.09, and 0.98, respectively. Median Tmax (range 5-11 days) and mean half-lives (range 31-39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings. CONCLUSION: The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Evaluation of a Real-Time Reverse Transcription-PCR Assay for Detection of Enterovirus D68 in Clinical Samples from an Outbreak in New York State in 2014.

An outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68) infection was reported in mid-August 2014 in the United States. In this study, we evaluated the diagnostic utility of an EV-D68-specific real-time reverse transcription-PCR (rRT-PCR) that was recently developed by the Centers for Disease Control and Prevention in clinical samples. Nasopharyngeal (NP) swab specimens from patients in a recent outbreak of respiratory illness in the lower Hudson Valley, New York State, were collected and examined for the presence of human rhinovirus or enterovirus using the FilmArray Respiratory Panel (RP) assay. Samples positive by RP were assessed using EV-D68 rRT-PCR, and the data were compared to results from sequencing analysis of partial VP1 and 5' untranslated region (5'-UTR) sequences of the EV genome. A total of 285 RP-positive NP specimens (260 from the 2014 outbreak and 25 from 2013) were analyzed by rRT-PCR; EV-D68 was detected in 74 of 285 (26.0%) specimens examined. Data for comparisons between rRT-PCR and sequencing analysis were obtained from 194 NP specimens. EV-D68 detection was confirmed by sequencing analysis in 71 of 74 positive and in 1 of 120 randomly selected negative specimens by rRT-PCR. The EV-D68 rRT-PCR showed diagnostic sensitivity and specificity of 98.6% and 97.5%, respectively. Our data suggest that the EV-D68 rRT-PCR is a reliable assay for detection of EV-D68 in clinical samples and has a potential to be used as a tool for rapid diagnosis and outbreak investigation of EV-D68-associated infections in clinical and public health laboratories.

Patient factors associated with telehealth quality and experience among adults with chronic conditions.

Objective: To evaluate patient-reported experiences of telehealth and disparities in access, use, and satisfaction with telehealth during the COVID-19 pandemic. Materials and methods: We examined data from the fifth wave of the COVID-19 & Chronic Conditions (C3) study conducted between December 2020 and March 2021. Results: Of the 718 participants, 342 (47.6%) reported having a telehealth visit within the past 4 months. Participants who had a recent telehealth visit were younger, reported worse overall health and chronic illness burden, and living below poverty level. Among participants who had a telehealth visit, 66.7% reported telephone visits and most participants (57.6%) rated telehealth quality as better-or-equal-to in-person visits. Inadequate health literacy was associated with lower likelihood of reporting telehealth quality and usefulness. In multivariable analyses, lower patient activation (adjusted odds ratio (AOR) 0.19, 95% CI, 0.05-0.59) and limited English proficiency (AOR 0.12, 95% CI, 0.03-0.47) were less likely to report telehealth as being better than in-person visits; lower patient activation (AOR 0.06, 95% CI, 0.003-0.41) and income below poverty level (AOR 0.36, 95% CI, 0.13-0.98) were associated with difficulty remembering telehealth visit information. Discussion: Most participants reported usefulness and ease of navigating telehealth. Lower socioeconomic status, limited English proficiency, inadequate health literacy, lower educational attainment, and low patient activation are risks for poorer quality telehealth. Conclusion: The COVID pandemic has accelerated the adoption of telehealth, however, disparities in access and self-reported visit quality persist. Since telemedicine is here to stay, we identify vulnerable populations and discuss potential solutions to reduce healthcare disparities in telehealth use.

Exploratory pilot study to characterize the immune landscapes of malignant pleural effusions and their corresponding primary tumors from patients with breast carcinoma and lung adenocarcinoma.

INTRODUCTION: Malignant pleural effusion (MPE) is a frequent complication of advanced malignancies. In this pilot study, we characterized the immune landscapes of MPEs, compared them to their primary tumor (PT) samples from breast carcinoma (BC) and lung adenocarcinoma (LADC), and tested the utility of multiplexed image technology in cytological samples. MATERIALS AND METHODS: We evaluated the immune contexture of 6 BC and 5 LADC MPEs and their PTs using 3 multiplex immunofluorescence panels. We explored the associations between sample characteristics and pleural effusion-free survival. RESULTS: No MPE samples had positive programmed death-ligand 1 expression in malignant cells, although 3 of 11 PTs has positive programmed death-ligand 1 expression (more than 1% expression in malignant cells). Overall, in LADC samples, cluster of differentiation 3 (CD3)+ T cells and CD3+CD8+ cytotoxic T cells predominated (median percentages for MPEs versus PTs: 45.6% versus 40.7% and 4.7% versus 6.6%, respectively) compared with BC. CD68+ macrophages predominated in the BC samples (medians for MPEs 61.2% versus PTs for 57.1%) but not in the LADC samples. Generally in PTs, CD3+CD8+ forkhead box P3+ T cells and the median distances from the malignant cells to CD3+CD8+Ki67+ and CD3+ programmed cell death protein 1 + T cells correlated to earlier MPE after PT diagnosis. CONCLUSIONS: The immune cell phenotypes in the MPEs and PTs were similar within each cancer type but different between BC versus LADC. An MPE analysis can potentially be used as a substitute for a PT analysis, but an expanded study of this topic is essential.

