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This study evaluated the role of the Pediatric Sleep Questionnaire (PSQ) and associated subscales in predicting the severity of obstructive sleep apnea (OSA) in children referred for attended polysomnography (PSG).This is a retrospective study of children (0-18 years) who completed PSQs the night of their initial diagnostic PSG (2019-2020). We excluded children with previous PSG, positive airway pressure titrations, or underlying genetic or craniofacial syndromes. Area under the receiver operating characteristic curve (AUC [95%CIs]) were estimated for prediction of varying severities of obstructive apnea-hypopnea index (oAHI 2, 5, 10, and 25/h) by the PSQ's sleep-related breathing disorders (SRBD) scale and subscales.Of 477 children, median (IQR) age at PSG was 5.7 (4.3); 60% of children were male, 21% were obese, and 4% had oAHI 25/h. SRBD score did not improve discrimination of OSA cases at any oAHI threshold, with AUC CI that crossed 50% at all severities. Snoring subscale scores were predictive at oAHI 2/h (AUC = 64.5% [59.5-69.5%]), oAHI 5/h (AUC = 64.3% [59.6-69.0%]), and oAHI 10 (AUC = 67.2% [62.0-72.4%]) thresholds, but were not predictive at oAHI 25/h. The addition of demographic data (age and gender) improved the classification of the SRBD scale.When utilized in children referred for attended PSG due to concerns for an underlying sleep disorder, the PSQ snoring subscale was more predictive of OSA at varying thresholds than the SRBD scale. While the original intent of the PSQ was not for the purpose of predicting severity in children referred for PSG, future directions include augmenting the questionnaire with additional clinical variables.

Background Breast-conserving surgery is a critical step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to guide in real-time the removal of cancer missed during the initial lumpectomy to reduce the number of second operations. The pegulicianine imaging agent is injected intravenously before surgery and its fluorescence signal is activated by proteases in tumor cells and cells at the tumor margin. The LUM Imaging System visualizes activated pegulicianine in the lumpectomy cavity via a hand-held detector and proprietary tumor detection software. This system was previously tested in multiple single-site studies and a prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design and Specific Aims: The current prospective, multi-center, randomized, blinded study was designed to show the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to demonstrate guided removal of residual cancer in the lumpectomy missed during the initial procedure and potentially reduce the rates of positive margins. This study is powered by an event-driven design that requires 70 truth-standard positive events. It is expected that approximately 390 women at fourteen medical centers across the US will be enrolled to achieve the number of events. Pegulicianine is injected 2-6 hours prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy followed by blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that have positive LUM signal. Pathologists are blinded to the source of tissue removed (SOC vs. LUM) when conducting the pathology assessment. The amount of additional tissue volume resected is also evaluated. Patient reported outcome data is collected as a quality-of-life survey before and after the subject’s lumpectomy.Eligibility Criteria: This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Patients must not have a history of allergic reaction to polyethylene glycol, contrast agents, or have received neoadjuvant therapy to treat their current breast cancer. Use of blue dyes before imaging with the LUM System are not allowed. Additional detailed eligibility criteria are listed in the protocol. Accrual and Study Progress To date, 350 subjects have participated in this trial. This study is funded in part by the National Cancer Institute (5R44CA211013). This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, Marie Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal study of the Lum imaging system for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer: The INCITE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-12-03.

Background: While substantial evidence indicates that Ki67, a marker of proliferation, is strongly associated with breast cancer outcomes, its clinical utility has been limited given concerns about scoring inter-rater reliability and appropriate cut points. Nonetheless, Ki67 has been used in multiple clinical trials and results from POETIC indicated that low baseline Ki67 (ie, 10% would improve its clinical validity. Citation Format: Veronica C. Shim, Robin J Baker, Wen Jing, Sally S Agersborg, Thomas K Lee, Wamda Goreal, Ninah Achacoso, Catherine Lee, Marvella Villasenor, Amy Lin, Malathy Kapali, Laurel A Habel. Ki67 assessment based on international Ki67 working group recommendations and correlation with 21-gene assay results in a large integrated health care system: We might not be there yet [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-10.

Background/objectives: The ability to manage medications independently may be affected in older adults due to physical and cognitive limitations. Numerous electronic medication adherence products (eMAPs) are available to aid medication management. Unfortunately, there are no available guidelines to support clinicians in recommending eMAPs. The objective of this study was to create and validate a clinician tool to guide use of eMAPs. Methods: Pharmacists who previously tested the usability of the eMAPs participated in a focus group to provide feedback on 5 metrics of the clinician guide: unassisted task completion, efficiency, usability, workload and an overall eMAP score. Participants were asked semistructured questions on how they would use the tool to inform recommendations of medication aids to patients. The discussions were audio-recorded and transcribed verbatim and qualitatively analyzed. The clinician guide was modified to reflect feedback. Results: Five pharmacists (80% female, mean years of practice: 15.8) participated in the focus group. The clinician guide was modified by removing 2 metrics and adding an additional 8 metrics: maximum number of alarms, number of days the product can accommodate for based on a daily dosing regimen, price, monthly subscription, portability, locking feature, average time to set the device and number of steps required to set the device. The definition and calculation for unassisted task completion were modified. Additional instructions and specific patient case examples were also included in the final clinician guide. Conclusion: Since significant variability exists between eMAPs, it is imperative to have a tool for frontline clinicians to use when appropriately recommending the use of these products for medication management in older adults.

Objective:To determine the association between delay in transfer to a central stroke unit from peripheral institutions and outcomes.Methods:We conducted a retrospective cohort study of all patients with acute stroke, admitted to a comprehensive stroke center (CSC) from three emergency departments (EDs), between 2016 and 2018. The primary outcomes were length of stay, functional status at 3 months, discharge destination, and time to stroke investigations.Results:One thousand four hundred thirty-five patients were included, with a mean age of 72.9 years, and 92.4% ischemic stroke; 663 (46.2%) patients were female. Each additional day of delay was associated with 2.0 days of increase in length of stay (95% confidence interval [CI] 0.8–3.2, p = 0.001), 11.5 h of delay to vascular imaging (95% CI 9.6–13.4, p < 0.0001), 24.2 h of delay to Holter monitoring (95% CI 7.9–40.6, p = 0.004), and reduced odds of nondisabled functional status at 3 months (odds ratio 0.98, 95% CI 0.96–1.00, p = 0.01). Factors affecting delay included stroke onset within 6 h of ED arrival (605.9 min decrease in delay, 95% CI 407.9–803.9, p < 0.0001), delay to brain imaging (59.4 min increase in delay for each additional hour, 95% CI 48.0–71.4, p < 0.0001), admission from an alternative service (3918.7 min increase in delay, 95% CI 3621.2–4079.9, p < 0.0001), and transfer from a primary stroke center (PSC; 740.2 min increase in delay, 95% CI 456.2–1019.9, p < 0.0001).Conclusion:Delay to stroke unit admission in a system involving transfer from PSCs to a CSC was associated with longer hospital stay and poorer functional outcomes.

