Beth Israel Deaconess Medical Center

Both sleep and wake encephalograms (EEG) change over the lifespan. While prior studies have characterized age-related changes in the EEG, the datasets span a particular age group, or focused on sleep and wake macrostructure rather than the microstructure. Here, we present sex-stratified data from 3372 community-based or clinic-based otherwise neurologically and psychiatrically healthy participants ranging from 11 days to 80 years of age. We estimate age norms for key sleep and wake EEG parameters including absolute and relative powers in delta, theta, alpha, and sigma bands, as well as sleep spindle density, amplitude, duration, and frequency. To illustrate the potential use of the reference measures developed herein, we compare them to sleep EEG recordings from age-matched participants with Alzheimer's disease, severe sleep apnea, depression, osteoarthritis, and osteoporosis. Although the partially clinical nature of the datasets may bias the findings towards less normal and hence may underestimate pathology in practice, age-based EEG reference values enable objective screening of deviations from healthy aging among individuals with a variety of disorders that affect brain health.

In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N=302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favoured olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) versus TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib versus decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD. This article is protected by copyright. All rights reserved.

Objective: Recent genomic studies by the Cancer Genome Atlas show much simpler genomic profiles in distal esophageal adenocarcinoma (EAC) than in adenocarcinoma of the gastroesophageal junction (AGEJ). However, the prognostic significance of categorizing patients in these two cancer groups remains unknown. Methods: We studied clinicopathologic and prognostic features of both cancers in 303 consecutive patients treated at the Veterans Affairs Boston Healthcare System over a 20-year period. Using uniform criteria and standardized routines, we studied and statistically compared the clinicopathologic and prognostic features between EAC and AGEJ. Results: In this cohort, over 99% of patients were white men with mean age of 69.1 years and an average body mass index of 28.0. No significant difference was detected in age, gender, ethnicity, body mass index, and history of tobacco abuse between the two groups. Compared to AGEJ patients, a significantly higher proportion of EAC patients had gastroesophageal reflux disease, long-segment Barrett's esophagus, common adenocarcinoma type, smaller tumor size, better differentiation, more stages I/II but fewer stages III/IV diseases, scarcer lymphovascular invasion, fewer nodal and distant metastases, and better overall, disease-free, and relapse-free survival. The 5-year overall survival rate was significantly higher in EAC patients (41.3%) than in AGEJ patients (17.2%) (p<0.001). This improved survival among EAC patients remained significant after censoring all cases discovered during surveillance, suggesting different pathogenesis mechanisms between EAC and AGEJ. Conclusions: Our findings suggest that EAC patients showed significantly better outcomes than AGEJ patients. Our results require validation in other patient populations.

Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition of the native immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms.

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.

Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.

Background Multiple HIV outbreaks among people who inject drugs (PWIDs) have occurred in the USA since 2015, highlighting the need for additional HIV prevention tools. Despite high levels of need, pre-exposure prophylaxis (PrEP) is drastically underutilized among PWIDs. Implicit bias toward PWID held by clinicians may impede PrEP scale-up among these underserved patients. This study examined how primary care providers’ (PCPs) clinical decisions related to PrEP can be impacted by biases when the patient has a history of substance use. Methods We conducted an online survey of PCPs ( n = 208). The survey included the implicit association test (IAT) to assess unconscious attitudes toward PWIDs, direct questions regarding clinicians’ explicit PWID attitudes, and an embedded experiment in which we systematically varied the risk behavior of a hypothetical patient and asked PCPs to make clinical judgments. Results A minority (32%) of PCPs reported explicit PWID bias. The IAT indicated strong implicit PWID bias (meant IAT score = 0.59, p < .0001) among 88% of the sample. Only 9% of PCPs had no implicit or explicit PWID bias. PWID patients were judged as less likely to adhere to a PrEP regimen, less responsible, and less HIV safety conscious than heterosexual or gay male patients. Anticipated lack of adherence mediated PCPs’ intent to prescribe PrEP to PWID. Conclusions PCPs’ bias may contribute to PrEP being under-prescribed to PWID. Implicit and explicit PWID biases were common in our sample. This study illustrates the need to develop and test tailored interventions to decrease biases against PWID in primary care settings.