Disparities in Patient Portal Use Among Adults With Chronic Conditions.

Importance: Disparities in patient access and use of health care portals have been documented. Limited research has evaluated disparities in portal use during and after the COVID-19 pandemic. Objective: To assess prevalence of health care portal use before, during, and after the most restrictive phase of the pandemic (2019-2022) among the COVID-19 & Chronic Conditions (C3) cohort and to investigate any disparities in use by sociodemographic factors. Design, Setting, and Participants: This cohort study uses data from the C3 study, an ongoing, longitudinal, telephone-based survey of participants with multiple chronic conditions. Participants were middle aged and older-adult primary care patients who had an active portal account, recruited from a single academic medical center in Chicago, Illinois, between 2019 and 2022. Data were analyzed between March and June 2022. Main Outcomes and Measures: Outcomes of portal use (ie, number of days of portal login by year) were recorded for all study participants by the electronic data warehouse. All parent studies had uniform sociodemographic data and measures of social support, self-efficacy, health literacy, and health activation. Results: Of 536 participants (mean [SD] age, 66.7 [12.0] years; 336 [62.7%] female), 44 (8.2%) were Hispanic or Latinx, 142 (26.5%) were non-Hispanic Black, 322 (60.1%) were non-Hispanic White, and 20 individuals (3.7%) identified as other race, including Asian, Native American or Alaskan Native, and self-reported other race. In multivariable analyses, portal login activity was higher during the 3 years of the COVID-19 pandemic compared with the 2019 baseline. Higher portal login activity was associated with adequate health literacy (incidence rate ratio [IRR], 1.51; 95% CI, 1.18-1.94) and multimorbidity (IRR, 1.38; 95% CI, 1.17-1.64). Lower portal activity was associated with older age (≥70 years: IRR, 0.69; 95% CI, 0.55-0.85) and female sex (IRR, 0.77; 95% CI, 0.66-0.91). Compared with non-Hispanic White patients, lower portal activity was observed among Hispanic or Latinx patients (IRR, 0.66; 95% CI, 0.49-0.89), non-Hispanic Black patients (IRR, 0.68; 95% CI, 0.56-0.83), and patients who identified as other race (IRR, 0.42; 95% CI, 0.28-0.64). Conclusions and Relevance: This cohort study using data from the C3 study identified changes in portal use over time and highlighted populations that had lower access to health information. The COVID-19 pandemic was associated with an increase in portal use. Sociodemographic disparities by sex and age were reduced, although disparities by health literacy widened. A brief validated health literacy measure may serve as a useful digital literacy screening tool to identify patients who need further support.

Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers. METHODS: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections. RESULTS: There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80-125%). Geometric mean Cmax and AUClast following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants. CONCLUSIONS: After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04988152.

Complete genome sequences of nine Rhodococcus equi phages.

We report genomes of nine phages isolated from Actinobacteria Rhodococcus equi NRRL B-16538. Six of these phages belong to actinobacteriophage cluster CR, which otherwise contains Gordonia phages; two form the CF cluster; and one is a singleton. Genome lengths are 62,017-80,980 bp with 63.9%-67.3% GC content.

Novel syndromic neurodevelopmental disorder caused by de novo deletion of CHASERR, a long noncoding RNA.

Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease. CHASERR is a highly conserved human lncRNA adjacent to CHD2-a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous de novo deletion in the CHASERR locus. We report similarities in severe developmental delay, facial dysmorphisms, and cerebral dysmyelination in these individuals, distinguishing them from the phenotypic spectrum of CHD2 haploinsufficiency. We demonstrate reduced CHASERR mRNA expression and corresponding increased CHD2 mRNA and protein in whole blood and patient-derived cell lines-specifically increased expression of the CHD2 allele in cis with the CHASERR deletion, as predicted from a prior mouse model of Chaserr haploinsufficiency. We show for the first time that de novo structural variants facilitated by Alu-mediated non-allelic homologous recombination led to deletion of a non-coding element (the lncRNA CHASERR) to cause a rare syndromic neurodevelopmental disorder. We also demonstrate that CHD2 has bidirectional dosage sensitivity in human disease. This work highlights the need to carefully evaluate other lncRNAs, particularly those upstream of genes associated with Mendelian disorders.