The mobile instant messaging application, WhatsApp Messenger (WhatsApp), has become a popular form of communication among adolescents, especially university students, and it has increasingly been used as a tool in collaborative learning in higher education. The use of WhatsApp for education to facilitate ubiquitous learning has been practised worldwide due to its popularity and potential to support teaching and learning processes derived from the diffusion of mobile technology and empowered by the use of smartphones. This study investigates the impact of the use of WhatsApp in a higher education learning environment on students’ perceived academic performance and team effectiveness. A convergent parallel mixed-methods research design was adopted with data collected through a self-administered online survey and two focus group interviews with students of a private university in the Sunway City, Malaysia. The findings of this study present insights into the popularity of WhatsApp among university students and that students use it for social and educational purposes due to its perceived ease of use and usefulness in enhancing academic performance and team effectiveness. Although WhatsApp is recognised as a rich and powerful collaborative tool for students with a positive impact on academic performance, it has a limited impact on the cohesion and openness of team effectiveness.

Background: Reducing 30-day readmission can potentially improve quality of stroke care. We investigated factors associated with 30-day readmission,1-year mortality and stroke recurrence post-ischemic stroke. Methods: Cohort included primary ischemic stroke discharges 1/1/2015 to 3/31/2021 from a large racial-ethnically diverse integrated healthcare delivery system. Assessment included demographics, comorbidity, NIHSS, IV thrombolytic, thrombectomy, hospital complications, and mRS score at discharge. Multivariate analysis was done to determine predictors for 30-day readmission, 1-year mortality and stroke recurrence. Results: Of 13,053 ischemic stroke patients,1,790 (13.7%) were readmitted within 30 days. The median time to readmission was 10 days (IQR 4-19). Readmission was most-commonly stroke-related (21.6%). Being older, having higher initial NIHSS or co-morbidity score or more hospital complications, not receiving IV thrombolysis, and being more disabled at discharged were seen more often among those who were readmitted (Table). In multivariate analysis, being older, having higher initial NIHSS and co-morbidity score were associated with higher odds of being readmitted by 30-day and having higher mortality and stroke recurrence at 1-year. Adjusted odds for stroke recurrence were elevated for black patients. Being readmitted by 30-day also predicted greater odds of 1-year stroke recurrence and 1-year mortality. On the other hand, receiving IV thrombolysis was associated with significantly less odds of being readmitted at 30-day (OR=0.74; 95% CI = 0.59 - 0.93) and less stroke recurrence (OR=0.75; 95% CI =0.64 - 0.87) and less mortality at 1-year (OR=0.57; 95% CI = 0.42 - 0.76). Conclusions: A number of factors predicted 30-day readmission as well as 1-year stroke recurrence and mortality. Receiving IV thrombolytic for acute stroke was strongly associated with lower odds of developing bad outcomes.

Background: Stroke is a major problem in Asia where more than half of the world population resides. Asian Americans are among the fastest growing racial-ethnic groups in the US, yet the incidence of stroke subtypes, stroke risk factors and outcomes have been largely unstudied in Asian Americans. We assessed acute stroke alert presentations in Asians compared to whites in a large integrated health care delivery system. Methods: In 2016, Kaiser Permanente Northern California launched a standardized telestroke program for 21 certified stroke centers to include immediate video evaluation by a teleneurologist. Non-cancelled stroke alerts included those patients who were potential candidates for further workup for acute ischemic stroke treatment. We evaluated all non-cancelled stroke alerts evaluated by Telestroke in 2019. Assessment included demographics, mode of arrival, initial NIHSS, neuroimaging results, IV thrombolytic, door-to-needle (DTN) time, large vessel occlusion (LVO), thrombectomy referral, and discharge disposition. Results: We identified 427 Asian and 1262 White patients with potential acute ischemic stroke. Compared with whites, Asians were younger, just as likely to arrive via EMS and arrived quicker from their last known well time, but presented with more severe NIHSS, were more likely to have bleeding on the initial head CT, and less likely to receive IV thrombolytic within 30 minutes from ED arrival (Table). Asians had less detected LVO, but those with LVO were transferred out for thrombectomy faster compared with whites. There were less stroke mimics in Asians presenting with stroke alerts, and no difference in inpatient mortality compared with whites. Conclusions: Several differences existed between Asian and white patients evaluated by Telestroke as non-cancelled stroke alerts. Further research is needed to understand these differences and assess outcomes for Asians as well as major Asian subgroups presenting with acute ischemic stroke.

The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.

Background Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression‐free survival (PFS) in patients with hormone receptor (HR)‐positive, HER2‐negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real‐world benefit of first‐line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. Methods This study included HR‐positive, HER2‐negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression‐free survival (PFS) was determined using Kaplan–Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil‐to‐lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time‐dependent variable. Results In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93–NR). Median PFS for patients with bone‐only metastases (n = 54) was not reached (95% CI 18.21–NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33–33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71–0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97–1.18, p = 0.203). Conclusion The effectiveness of palbociclib and endocrine therapy in the treatment of HR‐positive, HER2‐negative mBC in the real‐world setting is similar to the efficacy reported in the PALOMA‐2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression., The real‐world benefit of combination CDK4/6 inhibitor and endocrine therapy is similar to that reported in clinical trials. Treatment‐related neutropenia, assessed by absolute neutrophil count (ANC), may be correlated with lower risk of disease progression and a lower ANC threshold for dose reduction may be warranted.

QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7–8.7, P = 2.1e−10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.

