Penicillin or cephalosporin antibiotic allergy label: Influence on length of stay and hospital readmission.

Background: A penicillin or cephalosporin antibiotic (PCA) allergy label (PCAAL) has negative implications for both the patient and health care alike. Objective: A retrospective study was undertaken to evaluate the influence of a PCAAL on length of stay (LOS) and hospital readmissions. Methods: Over 4 weeks, inpatients with a PCAAL who were referred to the allergy service or opportunistically reviewed were grouped in the categories delabeled (group 1a) or advice not followed (ie, label carriage) (group 1b). Comparator groups without a PCAAL were identified, those either on a PCA (the PCA group [group 2]) or on a non-PCA (the non-PCA group [group 3]). Results: The study population comprised 77 patients as follows: group 1a (n = 19), group 1b (n = 6), group 2 (n = 36), and group 3 (n = 16). Those in group 1a were significantly older (median age 78 years) than those in group 1b (median age 53 years [P = .013]) or group 3 (median age 59 years [P = .013]).There was a trend toward lower LOS in group 1a (10 days) than in group 1b (11.5 days [P = not significant]). Group 2 had a significantly lower LOS (6 days) than either both group 1a (10 days [P = .043]) or group 3 (15 days [P = .002]). Group 3 had the highest rate of patients readmitted within 30 days (n = 5 [71.4%]). Conclusion: A PCAAL carries influence on both LOS and readmissions, thus identifying the prompt need for allergy review to provide specific recommendations: delabeling and transition to an appropriate antibiotic. The significantly older group of those with a PCAAL who received a PCA after delabeling (ie, a 20-year age difference) may also be a signal that more elderly and comorbid patients benefit from this intervention the most.

Ethnoracial Identity and Cognitive Impairment: A Community Study.

BACKGROUND: Identifying potentially modifiable risk factors associated with MCI in different ethnoracial groups could reduce MCI burden and health inequity in the population. METHODS: Among 2845 adults aged 65+ years, we investigated potential risk exposures including education, physical and mental health, lifestyle, and sensory function, and their cross-sectional associations with MCI. We compared proportions of exposures between Black and White participants and explored relationships among race, MCI, and exposures. Logistic regression modeled MCI as a function of each exposure in the overall sample adjusting for age, sex, educational level, and race, and investigating race*exposure interactions. RESULTS: Compared with White participants, Black participants had greater odds of MCI (OR 1.53; 95% CI, 1.13 to 2.06) and were more likely to report depressive symptoms, diabetes, and stroke, to have high blood pressure and BMI, and to be APOE - 4 carriers. Exposures associated with higher odds of MCI were diabetes, stroke, lifetime smoking, sleep disturbances, social isolation, loneliness, depression and anxiety symptoms, and vision and hearing loss. There were no significant interactions between race and any exposure. CONCLUSIONS: Black participants had 53% higher odds of MCI adjusting for age, sex, and education. The same exposures were associated with MCI in Black and White participants.

Lifestyle and incident dementia: A COSMIC individual participant data meta­analysis.

INTRODUCTION: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Long waitlists for outpatient drug allergy referrals: An Australian tertiary centre experience.

Drug allergy clinic waitlist time data are limited. A 24-month retrospective study of drug allergy referrals was undertaken at a tertiary hospital in Australia. One hundred six patients were reviewed with a median age of 50 years (IQR 40.5-67.3) and a female predominance (n = 76, 71%). Face-to-face consultations were common (n = 83, 78.3%) with the remainder being telephone consultations. General practitioners comprised just over one-third (n = 38, 35.9%) of the referrers but majority being from within the hospital, such as the emergency department (n = 22, 20.8%). Most patients (n = 100, 94.3%) were triaged as Category 1 or urgent. Antibiotic allergies were common (n = 75, 70.8%), of which majority were beta-lactam antibiotics (n = 71, 95%): 55 (73.3%) for penicillins and 16 (15.1%) for cephalosporins. The median waitlist time was 178 days (IQR 48.5-502.5) and only 18 (17%) of Category 1 were seen within urgent timeframe. Telephone consultation had a significantly shorter waitlist time (median 47 days; IQR 6-245) compared to face-to-face consultations (median 267 days; IQR 69-519) (p = 0.026). Large waitlist times are present for drug allergy, and given the majority of referrers are from hospitals, inpatient drug allergy assessment remains paramount. Beta-lactam antibiotic drug allergy labels remain common, and given their negative implications, further work is needed. Economic and human resources evaluations are required to address this shortfall.