Previous studies have examined the association between prenatal nitrogen dioxide (NO2)-a traffic emissions tracer-and fetal growth based on ultrasound measures. Yet, most have used exposure assessment methods with low temporal resolution, which limits the identification of critical exposure windows given that pregnancy is relatively short. Here, we used NO2 data from an ensemble model linked to residential addresses at birth to fit distributed lag models that estimated the association between weekly-resolved NO2 exposure and ultrasound biometric parameters in a Massachusetts-based cohort of 9,446 singleton births from 2011-2016. Ultrasound biometric parameters examined included biparietal diameter (BPD), head circumference, femur length, and abdominal circumference. All models were adjusted for sociodemographic characteristics, time trends, and temperature. We found that higher NO2 was negatively associated with all ultrasound parameters. The critical window differed depending on the parameter and when it was assessed. For example, for BPD measured after week 31, the critical exposure window appeared to be weeks 15-25; 10-parts per billion higher NO2 sustained from conception to the time of measurement was associated with a lower mean z-score of -0.11 (95% CI: -0.17, -0.05). Our findings indicate that reducing traffic emissions is one potential avenue to improving fetal and offspring health.

Background A large number of information and communication technology (ICT) based interventions exist for suicide prevention. However, not much is known about which of these ICTs are implemented in clinical settings and their implementation characteristics. In response, this scoping review aimed to systematically explore the breadth of evidence on ICT-based interventions for suicide prevention implemented in clinical settings and then to identify and characterize implementation barriers and facilitators, as well as evaluation outcomes, and measures. Methods We conducted this review following the Joanna Briggs Institute methodology for scoping reviews. A search strategy was applied to the following six databases between August 17–20, 2021: MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and Library, Information Science and Technology Abstracts. We also supplemented our search with Google searches and hand-searching reference lists of relevant reviews. To be included in this review, studies must include ICT-based interventions for any spectrum of suicide-related thoughts and behaviours including non-suicidal self-injury. Additionally, these ICTs must be implemented in clinical settings, such as emergency department and in-patient units. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) checklist to prepare this full report. Results This review included a total of 75 citations, describing 70 studies and 66 ICT-based interventions for suicide prevention implemented in clinical settings. The majority of ICTs were computerized interventions and/or applications (n = 55). These ICTs were commonly used as indicated strategies (n = 49) targeting patients who were actively presenting with suicide risk. The three most common suicide prevention intervention categories identified were post-discharge follow-up (n = 27), screening and/or assessment (n = 22), and safety planning (n = 20). A paucity of reported information was identified related to implementation strategies, barriers and facilitators. The most reported implementation strategies included training, education, and collaborative initiatives. Barriers and facilitators of implementation included the need for resource supports, knowledge, skills, motivation as well as engagement with clinicians with research teams. Studies included outcomes at patient, clinician, and health system levels, and implementation outcomes included acceptability, feasibility, fidelity, and penetration. Conclusion This review presents several trends of the ICT-based interventions for suicide prevention implemented in clinical settings and identifies a need for future research to strengthen the evidence base for improving implementation. More effort is required to better understand and support the implementation and sustainability of ICTs in clinical settings. The findings can also serve as a future resource for researchers seeking to evaluate the impact and implementation of ICTs.

Endothelial cells (ECs) are constitutively an anticoagulant surface but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid "scramblases", such as TMEM16F. TMEM16F-dependent PS externalization is well-characterized in platelets. In contrast, how ECs externalize phospholipids to support coagulation is not understood. We employed a focused genetic screen to evaluate the contribution of transmembrane phospholipid transport on EC procoagulant activity. We identified two TMEM16 family members, TMEM16F, and its closest paralog, TMEM16E, which were both required to support coagulation on ECs via PS externalization. Applying an intravital laser-injury model of thrombosis, we observed, unexpectedly, that PS externalization was concentrated at the vessel wall, not on platelets. TMEM16E-null mice demonstrated reduced vessel-wall dependent fibrin formation. The TMEM16 inhibitor benzbromarone prevented PS externalization and EC procoagulant activity and protected mice from thrombosis without increasing bleeding following tail transection. These findings indicate the activated endothelial surface is a source of procoagulant phospholipid contributing to thrombus formation. TMEM16 phospholipid scramblases may be a therapeutic target for thrombotic cardiovascular disease.