Antibodies, particularly of the immunoglobulin G (IgG) isotype, are a group of biomolecules that are extensively used as affinity reagents for many applications in research, disease diagnostics, and therapy. Most of these applications require antibodies to be modified with specific functional moieties, including fluorophores, drugs, and proteins. Thus, a variety of methodologies have been developed for the covalent labeling of antibodies. The most common methods stably attach functional molecules to lysine or cysteine residues, which unavoidably results in heterogeneous products that cannot be further purified. In an effort to prepare homogeneous antibody conjugates, bioorthogonal handles have been site-specifically introduced via enzymatic treatment, genetic code expansion, or genetically encoded tagging, followed by functionalization using bioorthogonal conjugation reactions. The resulting homogeneous products have proven superior to their heterogeneous counterparts for both in vitro and in vivo usage. Nevertheless, additional chemical treatment or protein engineering of antibodies is required for incorporation of the bioorthogonal handles, processes that often affect antibody folding, stability, and/or production yield and cost. Accordingly, concurrent with advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in site-specifically labeling native (nonengineered) antibodies without chemical or enzymatic treatments. In this review, we highlight recent strategies for producing site-specific native antibody conjugates and provide a comprehensive summary of the merits and disadvantages of these strategies.

Background Racial disparities exist in outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective To evaluate the contribution of race/ethnicity in SARS-CoV-2 testing, infection, and outcomes. Design Retrospective cohort study (1 February 2020 to 31 May 2020). Setting Integrated health care delivery system in Northern California. Participants Adult health plan members. Measurements Age, sex, neighborhood deprivation index, comorbid conditions, acute physiology indices, and race/ethnicity; SARS-CoV-2 testing and incidence of positive test results; and hospitalization, illness severity, and mortality. Results Among 3 481 716 eligible members, 42.0% were White, 6.4% African American, 19.9% Hispanic, and 18.6% Asian; 13.0% were of other or unknown race. Of eligible members, 91 212 (2.6%) were tested for SARS-CoV-2 infection and 3686 had positive results (overall incidence, 105.9 per 100 000 persons; by racial group, White, 55.1; African American, 123.1; Hispanic, 219.6; Asian, 111.7; other/unknown, 79.3). African American persons had the highest unadjusted testing and mortality rates, White persons had the lowest testing rates, and those with other or unknown race had the lowest mortality rates. Compared with White persons, adjusted testing rates among non-White persons were marginally higher, but infection rates were significantly higher; adjusted odds ratios [aORs] for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 2.01 (95% CI, 1.75 to 2.31), 3.93 (CI, 3.59 to 4.30), 2.19 (CI, 1.98 to 2.42), and 1.57 (CI, 1.38 to 1.78), respectively. Geographic analyses showed that infections clustered in areas with higher proportions of non-White persons. Compared with White persons, adjusted hospitalization rates for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 1.47 (CI, 1.03 to 2.09), 1.42 (CI, 1.11 to 1.82), 1.47 (CI, 1.13 to 1.92), and 1.03 (CI, 0.72 to 1.46), respectively. Adjusted analyses showed no racial differences in inpatient mortality or total mortality during the study period. For testing, comorbid conditions made the greatest relative contribution to model explanatory power (77.9%); race only accounted for 8.1%. Likelihood of infection was largely due to race (80.3%). For other outcomes, age was most important; race only contributed 4.5% for hospitalization, 12.8% for admission illness severity, 2.3% for in-hospital death, and 0.4% for any death. Limitation The study involved an insured population in a highly integrated health system. Conclusion Race was the most important predictor of SARS-CoV-2 infection. After infection, race was associated with increased hospitalization risk but not mortality. Primary funding source The Permanente Medical Group, Inc.

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes as treatment of refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL). Several risk factors including CAR-T-related toxicities and their treatments often lead to infectious complications (IC). The pattern and timeline for IC is not well established. We evaluated IC in 48 patients with R/R B-cell NHL following CAR-T. Overall, 15 patients (31%) experienced 22 infection events. Eight infections (4 bacterial, 3 viral and 1 fungal) and 14 infections (7 bacterial, 6 viral, 1 fungal) occurred early ( 4 prior antitumor regimens and elderly age (≥ 65 years) had a higher infection rate. Humoral response to two-doses of SARS CoV-2 mRNA vaccines was evaluated in 10 patients and anti-Spike IgG was detectable in 40%. Infections in patients receiving CAR-T cell therapy are common despite the use of infection prophylaxis. In our series, age ≥ 65 years and > 4 prior antitumor treatments were identified as risk factors. Forty per cent of patients developed SARS CoV-2 antibody response.

Genetic code expansion technology allows for the use of noncanonical amino acids (ncAAs) to create semisynthetic organisms for both biochemical and biomedical applications. However, exogenous feeding of chemically synthesized ncAAs at high concentrations is required to compensate for the inefficient cellular uptake and incorporation of these components into proteins, especially in the case of eukaryotic cells and multicellular organisms. To generate organisms capable of autonomously biosynthesizing an ncAA and incorporating it into proteins, we have engineered a metabolic pathway for the synthesis of O-methyltyrosine (OMeY). Specifically, we endowed organisms with a marformycins biosynthetic pathway-derived methyltransferase that efficiently converts tyrosine to OMeY in the presence of the co-factor S-adenosylmethionine. The resulting cells can produce and site-specifically incorporate OMeY into proteins at much higher levels than cells exogenously fed OMeY. To understand the structural basis for the substrate selectivity of the transferase, we solved the X-ray crystal structures of the ligand-free and tyrosine-bound enzymes. Most importantly, we have extended this OMeY biosynthetic system to both mammalian cells and the zebrafish model to enhance the utility of genetic code expansion. The creation of autonomous eukaryotes using a 21st amino acid will make genetic code expansion technology more applicable to multicellular organisms, providing valuable vertebrate models for biological and biomedical research.