Overestimation of Balance Ability Among Older Adults at Risk for Falls.

Objective: This study examined alignment of subjective balance confidence with Stopping Elderly Accidents, Deaths and Injuries (STEADI) fall risk. Methods: Cross-sectional analysis of 155 community-dwelling adults (60 + y/o) from 2016 to 2018 who completed a STEADI fall assessment. Descriptive statistics, Chi-Square analysis, and biserial point correlations were applied. Results: Adults who overestimate balance confidence, 55.6% (n = 50) reported a fall in the past year, 62.2% (n = 56) were worried about falling, 48.9% (n = 44) felt unsteady when standing/walking, and 70.0% (n = 63) had a score of ≥4 on the Stay Independent Questionnaire (SIQ). Physical performance for these adults were mean TUG score 10.9s (SD = 3.4), mean 30 second chair stands 10.8 (SD = 3.5), and mean 4-stage balance score 3.1 (SD = .76). Discussion: Older adults are more likely to overestimate their subjective balance confidence. Individuals are equally likely to have reported a fall in the past year if they were "at fall risk," regardless of their subjective balance confidence.

TTK/MPS1 inhibitor OSU-13 targets the mitotic checkpoint and is a potential therapeutic strategy for myeloma.

Despite substantial recent advances in treatment, multiple myeloma (MM) remains an incurable disease, with a shortage of treatment options for patients with high-risk disease, warranting the need for novel therapeutic targets and treatment approaches. Threonine and tyrosine kinase (TTK), also known as monopolar spindle 1 (MPS1), is a kinase essential for the mitotic spindle checkpoint whose expression correlates to unfavorable prognosis in several cancers. Here, we report the importance of TTK in MM, and the effects of the TTK inhibitor OSU-13. Elevated TTK expression correlated with amplification/ gain of 1q21 and decreased overall and event-free survival in MM. Treatment with OSU-13 inhibited TTK activity efficiently and selectively at a similar concentration range to other TTK inhibitor clinical candidates. OSU-13 reduced proliferation and viability of primary human MM cells and cell lines, especially those with high 1q21 copy numbers, and triggered apoptosis through caspase 3 and 7 activation. In addition, OSU-13 induced DNA damage and severe defects in chromosome alignment and segregation, generating aneuploidy. In vivo, OSU-13 decreased tumor growth in mice with NCI-H929 xenografts. Collectively, our findings reveal that inhibiting TTK with OSU-13 is a potential therapeutic strategy for MM, particularly for a subset of high-risk patients with poor outcome.

Immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis in a patient with chronic lymphocytic leukemia.

Haemophagocytic lymphohistiocytosis (HLH) is a rare complication of immune checkpoint inhibitor therapy. A 55-year-old male with stable chronic lymphocytic leukemia presented with fevers and symptomatic anaemia after nine cycles of nivolumab for metastatic melanoma. Investigations were consistent with autoimmune haemolytic anemia and corticosteroids were initiated. Thrombocytopenia and elevated liver enzymes without evidence of chronic lymphocytic leukaemia transformation was present. Ferritin was elevated, and thus HLH was considered and subsequently confirmed on a bone marrow biopsy. Corticosteroid monotherapy was continued, with resolution of fevers and improvement in cytopenias and liver enzymes. A six month corticosteroid tapering regimen was initiated, and he remains in HLH remission. This case highlights the importance of prompt recognition of immune checkpoint inhibitor-related HLH in patients with concurrent haematological malignancy.