Background: The aim was to determine what factors drive and enhance compassionate care behaviors in the ICU setting and which factors drain and negate such caring attitudes and behaviors. Methods: Qualitative, focus group discussions using video vignettes. 20 participants agreed to be part of 3 separate focus groups facilitated by the authors. Results: Thematic analysis revealed emphasis on behavior and nonverbal cues, clinical decision making, communication and sensitivity, and building humane relations. The results show that physicians feel driven by the humanity and sensitivity felt in ICU work, however, there exists structural incompetence, as well as the stress and personal -systemic imbalances of ICU work, which leads to burnout and erosion of such motivations, draining compassion. Conclusions: Regulatory and scheduling practices must be examined to foster the growth of compassionate behaviors and attitudes in healthcare, and these should be treated as essential patient centered metrics.

This cohort study investigates clinicopathologic and prognostic associations of hypercalcemia in patients with intrahepatic or extrahepatic cholangiocarcinoma.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

Epstein-Barr virus (EBV) immortalization of resting B lymphocytes (RBLs) to lymphoblastoid cell lines (LCLs) models human DNA tumor virus oncogenesis. RBL and LCL chromatin interaction maps are compared to identify the spatial and temporal genome architectural changes during EBV B cell transformation. EBV induces global genome reorganization where contact domains frequently merge or subdivide during transformation. Repressed B compartments in RBLs frequently switch to active A compartments in LCLs. LCLs gain 40% new contact domain boundaries. Newly gained LCL boundaries have strong CTCF binding at their borders while in RBLs, the same sites have much less CTCF binding. Some LCL CTCF sites also have EBV nuclear antigen (EBNA) leader protein EBNALP binding. LCLs have more local interactions than RBLs at LCL dependency factors and super-enhancer targets. RNA Pol II HiChIP and FISH of RBL and LCL further validate the Hi-C results. EBNA3A inactivation globally alters LCL genome interactions. EBNA3A inactivation reduces CTCF and RAD21 DNA binding. EBNA3C inactivation rewires the looping at the CDKN2A/B and AICDA loci. Disruption of a CTCF site at AICDA locus increases AICDA expression. These data suggest that EBV controls lymphocyte growth by globally reorganizing host genome architecture to facilitate the expression of key oncogenes.

Background: A major cause of burnout is moral distress: when one knows the right course of action, but institutional constraints make the right course impossible to pursue. Objective: To assess the frequency and severity with which radiologists experience moral distress, and to explore root causes and countermeasures. Methods: This study entailed a national survey evaluating moral distress in radiology. The survey incorporated the validated Moral Distress Scale for Health Care Professionals (along with additional questions). After modification for applicability to radiology, respondents were asked to assess 16 clinical scenarios in terms of frequency and moral distress severity. The survey was sent by email on May 10, 2022 to 425 members of radiology practices, based on a national radiology society's quality-and-safety list serve. Measure of Moral Distress for Health Care Professionals (MMD-HP) was calculated for each respondent as a summary measure of distress across scenarios (maximum possible score, 256). Results: After excluding 12 surveys (incomplete data), final analysis included 93/425 (22%) respondents. A total of 91/93 (98%) respondents experienced at least some moral distress for at least one scenario. A total of 17/93 (18%) respondents had left a clinical position due to moral distress; 26/93 (28%) had considered leaving a clinical position due to moral distress but did not leave. Mean MMD-HP was 73±51 for those who had left, 89±47 for those who had considered leaving, and 39±35 for those who had never considered leaving (p<.001). A total of 41/85 (48%) respondents felt that the COVID-19 pandemic had influenced their moral distress level. The three scenarios with highest moral distress across respondents related to systemic causes (higher case volume than can be read safely; high case volume preventing resident teaching; lack of administrative action or support). The most commonly selected countermeasure to alleviate moral distress was educating leadership on moral distress sources (71%). Conclusion: Moral distress is prevalent in radiology, typically relates to systemic causes, and is a reported contributor to radiologists changing jobs. Clinical Impact: Urgent action is required by radiology practice leadership to address moral distress, as radiologists commonly practice in environments contradictory to their core values as physicians.