Susceptibility and severity of COVID-19 infection vary widely. Prior exposure to endemic coronaviruses, common in young children, may protect against SARS-CoV-2. We evaluated risk of severe COVID-19 among adults with and without exposure to young children in a large, integrated healthcare system. Adults with children 0–5 years were matched 1:1 to adults with children 6–11 years, 12–18 years, and those without children based upon a COVID-19 propensity score and risk factors for severe COVID-19. COVID-19 infections, hospitalizations, and need for intensive care unit (ICU) were assessed in 3,126,427 adults, of whom 24% (N = 743,814) had children 18 years or younger, and 8.8% (N = 274,316) had a youngest child 0–5 years. After 1:1 matching, propensity for COVID-19 infection and risk factors for severe COVID-19 were well balanced between groups. Rates of COVID-19 infection were slightly higher for adults with exposure to older children (incident risk ratio, 1.09, 95% confidence interval, [1.05–1.12] and IRR 1.09 [1.05–1.13] for adults with children 6–11 and 12–18, respectively), compared to those with children 0–5 years, although no difference in rates of COVID-19 illness requiring hospitalization or ICU admission was observed. However, adults without exposure to children had lower rates of COVID-19 infection (IRR 0.85, [0.83–0.87]) but significantly higher rates of COVID-19 hospitalization (IRR 1.49, [1.29–1.73]) and hospitalization requiring ICU admission (IRR 1.76, [1.19–2.58]) compared to those with children aged 0–5. In a large, real-world population, exposure to young children was associated with less severe COVID-19 illness. Endemic coronavirus cross-immunity may play a role in protection against severe COVID-19.

BackgroundStudies on the Omicron variant infection have generally been restricted to descriptions of its initial clinical and epidemiological characteristics. We investigated the timeline-related advancement in individuals with Omicron variant.MethodsWe conducted a retrospective, single-centered study including 226 laboratory-confirmed cases with Omicron variant between April 6th and May 11th, 2022 in Shanghai, China. Final date of follow-up was May 30, 2022.ResultsAmong 226 enrolled patients, the median age was 52 years old, and 118 (52.2%) were female. The duration from onset of symptoms to hospitalization was 3 days (interquartile range [IQR]: 2-4 days) for symptomatic patients. Cough occurred in 168 patients (74.3%). The median interval to negative reverse-transcriptase PCR tests of nasopharynx swab was 10 days ([IQR]: 8-13 days). No radiographic progressions were found in 196 patients on the 7th day after onset of symptoms. The median duration of fever in all participants was 5 days (IQR: 4–6 days). The median PCR conversion time of Paxlovid-treated patients was 8 days (IQR: 7-10 days) compared with that of Lianhuaqingwen (10 days, IQR: 8-13 days) (p=0.00056). Booster vaccination can significantly decrease the severity of Omicron infection when compared with unvaccinated, partially or fully vaccinated patients (p=0.009). The median time of PCR conversion in individuals aged under 14 recovered significantly faster than older patients (median 8 days versus 11 days, P < 0.0001). In multivariate logistic analysis, erythrocyte sedimentation rate (ESR) (OR=1.05) was independently related to the severity of the infection.ConclusionsThe majority clinical symptoms of Omicron infection were not severe. Early and aggressive administration of Paxlovid can significantly reduce the PCR conversion time. Booster vaccination should also be highly recommended in population over 14 years old.

Introduction: Diabetes (DM) is a risk factor for fracture but women with DM have less osteoporosis by bone density (BMD) , due in part to higher body mass index (BMI) . The FRAX fracture risk calculator incorporates age, race/ethnicity, BMD, BMI, and other risk factors but not DM. Few studies have examined FRAX by DM and obesity status in different race groups. We compared predicted fracture risk in US Asian and White women by DM and obesity status. Methods: We studied 3,640 Asian (26% DM, 24% osteoporosis, 15% obese) and 11,7White (11% DM, 12% osteoporosis, 40% obese) women aged 65-75y with BMD, excluding those with recent fracture, osteoporosis therapy, dialysis/transplant, metabolic bone disease or advanced cancer. DM (≥2 visit diagnoses + DM treatment) , obesity (BMI ≥30 kg/m2) and osteoporosis (BMD T score ≤-2.5) were obtained from electronic health data. Using the US FRAX with BMD, 10-year predicted hip fracture risk ≥3% was considered high (above treatment threshold) . Results: The overall proportions with FRAX-Hip ≥3% were higher for those with No DM vs. DM (White 18% vs. 11%; Asian 9% vs. 7%) . However, within both DM and no DM groups, FRAX-Hip ≥3% was much higher in non-obese vs. obese women of both races (FIGURE) . Conclusion: Predicted hip fracture risk varies by DM and especially by obesity status in White and Asian women. Future studies should examine the accuracy of FRAX for actual hip fracture risk in these subgroups. Disclosure J.C.Lo: None. M.Chandra: None. N.P.Gordon: None. C.Lee: None. Funding National Institute on Aging, National Institutes of Health (AG069992)

There are an estimated 50,000 LGBT teachers in English schools. In common with all workplaces, under the Equality Act 2010, schools have a responsibility to protect Lesbian, Gay, Bisexual and Transgender (LGBT) teachers from harassment in the workplace. From September 2020, for the first time, schools in England have been required to teach Relationships, Sex and Health Education (RSHE) that is inclusive of LGBT relationships. Representatives of faith communities and parents of school children in Birmingham and other major cities have protested outside school gates in opposition to the introduction of LGBT inclusive RSHE. This article explores what is at the heart of the moral panic about the inclusion of LGBT identities in the curriculum. As schools introduce inclusive RSHE, we must consider the impact of protests on LGBT teacher health, well-being and identity. More than half of LGBT teachers have suffered from anxiety or depression linked to their sexual identity and role as a teacher and so supportive and unequivocal support and intervention is needed to ensure schools are safe places, free from hostility, for LGBT teachers, pupils and their families.

Operative complications affect recurrence in non-breast malignancies. Rising rates of mastectomy with immediate reconstruction and their increased post-operative complications fuel concerns for poorer outcome in breast cancer (BC). We sought to determine the effect of complications on recurrence in BC patients. A single-institution retrospective review was conducted of incident BC treated with mastectomy and immediate reconstruction. Overall survival and recurrence were compared between patients with complications to those without. Of 201 patients (350 mastectomies, 86 nipple-sparing), 62 (30.8%) had a surgical complication. Patients with complications were older, but groups were similar for type of reconstruction, tobacco use, hormone receptor status, HER2, lymphovascular invasion, and pathologic stage (all p > 0.05). Twenty-two complications (10.9%) were infection, 5 (2.5%) dehiscence, 14 flap necrosis (7%), 21 hematomas (10.4%), and 8 nipple necroses (9%). Recurrence occurred in 18 (8.9%) patients: 4 local, 2 regional, and 12 distant. After 8.9 years of median follow-up, patients with complications trended towards higher recurrence (hazard ratio (HR) 2.23, log-rank p = 0.08, Cox regression p = 0.05), particularly with nipple necrosis (HR 3.28, log-rank p = 0.09, regression p = 0.06). Patients with other complications had similar recurrence-free survival to those without (all p > 0.05). Higher stage (HR 13.66, log-rank p = 0.03) and adjuvant radiation (HR 2.78, log-rank p = 0.04) cases were more likely to recur. Patients with complications had similar overall survival to those without (log-rank p > 0.05). BC patients with surgical complications do not have lower overall survival. This finding may be due to the improved prognosis compared to non-breast malignancies.

