Search

Mental health issues are a growing concern in the workplace, linked to negative outcomes including reduced productivity, increased absenteeism, and increased turnover. Employer-sponsored mental health benefits that are accessible and proactive may help address these concerns. The aim of this retrospective cohort study was to evaluate the impact of a digital mental health benefit (Spring Health) on frontline healthcare service workers' clinical and workplace outcomes. The benefit was sponsored by a national health services company from 2021–2022 and included mental health screening, care navigation, psychotherapy and/or medication management. We hypothesized program use would be associated with improvements in depression and anxiety symptoms, and increased productivity and retention. Participants were employees enrolled in the benefit program, had at least moderate anxiety or depression, at least 1 treatment appointment, and at least 2 outcome assessments. Clinical improvement measures were PHQ-9 scale (range, 0–27) for depression and GAD-7 scale (range, 0–21) for anxiety; workplace measures were employee retention and the Sheehan Disability Scale (SDS) for functional impairment. A total of 686 participants were included. Participants using the mental health benefit had a 5.60 point (95% CI, 4.40–6.79, d = 1.28) reduction in depression and a 5.48 point (95% CI, 3.88–7.08, d = 1.64) reduction in anxiety across 6 months. 69.9% (95% CI, 61.8%–78.1%) of participants reliably improved (≥5 point change) and 84.1% (95% CI, 78.2%–90.1%) achieved reliable improvement or recovery (<10 points). Participants reported 0.70 (95% CI, 0.26–1.14) fewer workdays per week impacted by mental health issues, corresponding to $3,491 (95% CI, $1305–$5677) salary savings at approximately federal median wage ($50,000). Furthermore, employees using the benefit were retained at 1.58 (95% CI, 1.4–1.76) times the rate of those who did not. Overall, this evaluation suggests that accessible, proactive, and comprehensive mental health benefits for frontline health services workers can lead to positive clinical and workplace outcomes. [ABSTRACT FROM AUTHOR]

Background: The number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Given the low specificity of CT screening, non-invasive adjuvant methods are needed to differentiate cancerous lesions from benign nodules to help avoid unnecessary invasive procedures in the asymptomatic population. We have constructed a serum-based multi-biomarker panel and assessed its clinical accuracy in a retrospective analysis of samples collected from participants with suspicious radiographic findings in the Prostate, Lung, Chest and Ovarian (PLCO) cancer screening trial. Methods: Starting with a set of 9 candidate biomarkers, we identified 8 that exhibited limited pre-analytical variability with increasing clotting time, a key pre-analytical variable associated with the collection of serum. These 8 biomarkers were evaluated in a training study consisting of 95 stage I NSCLC patients and 186 smoker controls where a 5-biomarker pulmonary nodule classifier (PNC) was selected. The clinical accuracy of the PNC was determined in a blinded study of asymptomatic individuals comprising 119 confirmed malignant nodule cases and 119 benign nodule controls selected from the PLCO screening trial. Results: A PNC comprising 5 biomarkers: CEA, CYFRA 21-1, OPN, SCC, and TFPI, was selected in the training study. In an independent validation study, the PNC resolved lung cancer cases from benign nodule controls with an AUC of 0.653 (p < 0.0001). CEA and CYFRA 21-1, two of the markers included in the PNC, also accurately distinguished malignant lesions from benign controls. Conclusions: A 5-biomarker blood test has been developed for the diagnostic evaluation of asymptomatic individuals with solitary pulmonary nodules. [ABSTRACT FROM AUTHOR]

Background: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging. Results: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775). Conclusions: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses. [ABSTRACT FROM AUTHOR]