A 55-year-old man had skin cancer and treatment was started. He also had a blood cancer around the same time that was not causing any problems. The skin cancer treatment started to cause problems many weeks later. His immune system started to react and become more active and so his liver started to suffer. The treatment for his skin cancer was stopped and steroids were started, which eventually improved his condition. These treatments for skin cancer can activate the immune system, but to this extent is not very common. It is important to know that it is possible and needs to be actioned early.

Characterization of monoclonal gammopathy of undetermined significance progression to multiple myeloma through meta-analysis of GEO data.

The etiology of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is still obscure as are the processes that enable the progression of MGUS to MM. Understanding the unique vs. shared transcriptomes can potentially elucidate why individuals develop one or the other. Furthermore, highlighting key pathways and genes involved in the pathogenesis of MM or the development of MGUS to MM may allow the discovery of novel drug targets and therapies. We employed STARGEO platform to perform three separate meta-analysis to compare MGUS and MM transcriptomes. For these analyses we tagged (1) 101 MGUS patient plasma cells from bone marrow samples and 64 plasma cells from healthy controls (2) 383 MM patient CD138+ cells from bone marrow and the 101 MGUS samples in the first analysis as controls (3) 517 MM patient peripheral blood samples and 97 peripheral blood samples from healthy controls. We then utilized Ingenuity Pathway Analysis (IPA) to analyze the unique genomic signatures within and across these samples. Our study identified genes that may have unique roles in MGUS (GADD45RA and COMMD3), but also newly identified signaling pathways (EIF2, JAK/STAT, and MYC) and gene activity (NRG3, RBFOX2, and PARP15) in MGUS that have previously been shown to be involved in MM suggesting a spectrum of molecular overlap. On the other hand, genes such as DUSP4, RN14, LAMP5, differentially upregulated in MM, may be seen as tipping the scales from benignity to malignancy and could serve as drug targets or novel biomarkers for risk of progression. Furthermore, our analysis of MM identified newly associated gene/pathway activity such as inhibition of Wnt-signaling and defective B cell development. Finally, IPA analysis, suggests the multifactorial, oncogenic qualities of IFNγ signaling in MM may be a unifying pathway for these diverse mechanisms and prompts the need for further studies.

Tocilizumab in grade 4 hepatitis secondary to immune checkpoint inhibitor: a case report and review of the literature.

First- and second-line treatments for immune checkpoint inhibitor-related hepatotoxicity (IRH) are well established; however, evidence for third-line therapies is limited. We present a 68-year-old female with relapsed metastatic non-small-cell lung carcinoma despite multiple treatments. A fortnight after the second cycle of CTLA-4 inhibitor immunotherapy, she developed scleral icterus and mild jaundice with significant elevation in liver enzymes. A diagnosis of IRH was made, and despite corticosteroids, mycophenolate and tacrolimus, liver enzymes continued to worsen. One infusion of tocilizumab was given, which resulted in a remarkable improvement. Prednisolone and tacrolimus were then tapered over the ensuing months, and mycophenolate was continued. Given the rapid improvement in liver enzymes with tocilizumab, this treatment should be considered as a third-line treatment in IRH.

A lady had cancer of the lung. A new medication was started but the liver became damaged. Three medications were tried to help the liver. None of these worked. Another drug (called tocilizumab) was tried and worked. The liver got better.

Social Isolation and Loneliness in a Population Study of Cognitive Impairment: The MYHAT Study.

In this study, we examined associations of social isolation and loneliness with cognitive impairment among older adults from a Rust Belt region in Southwest Pennsylvania. We used data from the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. We found that (a) 11 items combined into two reliable composites of social isolation and loneliness; (b) unique to this study, providing unpaid help to others was an indicator of reduced social isolation; (c) social isolation and loneliness were positively associated with cognitive impairment; and (d) these associations were appreciably attenuated by general health and physical functional status and depressive symptoms, respectively. We concluded that social isolation and loneliness are differentially associated with older adults' cognitive health, and that their effects might operate through separate pathways. Approaches to address social isolation and loneliness should consider the community context and its implications for older adults' cognitive health.