Background: Distal pancreatitis is an atypical imaging subtype of acute pancreatitis involving only the pancreatic body and tail, with sparing of the head. If no cause is identified, then suspicion for a small imaging-occult cancer may be warranted. Objective: To determine the frequency of subsequently diagnosed pancreatic cancer in patients with unexplained acute distal pancreatitis and to compare this frequency to that found in patients with unexplained nondistal pancreatitis. Methods: This retrospective study included patients who underwent contrast-enhanced CT between January 1, 2019 and December 31, 2020 showing acute pancreatitis without identifiable explanation. Studies were classified as showing distal or nondistal acute pancreatitis using a consensus process. Fisher's exact test was used to compare frequency of subsequent pancreatic cancer histologic diagnosis between groups; negative classification required ≥6 months of imaging follow-up and/or ≥12 months of clinical follow-up. Interreader agreement among seven readers of varying experience was assessed by Fleiss kappa. Results: Among 215 patients with acute pancreatitis, 116/215 (54%) had no identifiable explanation, forming the study sample. A total of 100/116 (86%) (57±18 years; 59 men, 41 women) patients had nondistal acute pancreatitis; 16/116 (14%) (66±14 years; 10 men, 6 women) had distal acute pancreatitis. Among patients with nondistal pancreatitis, none were subsequently diagnosed with pancreatic cancer; 62 had sufficient follow-up (median, 2.5 years) to be classified as negative for pancreatic cancer. Among patients with distal pancreatitis, nine were subsequently diagnosed with pancreatic cancer (median interval to suspected cancer on subsequent CT, 174 days); five had sufficient follow-up (median, 3.1 years) to be classified as negative for pancreatic cancer. Frequency of pancreatic cancer was higher (p<.001) in patients with distal (9/14 [64%]; 95% CI 35-87%) than with nondistal (0/62 [0%]; 95% CI, 0-6%) pancreatitis. Interreader agreement for distal versus nondistal pancreatitis classification was excellent (κ=0.81). Conclusion: Distal pancreatitis without identifiable cause on CT is an uncommon but unique imaging subtype of acute pancreatitis that is associated with a high frequency of pancreatic cancer. Clinical Impact: In patients with acute distal pancreatitis without identifiable cause, endoscopic ultrasound-guided biopsy should be considered to evaluate for an underlying small cancer.

Study objective: To determine the association between emergency physicians' ages and patient mortality after emergency department visits. Methods: This observational study used a 20% random sample of Medicare fee-for-service beneficiaries aged 65 to 89 years treated by emergency physicians at EDs from 2016 to 2017. We investigated whether 7-day mortality after ED visits differed by the age of the emergency physician, adjusting for patient and physician characteristics and hospital fixed effects. Results: We observed 2,629,464 ED visits treated by 32,570 emergency physicians (mean age 43.5). We found that patients treated by younger emergency physicians had lower mortality rates compared with those treated by older physicians. Adjusted 7-day mortality was 1.33% for patients treated by emergency physicians aged less than 40 years, 1.36% (adjusted difference, 0.03%; 95% confidence interval [CI], -0.001% to 0.06%) for physicians ages 40 to 49, 1.40% (0.08%; 95% CI 0.04% to 0.12%) for physicians ages 50 to 59, and 1.43% (0.11%; 95% CI 0.06% to 0.16%) for those with a physician age of 60 years and more. Similar patterns were observed when stratified by the patient's disposition (discharged vs admitted), and the association was more pronounced for patients with higher severity of illness. Conclusions: Medicare patients aged 65 to 89 years treated by emergency physicians aged under 40 years had lower 7-day mortality rates than those treated by physicians aged 50 to 59 years and 60 years or older within the same hospital. Potential mechanisms explaining the association between emergency physician age and patient mortality (eg, differences in training received and other unobservable patient/physician characteristics) are uncertain and require further study.