Sclerostin domain containing 1 (SOSTDC1) protein regulates processes from development to cancer by modulating activity of bone morphogenetic protein (BMP) and wingless/int (Wnt) signaling pathways. As dysregulation of both BMP and Wnt signaling has been observed in breast cancer, we investigated whether disruption of SOSTDC1 signaling occurs in breast cancer. SOSTDC1 mRNA expression levels in breast tissue were examined using a dot blot. Affymetrix microarray data on SOSTDC1 levels were correlated with breast cancer patient survival using Kaplan-Meier plots. Correlations between SOSTDC1 protein levels and clinical parameters were assessed by immunohistochemistry of a breast cancer tissue microarray. SOSTDC1 secretion and BMP and Wnt signaling were investigated using immunoblotting. We found that SOSTDC1 is expressed in normal breast tissue and this expression is reduced in breast cancer. High levels of SOSTDC1 mRNA correlated with increased patient survival; conversely, SOSTDC1 protein levels decreased as tumor size and disease stage increased. Treatment of breast cancer cells with recombinant SOSTDC1 or Wise, a SOSTDC1 orthologue, demonstrated that SOSTDC1 selectively blocks BMP-7-induced Smad phosphorylation without diminishing BMP-2 or Wnt3a-induced signaling. In conclusion, SOSTDC1 mRNA and protein are reduced in breast cancer. High SOSTDC1 mRNA levels correlate with increased distant metastasis-free survival in breast cancer patients. SOSTDC1 differentially affects Wnt3a, BMP-2, and BMP-7 signaling in breast cancer cells. These results identify SOSTDC1 as a clinically important extracellular regulator of multiple signaling pathways in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: The global transcriptional profile during the first 4 weeks of treatment with pegylated interferon alfa (PEG-IFN-α) therapy for chronic hepatitis C (CHC) was evaluated. cDNA array technology was used to assess expression of 10,918 human genes in peripheral blood cells obtained from 17 CHC patients at days 0, 7, and 28 following treatment with PEG-IFN-α and ribavirin. Hierarchical average linkage clustering identified seven temporal profiles of differential expression comprising 148 genes. Gene expression profiles were comparable between the PEG-IFN-α-2a and PEG-IFN-α-2b therapy. Genes representing a broad range of molecular functions were differentially regulated with distinct temporal patterns of expression. The initial global response to interferon treatment appears to be a net up-regulation of genes, consistent with gene responses identified previously in vitro, though by 4 weeks an overall down-regulation of genes was observed. Novel transcription factors potentially involved in secondary gene regulation cascades, a potential dsRNA receptor and members of the ubiquitin signaling, including a novel predicted deubiquitinating peptidase were all identified as being up-regulated upon treatment with IFN. The overall findings provide new light on possible physiological effects of IFN-α and open new lines of investigations on the mode of action of PEG-IFN-α combination therapy. [Copyright &y& Elsevier]

Background: The lipocalin (LCN) family of structurally conserved hydrophobic ligand binding proteins is represented in all major taxonomic groups from prokaryotes to primates. The importance of lipocalins in reproduction and the similarity to known epididymal lipocalins prompted us to characterize the novel human epididymal LCN6. Methods and Results: LCN6 cDNA was identified by database analysis in a comprehensive human library sequencing program. Macaca mulatta (rhesus monkey) cDNA was obtained from an epididymis cDNA library and is 93% homologous to the human. The gene is located on chromosome 9q34 adjacent LCN8 and LCN5. LCN6 amino acid sequence is most closely related to LCN5, but the LCN6 beta-barrel structure is best modeled on mouse major urinary protein 1, a pheromone binding protein. Northern blot analysis of RNAs isolated from 25 human tissues revealed predominant expression of a 1.0 kb mRNA in the epididymis. No other transcript was detected except for weak expression of a larger hybridizing mRNA in urinary bladder. Northern hybridization analysis of LCN6 mRNA expression in sham-operated, castrated and testosterone replaced rhesus monkeys suggests mRNA levels are little affected 6 days after castration. Immunohistochemical staining revealed that LCN6 protein is abundant in the caput epithelium and lumen. Immunofluorescent staining of human spermatozoa shows LCN6 located on the head and tail of spermatozoa with the highest concentration of LCN6 on the post-acrosomal region of the head, where it appeared aggregated into large patches. Conclusions: LCN6 is a novel lipocalin closely related to Lcn5 and Lcn8 and these three genes are likely products of gene duplication events that predate rodent-primate divergence. Predominant expression in the epididymis and location on sperm surface are consistent with a role for LCN6 in male fertility. [ABSTRACT FROM AUTHOR]

We have determined the extent of the primary transcription unit for the two highly expressed genes nmt1 and nmt2 of Schizosaccharomyces pombe. Transcription run-on analysis in permeabilized yeast cells was employed to map polymerase density across the 3′-flanking region of these two genes. Surprisingly, polymerases were detected 4.3 kb beyond the nmt1 polyadenylation [poly(A)] site and 2.4 kb beyond the nmt2 poly(A) site, which in each case have transcribed through an entire convergent downstream transcription unit. However, the steady-state levels of both downstream genes were unaffected by the high level of nmt1 or nmt2 nascent transcription. Analysis of nmt1 and nmt2 RNA 3′ end formation signals indicates that efficient termination of transcription requires not only a poly(A) signal but also additional pause elements. The absence of such pause elements close to the poly(A) sites of these genes may account for their extended nascent transcripts. [ABSTRACT FROM AUTHOR]