A case of T-cell-Epstein-Barr virus-haemophagocytic lymphohistiocytosis and sustained remission following ruxolitinib therapy.

Objectives: Epstein-Barr virus (EBV) is a common cause of secondary haemophagocytic lymphohistiocytosis (HLH). While B cells are reservoirs for EBV, infection within T cells and NK cells in this disease can be difficult to treat. Methods: A 19-year-old female presented with a 6-week history of coryzal symptoms on a background of Crohn's disease. On examination, she was febrile and tachycardic with mild tonsillar enlargement and splenomegaly. New trilineage cytopenias and elevation in liver enzymes were detected, with acute EBV subsequently confirmed on whole blood PCR. A diagnosis of EBV-associated HLH was supported further with elevated serum ferritin, triglycerides and soluble CD25, low fibrinogen and the presence of haemophagocytosis in the bone marrow. Results: Corticosteroids, IVIG and rituximab were given, and anakinra was subsequently added due to ongoing fevers. EBV infection was then demonstrated within CD8+ T cells on EBER Flow-FISH assay. Ruxolitinib was commenced and her fevers abated on day 5, with improvement in other HLH parameters. She was discharged after a 39-day hospital admission. To date, she has remained in remission of HLH, despite developing COVID-19 infection during the convalescence phase of HLH. Conclusion: EBV viraemia requires adequate treatment to control EBV-associated HLH as rituximab may be insufficient, and corticosteroid resistance can result in continued EBV infection in CD8+ T cells. This entity is known as T-cell-EBV-HLH. Ruxolitinib is a novel treatment strategy in this specific context and has several advantages, including inhibition of corticosteroid resistance to promote apoptosis of EBV-infected T cells.

Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing.

INTRODUCTION: Previous meta-analyses have linked social connections and mild cognitive impairment, dementia, and mortality. However, these used aggregate data from North America and Europe and examined a limited number of social connection markers. METHODS: We used individual participant data (N = 39271, Mage  = 70.67 (40-102), 58.86% female, Meducation  = 8.43 years, Mfollow-up  = 3.22 years) from 13 longitudinal ageing studies. A two-stage meta-analysis of Cox regression models examined the association between social connection markers with our primary outcomes. RESULTS: We found associations between good social connections structure and quality and lower risk of incident mild cognitive impairment (MCI); between social structure and function and lower risk of incident dementia and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality. DISCUSSION: Different aspects of social connections - structure, function, and quality - are associated with benefits for healthy aging internationally. HIGHLIGHTS: Social connection structure (being married/in a relationship, weekly community group engagement, weekly family/friend interactions) and quality (never lonely) were associated with lower risk of incident MCI. Social connection structure (monthly/weekly friend/family interactions) and function (having a confidante) were associated with lower risk of incident dementia. Social connection structure (living with others, yearly/monthly/weekly community group engagement) and function (having a confidante) were associated with lower risk of mortality. Evidence from 13 longitudinal cohort studies of ageing indicates that social connections are important targets for reducing risk of incident MCI, incident dementia, and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality.

Dose-response relationship between late-life physical activity and incident dementia: A pooled analysis of 10 cohort studies of memory in an international consortium.