Background Physical activity (PA) has the potential to attenuate cardiovascular disease risk in midlife women through multiple pathways, including improving lipid profiles. Longitudinal patterns of PA and blood lipid levels have not been studied in midlife women. Our study identified trajectories of PA and blood lipids across midlife and characterized the associations between these trajectories. Methods We evaluated 2,789 participants from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study with follow-up over the menopause transition. Women reported PA using the Kaiser Physical Activity Survey at seven study visits across 17 years of follow-up. Serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at eight study visits across the same 17-year follow-up period. We used group-based trajectory models to characterize trajectories of PA and blood lipids over midlife and dual trajectory models to determine the association between PA and blood lipid trajectories adjusted for race/ethnicity, body mass index category, smoking, and lipid-lowering medication use. Results Women were 46 years old, on average, at study entry. Forty-nine percent were non-Hispanic white; 32 % were Black; 10 % were Japanese; and 9 % were Chinese. We identified four PA trajectories, three HDL cholesterol trajectories, four LDL cholesterol trajectories, and two triglyceride trajectories. The most frequently occurring trajectories were the consistently low PA trajectory (69 % of women), the low HDL cholesterol trajectory (43 % of women), the consistently moderate LDL cholesterol trajectory (45 % of women), and the consistently low triglycerides trajectory (90 % of women). In dual trajectory analyses, no clear associations were observed between PA trajectories and HDL cholesterol, LDL cholesterol, or triglycerides trajectories. Conclusions The most frequently observed trajectories across midlife were characterized by low physical activity, low HDL cholesterol, moderate LDL cholesterol, and low triglycerides. Despite the absence of an association between long-term trajectories of PA and blood lipids in this study, a large body of evidence has established the importance of clinical and public health messaging and interventions targeted at midlife women to promote regular and sustained PA during midlife to achieve other cardiovascular and metabolic benefits.

Background: MAPK activating mutations are common in melanoma, with 40% of cases attributed to oncogenic BRAF mutations and 20-25% NRAS mutations. Secondary MAPK activation is a known resistance mechanism to approved BRAF inhibitors in BRAFV600 melanoma. While BRAF inhibitors are approved for Class I BRAFV600 melanomas, patients with dimer-driven BRAF Class II/III and RAF1-dependent NRAS activated melanomas lack approved targeted therapy. Development of next-gen pan-RAF inhibitors targeting all RAF proteins and mutant dimers remains a priority. Emerging clinical data from pan-RAF inhibitors combined with MEK inhibitors suggests increased benefit for MAPK-altered melanoma patients. Exarafenib (KIN-2787) is a clinical stage, novel, highly selective pan-RAF inhibitor designed to be effective in RAF-dependent cancers.Methods: KIN-2787 was evaluated using enzyme assays across the human kinome and activity against oncogenic RAF alterations were validated in BaF3 cells. MAPK pathway suppression and cell growth inhibition were assessed across a panel of human tumor cell lines. Combination dose matrices were performed with KIN-2787 and binimetinib (bini) to evaluate synergistic cell growth inhibition. Extended cell growth studies were performed by Incucyte. In vivo KIN-2787 efficacy was evaluated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of human BRAF and NRAS mutant cancer.Results: Exarafenib demonstrated exceptional kinome selectivity with minimal off-target kinases significantly inhibited relative to BRAF. Exarafenib potently inhibited a broad panel of oncogenic BRAF mutations in biochemical and BaF3 cell assays. Functional MAPK signaling and viability studies in human tumor cell lines highlighted exarafenib activity in BRAF and NRAS mutant melanoma with minimal activity in normal (BRAF WT) cells. Synergy with the MEK inhibitor bini was determined and the exarafenib + bini combination durably inhibited growth in NRAS mutant melanoma cell lines. In line with cellular studies, treatment with exarafenib demonstrated significant tumor growth inhibition at 30 mg/kg BID in CDX and PDX models of human NRAS mutant melanoma. 10 mg/kg BID exarafenib combined with a clinically relevant dose of bini resulted in combination benefit and durable suppression of the MAPK pathway, relative to either agent alone.Conclusions: The superior kinome selectivity of exarafenib and its activity across multiple RAF-dependent melanoma models position it as a potentially class-leading pan-RAF inhibitor. In addition to efficacy in BRAF mutant tumors, these data support use of exarafenib in combination therapy with MEK inhibitors in NRAS mutant melanoma. A Ph I dose escalation clinical trial evaluating the safety and efficacy of exarafenib in monotherapy and in combination with binimetinib is ongoing (NCT04913285). Citation Format: Tim S. Wang, Catherine Lee, Paul Severson, Robert J. Pelham, Richard Williams, Nichol L. G. Miller. Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4927.

ObjectivesTo examine the cost-effectiveness of Multi-specialty INterprofessional Team (MINT) Memory Clinic care in comparison to the provision of usual care.DesignUsing a Markov-based state transition model, we performed a cost-utility (costs and quality-adjusted life years, QALY) analysis of MINT Memory Clinic care and usual care not involving MINT Memory Clinics.SettingA primary care-based Memory Clinic in Ontario, Canada.ParticipantsThe analysis included data from a sample of 229 patients assessed in the MINT Memory Clinic between January 2019 and January 2021.Primary outcome measuresEffectiveness as measured in QALY, costs (in Canadian dollars) and the incremental cost-effectiveness ratio calculated as the incremental cost per QALY gained between MINT Memory Clinics versus usual care.ResultsMINT Memory Clinics were found to be less expensive ($C51 496 (95% Crl $C4806 to $C119 367) while slightly improving quality of life (+0.43 (95 Crl 0.01 to 1.24) QALY) compared with usual care. The probabilistic analysis showed that MINT Memory Clinics were the superior treatment compared with usual care 98% of the time. Variation in age was found to have the greatest impact on cost-effectiveness as patients may benefit from the MINT Memory Clinics more if they receive care beginning at a younger age.ConclusionMultispecialty interprofessional memory clinic care is less costly and more effective compared with usual care and early access to care significantly reduces care costs over time. The results of this economic evaluation can inform decision-making and improvements to health system design, resource allocation and care experience for persons living with dementia. Specifically, widespread scaling of MINT Memory Clinics into existing primary care systems may assist with improving quality and access to memory care services while decreasing the growing economic and social burden of dementia.