INTRODUCTION: Though consistent evidence suggests that physical activity may delay dementia onset, the duration and amount of activity required remains unclear. METHODS: We harmonized longitudinal data of 11,988 participants from 10 cohorts in eight countries to examine the dose-response relationship between late-life physical activity and incident dementia among older adults. RESULTS: Using no physical activity as a reference, dementia risk decreased with duration of physical activity up to 3.1 to 6.0 hours/week (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.67 to 1.15 for 0.1 to 3.0 hours/week; HR 0.68, 95% CI 0.52 to 0.89 for 3.1 to 6.0 hours/week), but plateaued with higher duration. For the amount of physical activity, a similar pattern of dose-response curve was observed, with an inflection point of 9.1 to 18.0 metabolic equivalent value (MET)-hours/week (HR 0.92, 95% CI 0.70 to 1.22 for 0.1 to 9.0 MET-hours/week; HR 0.70, 95% CI 0.53 to 0.93 for 9.1 to 18.0 MET-hours/week). DISCUSSION: This cross-national analysis suggests that performing 3.1 to 6.0 hours of physical activity and expending 9.1 to 18.0/MET-hours of energy per week may reduce dementia risk.

Psychosocial implications of early COVID-19 restrictions on older adults in a small-town region in Southwestern, Pennsylvania (USA).

OBJECTIVES: The restrictions put in place in 2020 to mitigate the spread of the coronavirus disease 2019 limited or eliminated social connections that are vital for psychosocial well-being. The objectives of this research were to examine the impact of early pandemic-related restrictions on feelings of loneliness, depression, and anxiety as well as social activity disruption and their concomitant associations in a sample of community-dwelling older adults residing in a small-town region in the USA. DESIGN AND SETTING: Cross-sectional data collected from an ongoing population-based cohort study in Southwestern, Pennsylvania. PARTICIPANTS: Analyses included 360 adults aged 65 years and older whose annual study assessment occurred during the first 120 days of pandemic-related restrictions. MEASUREMENTS: Self-reported feelings of loneliness, depression, and anxiety due to the pandemic-related restrictions were each measured using a single question. Depressive symptoms and anxiety were also assessed with the modified Center for Epidemiologic Studies-Depression and Generalized Anxiety Disorder-7 item tools. Disruption in a variety of common social activities was also assessed. RESULTS: Feeling lonely affected 36% of participants who were more likely to be female, not currently married, and living alone. Giving up in-person visits with family was associated with significantly higher odds of feeling lonely, and feeling lonely was associated with significantly higher odds of feelings of anxiety and depression. CONCLUSIONS: Loneliness is a serious outcome of pandemic-related restrictions among older adults, potentially linked to loss of connection with family, and may be associated with increased feelings of depression and anxiety.

The choice of anti-LEDGF/DFS70 assay matters: a comparative study of six assays.

Lens-epithelial derived growth factor (LEDGF/DFS70) autoantibodies result in the commonly observed dense fine speckled (DFS) pattern by anti-nuclear antibody (ANA) assay. However, there is no consensus approach for confirmation of this autoantibody specificity. To evaluate current approaches, we examined inter-assay agreement between six anti-LEDGF/DFS70 assays. A total of 395 consecutive sera samples from routine ANA diagnostics were obtained, tested by routine ANA, anti-ENA line immunoblot assay (LIA) and anti-dsDNA assay and with six anti-DFS/LEDGF assays: the EuroLine-LIA (Euro-LIA), Medical and Biological Laboratories ELISA (MBL-ELISA), Phadia-EliA (EliA), QUANTA Flash CLIA, EuroImmun ELISA (Euro-ELISA) and Immco-Diagnostics HEp-2 ELITE/DFS-Knockout (HEp-2KO). Of 395 sera, 108 tested positive by at least one assay. Despite general good concordance between all assays across the cohort (Gwet's AC1=0.89), within the target DFS-ANA pattern group inter-assay agreement was poor (AC1=0.59). Euro-LIA, CLIA and MBL-ELISA assays were most concordant, but CLIA and Euro-LIA were also most likely to identify discordant positive results. EliA and Euro-ELISA had poorer agreement, which could be attributable to ill-matched cut-offs between assays. HEp-2KO was frequently discordant with all other assays tested. Euro-LIA, CLIA and MBL-ELISA were most concordant at manufacturer's specifications and are suited for use in clinical laboratories. Modified assay thresholds are required to ensure comparative results for Euro-ELISA and EliA. HEp-2KO assay is frequently discordant with all other assays, making it less suited for routine diagnostics. The study highlights the importance of considering inter-assay variability when developing a diagnostic strategy for anti-LEDGF/DFS70 autoantibodies in clinical laboratories.

Associations between social connections and cognition: a global collaborative individual participant data meta-analysis.

BACKGROUND: Poor social connections (eg, small networks, infrequent interactions, and loneliness) are modifiable risk factors for cognitive decline. Existing meta-analyses are limited by reporting aggregate responses, a focus on global cognition, and combining social measures into single constructs. We aimed to investigate the association between social connection markers and the rate of annual change in cognition (ie, global and domain-specific), as well as sex differences, using an individual participant data meta-analysis. METHODS: We harmonised data from 13 longitudinal cohort studies of ageing in North America, South America, Europe, Africa, Asia, and Australia. Studies were eligible for inclusion if they had baseline data for social connection markers and at least two waves of cognitive scores. Follow-up periods ranged from 0 years to 15 years across cohorts. We included participants with cognitive data for at least two waves and social connection data for at least one wave. We then identified and excluded people with dementia at baseline. Primary outcomes were annual rates of change in global cognition and cognitive domain scores over time until final follow-up within each cohort study analysed by use of an individual participant data meta-analysis. Linear mixed models within cohorts used baseline social connection markers as predictors of the primary outcomes. Effects were pooled in two stages using random-effects meta-analyses. We assessed the primary outcomes in the main (partially adjusted) and fully adjusted models. Partially adjusted models controlled for age, sex, and education; fully adjusted models additionally controlled for diabetes, hypertension, smoking, cardiovascular risk, and depression. FINDINGS: Of the 40 006 participants in the 13 cohort studies, we excluded 1392 people with dementia at baseline. 38 614 individual participants were included in our analyses. For the main models, being in a relationship or married predicted slower global cognitive decline (b=0·010, 95% CI 0·000-0·019) than did being single or never married; living with others predicted slower global cognitive (b=0·007, 0·002-0·012), memory (b=0·017, 0·006-0·028), and language (b=0·008, 0·000-0·015) decline than did living alone; and weekly interactions with family and friends (b=0·016, 0·006-0·026) and weekly community group engagement (b=0·030, 0·007-0·052) predicted slower memory decline than did no interactions and no engagement. Never feeling lonely predicted slower global cognitive (b=0·047, 95% CI 0·018-0·075) and executive function (b=0·047, 0·017-0·077) decline than did often feeling lonely. Degree of social support, having a confidante, and relationship satisfaction did not predict cognitive decline across global cognition or cognitive domains. Heterogeneity was low (I2=0·00-15·11%) for all but two of the significant findings (association between slower memory decline and living with others [I2=58·33%] and community group engagement, I2=37·54-72·19%), suggesting robust results across studies. INTERPRETATION: Good social connections (ie, living with others, weekly community group engagement, interacting weekly with family and friends, and never feeling lonely) are associated with slower cognitive decline. FUNDING: EU Joint Programme-Neurodegenerative Disease Research grant, funded by the National Health and Medical Research Council Australia, and the US National Institute on Aging of the US National Institutes of Health.

Redefining CD56 as a Biomarker and Therapeutic Target in Multiple Myeloma.