This article draws on literature related to university leadership and lesbian, gay, bisexual, transgender, queer plus (LGBTQ+) identities to argue for LGBTQ+ specific leadership programmes in highe...

Introduction Persons with intellectual disabilities (ID) often have complex health needs due to the development of multiple comorbidities. Given the higher associated use of problematic medications, such as antipsychotics, and polypharmacy, persons with ID may be particularly vulnerable to adverse side effects. With their medication expertise, pharmacists have the potential to address medication related challenges experienced by this population. Objective Explore what is known about the care pharmacists provide to persons with ID. Design Following Arksey and O'Malley's 5-stage framework for scoping reviews, searches of the PubMed (MEDLINE), Ovid EMBASE, Ovid International Pharmaceutical Abstracts, Scopus and APA PsycINFO databases were conducted in January 2019 with no limits on publication date. Studies of participants diagnosed with ID or healthcare providers/caregivers of persons with ID that referenced a pharmacist care intervention were included. Studies with non-human populations and editorials, commentaries, letters to the editor or discussion papers were excluded. Results Twenty-six studies were included in the review. Seventy-six pharmacist care interventions were identified in cognitive pharmacy services (n = 46); educational and advisory services (n = 20); and medication prescription processing (n = 10). Fifty-one outcomes were referenced including drug-related interventions (n = 14), drug related problems (n = 9), cost/time-effectiveness (n = 7), secondary symptoms (n = 6), other outcomes (n = 5), general medication usage (n = 4), caregiver and healthcare team satisfaction levels (n = 3), and educational/knowledge (n = 3). Conclusion Pharmacists perform a variety of health care services to persons with ID but the impact of these interventions cannot be accurately measured due to a lack of: 1) universal definitions for ID; 2) reporting of multifactorial conditions contributing to a spectrum of ID severity; and 3) standardized reporting of ID-specific outcomes. Addressing these gaps is necessary for the development of a comprehensive evidence base regarding pharmacist involvement for medication challenges in persons with ID.

Background The standard of care for clinically node-negative (cN0) patients following positive sentinel lymph node biopsy (SLNB) was completion axillary lymph node dissection (CALND). Publication of ACOSOG Z0011 in 2010 changed this standard for patients undergoing lumpectomy. Clinicians have since expanded this practice to mastectomy patients, and ongoing prospective studies are seeking to validate this practice. Here, we evaluate patient and tumor characteristics that led surgeons to forego a second surgery for CALND in cN0 mastectomy patients with positive SLNB. Patients and Methods A single institution, retrospective review of cN0 patients with invasive primary breast cancer and positive SLNB from 2010 to 2016 was performed. Patients with T4 disease, positive preoperative axillary biopsy, prior neoadjuvant therapy or axillary surgery were excluded. Patients with positive SLNB undergoing CALND were compared with patients for whom CALND was omitted. Statistical analysis was performed using Kruskal-Wallis tests for continuous variables and χ2 tests or Fischer exact tests for categorical variables. Results Of 259 patients with positive SLNB, 180 (69.4%) patients underwent mastectomy. CALND was performed at the time of mastectomy in 54 (30%) patients, at time of second operation in 22 (12.2%) patients, and not performed in 104 (57%) patients. Delayed CALND was significantly associated with younger age, larger tumors, increased number of positive sentinel nodes, invasive lobular carcinoma, extranodal extension, and lymphovascular invasion. Conclusions The management of cN0 patients with positive SLNB that do not meet ACOSOG Z0011 criteria is evolving and is influenced by tumor and patient characteristics in an attempt to balance the morbidity of CALND with the low rate of local regional recurrence.

Background:Results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial supports omission of completion axillary lymph node dissection (CLND) after breast-conservation surgery with a positive sentinel lymph node biopsy (SLNB). We hypothesized that CLND also does not impact outcomes in women with clinically node-negative (cN0), pathologically node-positive breast cancer undergoing mastectomy.Materials and Methods:A single-institution retrospective review was performed of patients with SLN-positive breast cancer treated from July 1999 through May 2018. Clinicopathologic and outcome data were collected. Patients with SLNBs were compared with those receiving SLNB and CLND. The Kruskal-Wallis, chi-square, and Fisher exact tests were used to assess for differences between continuous and categorical variables. The log-rank test was used for time-to-event analyses, and Cox proportional hazards models were fit for locoregional and distant recurrence and overall survival (OS).Results:Of 329 patients with SLN-positive breast cancer undergoing mastectomy, 60% had CLND (n=201). Median age at diagnosis was 53 years (interquartile range [IQR], 46–62 years). The median number of SLNs sampled was 3 (IQR, 2–4), and the median number of positive SLNs was 1 (IQR, 1–2). Patients receiving CLND had higher tumor grades (P=.02) and a higher proportion of hormone receptor negativity (estrogen receptor, 19%; progesterone receptor, 27%; bothP=.007). A total of 44 patients (22%) had increased N stage after CLND. Median follow-up was 51 months (IQR, 29–83 months). No association was found between CLND and change in OS and locoregional or distant recurrence. Completion of postmastectomy radiotherapy was associated with improved OS (P=.04).Conclusions:CLND is not significantly correlated with reduced recurrence or improved OS among patients who have cN0, SLN-positive breast cancer treated with mastectomy. CLND was significantly correlated with receipt of adjuvant systemic therapy. Completion of postmastectomy radiotherapy was associated with improved OS.