Multiple myeloma cells aberrantly express surface antigens compared with normal plasma cells. Among others, CD56 is present at variable levels in approximately 70% of patients with multiple myeloma; however, very little is known about CD56 role in multiple myeloma. We demonstrated that patients with multiple myeloma with more than 10% of CD56-expressing clonal multiple myeloma cells have inferior clinical outcomes. By gain-of and loss-of function models, we revealed that CD56 promotes multiple myeloma cell growth, survival, and adhesion to stromal cells. These protumoral effects are induced by the activation of the RSK2/CREB1 signaling pathway, with increased mRNA and protein levels of the anti-apoptotic genes BCL2 and MCL1. Consequently, the genomic and pharmacological inhibition of RSK2 or CREB1 specifically induced multiple myeloma cell death in CD56-expressing multiple myeloma cells. Finally, we observed that CD56 signaling decreases CRBN expression, reducing responses to lenalidomide. RSK2 or CREB1 inhibition increased CRBN levels and were synergic with lenalidomide in inducing cell death, especially in CD56-expressing multiple myeloma cells. In conclusion, our findings demonstrate that CD56 promotes multiple myeloma cell growth, and pave the way to novel therapies based on targeting CD56, along with the use of CD56 as a predictive biomarker for multiple myeloma therapies. IMPLICATIONS: Multiple myeloma is an incurable, genetically heterogeneous disease, without available tailored therapeutic approaches. CD56 signaling promotes multiple myeloma growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing patients with multiple myeloma.

Education, Occupational Complexity, and Incident Dementia: A COSMIC Collaborative Cohort Study.

BACKGROUND: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia. OBJECTIVE: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts. METHOD: We used data from 10,195 participants (median baseline age = 74.1, range = 58∼103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated failure time model was applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed. RESULT: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28%of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with 'high school completion' or 'above high school' compared to 'middle school completion or below'. CONCLUSION: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course.

Functional expression of aryl hydrocarbon receptor as a potential novel therapeutic target in human multiple myeloma.

The etiology of multiple myeloma (MM) remains incompletely understood; however, epidemiologic studies have suggested a possible link between exposure to environmental aromatic hydrocarbons-which serve as exogenous ligands for the aryl hydrocarbon receptor (AHR), which has been implicated in cancer biology-and development of monoclonal gammopathy of undetermined significance (MGUS) and MM. Herein, we demonstrate the functional expression of AHR in MM cell lines and primary human MM samples. AHR is expressed in putative MM 'stem cells' and advanced clinical stages of MM, and functionally contributes to MM tumor cell phenotype and proliferation. Antagonism of AHR directly impairs MM cell viability and increases MM cell susceptibility to immune-mediated clearance. Furthermore, our findings indicate that AHR antagonism may represent an effective means to enhance the function of other drugs, such as anti-CD38 antibodies, in future clinical studies. Taken together, these data identify AHR as a novel target for MM therapy.

Prevalence of SARS-CoV-2 antibodies in pediatric healthcare workers.

OBJECTIVES: To determine SARS-CoV-2-antibody prevalence in pediatric healthcare workers (pHCWs). DESIGN: Baseline prevalence of anti-SARS-CoV-2-IgG was assessed in a prospective cohort study from a large pediatric healthcare facility. Prior SARS-CoV-2 testing history, potential risk factors and anxiety level about COVID-19 were determined. Prevalence difference between emergency department (ED)-based and non-ED-pHCWs was modeled controlling for those covariates. Chi-square test-for-trend was used to examine prevalence by month of enrollment. RESULTS: Most of 642 pHCWs enrolled were 31-40years, female and had no comorbidities. Half had children in their home, 49% had traveled, 42% reported an illness since January, 31% had a known COVID-19 exposure, and 8% had SARS-CoV-2 PCR testing. High COVID-19 pandemic anxiety was reported by 71%. Anti-SARS-CoV-2-IgG prevalence was 4.1%; 8.4% among ED versus 2.0% among non-ED pHCWs (p < 0.001). ED-work location and known COVID-19 exposure were independent risk factors. 31% of antibody-positive pHCWs reported no symptoms. Prevalence significantly (p < 0.001) increased from 3.0% in April-June to 12.7% in July-August. CONCLUSIONS: Anti-SARS-CoV-2-IgG prevalence was low in pHCWs but increased rapidly over time. Both working in the ED and exposure to a COVID-19-positive contact were associated with antibody-seropositivity. Ongoing universal PPE utilization is essential. These data may guide vaccination policies to protect front-line workers.