Background Semi-competing risks arise when interest lies in the time-to-event for some non-terminal event, the observation of which is subject to some terminal event. One approach to assessing the impact of covariates on semi-competing risks data is through the illness-death model with shared frailty, where hazard regression models are used to model the effect of covariates on the endpoints. The shared frailty term, which can be viewed as an individual-specific random effect, acknowledges dependence between the events that is not accounted for by covariates. Although methods exist for fitting such a model to right-censored semi-competing risks data, there is currently a gap in the literature for fitting such models when a flexible baseline hazard specification is desired and the data are left-truncated, for example when time is on the age scale. We provide a modeling framework and openly available code for implementation. Methods We specified the model and the likelihood function that accounts for left-truncated data, and provided an approach to estimation and inference via maximum likelihood. Our model was fully parametric, specifying baseline hazards via Weibull or B-splines. Using simulated data we examined the operating characteristics of the implementation in terms of bias and coverage. We applied our methods to a dataset of 33,117 Kaiser Permanente Northern California members aged 65 or older examining the relationship between educational level (categorized as: high school or less; trade school, some college or college graduate; post-graduate) and incident dementia and death. Results A simulation study showed that our implementation provided regression parameter estimates with negligible bias and good coverage. In our data application, we found higher levels of education are associated with a lower risk of incident dementia, after adjusting for sex and race/ethnicity. Conclusions As illustrated by our analysis of Kaiser data, our proposed modeling framework allows the analyst to assess the impact of covariates on semi-competing risks data, such as incident dementia and death, while accounting for dependence between the outcomes when data are left-truncated, as is common in studies of aging and dementia.

Background Neonatal jaundice, also known as hyperbilirubinemia in term and preterm infants, is treated with phototherapy when bilirubin results exceed gestational age- and age-specific medical decision levels (MDL) to prevent kernicterus and bilirubin-induced neurological damage. During phototherapy, unconjugated bilirubin is converted to water-soluble isomers that are excreted in the urine. Presently, the electronic medical record (EMR) at our hospital cannot use gestational age to stratify reference ranges thereby the associated flags and alerts would not be triggered, leading to delays in reviewing bilirubin results and placing phototherapy orders. The aim of this project is to replace the current manual assessment process for phototherapy with a newly designed alert to notify clinicians of elevated bilirubin results for preterm infants ( Method A SmartZone alert, built with Cerner command language and Discern Expert rules, evaluates total or neonatal bilirubin results for patients in the Newborn and Infant Critical Care Unit (NICCU), calculates the patient’s age using the recorded gestational age and birth time, and utilizes the following rules: 1) bilirubin result must exceed the pre-defined gestational age-specific MDLs, and 2) calculated gestational age is Result The SmartZone alert was implemented on 01/11/2022. Between 1/1/2021 - 1/11/2022, 95 preterm infants in the NICCU had neonatal and total bilirubin results, in which 19 met the criteria for the alert to be triggered, and 17 had phototherapy orders. Further analysis revealed that 12 orders were placed 72 hours after bilirubin results were verified. Between 1/12/2022 – 2/13/2022, 13 newly admitted preterm infants in the NICCU had neonatal and total bilirubin results, in which one triggered the alert, and phototherapy was ordered within 15 hours. Conclusion A SmartZone alert was implemented to encourage consistent and timely consideration of phototherapy for preterm infants

Greater difficulty in controlling blood pressure (BP) and adverse lifestyle practices such as higher salt intake or less physical activity may account for some of the differences between BP control rates in Black vs White adults, thereby exposing Black adults to a higher risk of vascular events.To determine whether a lifestyle coaching intervention or an enhanced pharmacotherapy protocol is more effective than usual care in improving BP control rates in Black adults treated within an integrated health care delivery system.Shake, RattleRoll, a cluster randomized clinical trial, was conducted from June 5, 2013, to June 11, 2018, in a large integrated health care delivery system. Enrollment was completed during a 12-month period and interventions were implemented for 12 months. Follow-up lasted 48 months after enrollment. Panels of Black adult members of the health care delivery system with BP of at least 140/90 mm Hg from 98 adult primary care physicians were randomly assigned at the primary care physician level to usual care (UC group [n = 1129]), enhanced pharmacotherapy monitoring (EP group [n = 346]) of current BP management protocol, or diet and lifestyle coaching consisting of photographs, stories, and recipes, for example, that are appropriate for Black adults (LC group [n = 286]) focused on the Dietary Approaches to Stop Hypertension (DASH) diet. Data were analyzed from June 1, 2016, to March 25, 2022.The UC group received care per customary protocol. The EP group was contacted by a research nurse and/or a clinical pharmacist to discuss barriers to hypertension control, and drug therapy emphasized the use of thiazide diuretic intensification and addition of spironolactone as needed. The LC group received as many as 16 telephone sessions with a lifestyle coach and an emphasis on implementing reduction of sodium intake and the DASH diet.Intention-to-treat analysis of BP control rates at end of the 12-month intervention.Among the 1761 participants, the mean (SD) age was 61 (13) years, and 1214 (68.9%) were women. At the end of the 12-month intervention period, there was no significant difference in BP control rate among study groups (UC, 61.8% [95% CI, 58.8%-64.9%]; EP, 64.5% [95% CI, 59.0%-69.4%]; LC, 67.8% [95% CI, 62.1%-73.2%]; LC vs EP, P = .07). However, greater BP control was present in the LC group vs UC at 24 months (UC, 61.2% [95% CI, 57.3%-64.7%]; EP, 67.6% [95% CI, 61.9%-72.8%]; LC, 72.4% [95% CI, 66.9%-78.1%]; LC vs UC, P = .001), and 48 months (UC, 64.5% [95% CI, 61.6%-67.2%]; EP, 66.5% [95% CI, 61.3%-71.3%]; LC, 73.1% [95% CI, 67.6%-77.9%]; LC vs UC, P = .006) after enrollment. The contribution of BP medication adherence to explain group differences was inconclusive.In this cluster randomized clinical trial including Black adults with persistent uncontrolled hypertension, a 12-month LC intervention was more effective at controlling BP than UC at 24 and 48 months after enrollment. Further research is needed to explore the potential implementation of this intervention into clinical practice.ClinicalTrials.gov Identifier: NCT01892592.

This study evaluated feasibility and patient outcomes for targeted axillary lymph node (LN) dissection (TAD) with SAVI SCOUT® ultrasound-guided radar reflector localization (RRL).In this IRB-approved retrospective study, 800 consecutive patients who underwent ultrasound-guided RRL between November 2017 and June 2020 were reviewed. Of these patients, those with axillary LN RRL were included in this study. Reports in the electronic medical record were reviewed to determine RRL placement, retrieval, and surgical outcomes.A total of 147 patients met inclusion criteria. Of these, axillary RRL was performed for biopsy-proven metastatic disease in 134 and inconclusive or benign biopsy in 13. RRL was successful in 146/151 lymph nodes (97%). Two patients had placement10 mm from target and 3 had no post-placement signal. In all 5, the targets were successfully retrieved at surgery. Specimen radiographs were performed in 135 cases and confirmed the intended target in all 135 (100%). In 109 patients who underwent TAD + sentinel lymph node biopsy (SLNB), the RRL LN and the SLN(s) were different in 18 (17%). In 3 of these, the RRL LN was the only malignant LN (3%). In the 105 patients who underwent neoadjuvant chemotherapy, 43% (45/105) achieved nodal pCR and 85% (89/105) had3 metastatic lymph nodes at surgery.Ultrasound-guided RRL of axillary LNs is a feasible approach to facilitate TAD with high placement and retrieval success rates. This enables TAD as an alternative to complete axillary LN dissection (cALND), sparing some patients with low nodal tumor burden from cALND.

Purpose. It is unknown whether cancer treatment or modifiable risk factors contribute more to the burden of long-term disease risks among B-cell non-Hodgkin’s lymphoma (B-NHL) survivors. Methods. B-NHL survivors were identified in the Utah Cancer Registry from 1997 to 2015. Population attributable fractions (PAF) were calculated to assess the role of clinical and lifestyle factors for 6 cardiovascular, pulmonary, and renal diseases. Results. Cancer treatment contributed to 11% of heart and pulmonary conditions and 14.1% of chronic kidney disease. Charlson Comorbidity Index (CCI) at baseline contributed to all six diseases with a range of 9.9% of heart disease to 26.5% of chronic kidney disease. High BMI at baseline contributed to 18.4% of congestive heart failure and 7.9% of pneumonia, while smoking contributed to 4.8% of COPD risk. Conclusion. Cancer treatment contributed more to heart disease, COPD, and chronic kidney disease among B-NHL survivors. High BMI at baseline contributed more to congestive heart failure and pneumonia than cancer treatment, whereas smoking at baseline was not a major contributor in this B-NHL survivor cohort. Baseline comorbidities consistently demonstrated high attributable risks for these diseases, demonstrating a strong association between preexisting comorbidities and aging-related disease risks.

For women with genetic risk of breast cancer, the addition of screening breast MRI to mammography has become a standard. The order and interval of annual imaging can be variable among providers. To evaluate the clinical implications related to the timing, we conducted a chart review on a cohort of women (N = 276) with high-risk (BRCA1, BRCA2, CDH1, PTEN and TP53) and moderate high-risk (ATM and CHEK2) predisposition to breast cancer in a 48-month follow up. The estimated MRI detection rate in the entire group is 1.75% (18 per 1000 MRI tests). For the high-risk group, the estimated rate is 2.98% (30 per 1000 MRI tests). Many women discovered their genetic risk at an age much older (average age of the high-risk group was 48 years) than the age recommended to initiate enhanced screening (age 20 to 25 years). In total, 4 of the 11 primary breast cancers detected were identified by screening MRI within the first month after initial visit, which were not detected by previous mammography, suggesting the benefit of initiating MRI immediately after the discovery of genetic risk. Breast screening findings for women with Lynch syndrome and neurofibromatosis type 1 were also included in this report.

The present literature is conflicting regarding the management of microinvasive ductal carcinoma in situ (miDCIS) as to following recommendations for DCIS (margin status, surgical axillary staging, and possible observation) versus invasive breast cancer. We hypothesize that miDCIS represents more aggressive disease than pure DCIS.We performed a retrospective review of female miDCIS patients compared with age-matched cohorts of DCIS and T1b/c patients with invasive breast cancer. We collected demographic, clinicopathologic, treatment, and outcome information. Analysis of variance or Kruskal-Wallis tests were used to analyze continuous variables and chi-square or Fisher's exact tests for categorical variables. Survival outcomes were analyzed using Kaplan-Meier curves.We included 375 patients (125 in each group) with median age 59 y (range 33-91 y). miDCIS tumors were more likely to be hormone receptor negative and human epidermal growth factor receptor 2 positive compared with DCIS or invasive ductal carcinoma (IDC; all P 0.001). Subgroup analysis by miDCIS focality demonstrated no significant differences. The number of involved lymph nodes was not significantly different from DCIS patients but was significantly fewer than invasive cancer patients. Of 115 miDCIS patients (88%) staged with sentinel lymph node biopsy, eight (7%) had nodal metastases. Six miDCIS patients (5%) were treated with adjuvant chemotherapy. Over a median follow-up of 23.3 mo, there were no significant differences in local or distant recurrence.Based on our results, miDCIS has more aggressive pathologic features compared with DCIS and warrants surgical treatment and nodal staging similar to the management of IDC. In addition, similar to IDC, nodal and receptor status may influence medical management.

BACKGROUND AND OBJECTIVES The benefit of tissue plasminogen activator (tPA) in acute ischemic stroke is time dependent. A 15-minute decrease in door-to-needle (DTN) time has been associated with increased odds of ambulating independently, faster discharge, and decreased odds of death. We investigated common causes of delay in DTN times in a community hospital setting in order to identify areas for improvement. METHODS A retrospective medical record review was conducted at a 574-bed community hospital. This included 100 patients who received tPA from 2016 to 2019. Time segments were classified a priori to reflect key work elements from the time between hospital arrival to tPA and recorded for each chart. Linear regression models were used to identify work elements associated with increased DTN time. RESULTS Median DTN time was 54:29 minutes. Linear regression analyses determined that differences in NIHSS score (P = .030), triage to computed tomography (CT) start (P = .017), triage to stroke physician page (P = .016), and CT report to tPA administration (P < .001) were associated with increased DTN time. CT report to tPA administration was most strongly associated with a Pearson coefficient of 0.868 (P < .001) with increased DTN time. CONCLUSIONS The DTN time at our institution was above the recommended target. Our findings suggest that reducing the CT report time interval may decrease DTN time.

The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes. Yu et al. report a preparation that enables transplantation of pancreatic islets underneath the skin and achieves long-term euglycaemia in several preclinical models of type 1 diabetes, thus providing a simple method that might enable a more widespread adoption of islet transplantation in the clinic.