Transcription ‘run-on’ (TRO) analysis using permeabilized yeast cells indicates that transcription terminates between 180 and 380 bp downstream of the poly(A) site of the Schizosaccharomyces pombe ura4 gene. Two signals direct RNA polymerase II (pol II) to stop transcription: the previously identified 3′ end formation signals located close to the poly(A) site and an additional downstream element (DSE) located at the region of termination. The downstream signal (135 bp) appears to act by pausing the elongating polymerase. TRO analysis indicates that elevated levels of transcribing polymerases accumulate over the DSE and that removal of this signal leads to transcription proceeding beyond the normal termination region. Furthermore, when inserted between two competing polyadenylation signals, this DSE increases the utilization of upstream poly(A) sites in vivo. We show that polymerase pausing over an extended region of template ensures termination of pol II transcription close to the poly(A) site. [ABSTRACT FROM AUTHOR]

Background: A digital Diabetes Prevention Program (dDPP) has been shown to reduce the 8-year risk of diabetes in the first year of implementation in a workforce setting. We asked whether the dDPP reduced the risk of diabetes in a second year. Methods: Individuals were included in the study if they (i) participated in an employer-sponsored wellness program with year-end biometric screening for 4 consecutive years (2016 to 2019), (ii) had prediabetes-range fasting glucose (100 to 125 mg/dL) or Hb1Ac (5.7% to 6.4%), (iii) a BMI ≥25 kg/m2 at the end of 2017, and (iv) completed ≥9 lessons in a dDPP initiated at the beginning of 2018. In the first year of the dDPP, individuals participated in weekly online lessons. In the second year, no new content was introduced, but individuals had access to lessons delivered in year 1. Results: The baseline characteristics from the 2017 year-end screen are provided (Table). On average, participants (n=401) completed 25.1 lessons (SD: 12.3). In the second year of intervention, levels of BMI, fasting glucose, triglycerides and HDL-C, all components of the 8-year diabetes risk score, improved relative to changes observed in the year before intervention. The 8-year risk of developing diabetes was also reduced (Table). Conclusions: The risk of developing type 2 diabetes was reduced in the second year of a dDPP. Disclosure: C.E. Birse: Employee; Self; Quest Diagnostics. M.S. Fragala: Employee; Self; Quest Diagnostics. A.R. Arellano: None. L.A. Bare: Employee; Self; Quest Diagnostics. C. Castro Sweet: Employee; Self; Omada Health. R.J. Lagier: Employee; Self; Quest Diagnostics. Employee; Spouse/Partner; Thermo Fisher Scientific. [ABSTRACT FROM AUTHOR]

Background: Digital behavioral counseling has previously been shown to reduce levels of risk factors for diabetes including fasting glucose and HbA1c. We asked whether the 8-year risk of developing diabetes could be reduced within the first year of a digital counseling program. Methods: Individuals were included in the study if they (i) participated in an employer-sponsored wellness program with year-end biometric screening for 3 consecutive years (2016, 2017, and 2018), (ii) had prediabetes-range fasting glucose (100 to 125 mg/dL) or Hb1Ac (5.7% to 6.4%), (iii) a BMI ≥25 kg/m2 at the end of 2017, and (iv) completed at least 9 lessons in a digital behavioral counseling program initiated at the beginning of 2018. Paired t-Tests were used to assess changes in yearly trajectories of diabetes risk factors before and after intervention (Table). Results: The baseline characteristics of the cohort at the 2017 year-end screen are provided (Table). On average, participants (n=460) were engaged in the counseling program for 9.1 months (SD: 1.2) and completed 25.1 lessons (SD: 12.3). After participation, levels of all biometric variables included in the 8-year risk model* shifted in a favorable direction; the 8-year risk of developing diabetes was reduced (Table). Conclusions: Digital behavioral counseling was effective in reducing risk factors and the 8-year risk of diabetes during the first year of the program. Disclosure: C.E. Birse: Employee; Self; Quest Diagnostics. Stock/Shareholder; Self; Quest Diagnostics. M.S. Fragala: Employee; Self; Quest Diagnostics. A. Satish: None. K.C. McNamara: Employee; Self; Omada Health, Inc. C.M. Castro Sweet: Employee; Self; Omada Health, Inc. R.J. Lagier: Employee; Self; Quest Diagnostics. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for a number of disorders ranging from type II diabetes to cardiovascular disease, however, the molecular basis for these associations has not been be fully clarified. A number of adipokines, cytokines expressed exclusively or at an elevated level in adipose tissue, have been identified that play key roles in regulating energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolism and satiety. Dysregulated expression of adipokines may link obesity with its related metabolic disorders. We have developed a proteomics platform that enables the direct identification and functional characterization of adipokines from cells derived from human subcutaneous and visceral adipose depots. Adipocytes isolated from different fat depots (subcutaneous and visceral) from subjects with a spectrum of BMI (19-42) and diabetic progression, were subjected to Mass Spectrometric (MS) analyses. Preadipocytes isolated from adipose tissue were differentiated for 2 weeks, before being incubated in conditioned medium. Secreted and shed proteins released into the medium were labeled with ICAT and digested with trypsin. The cysteine-containing peptides were subjected to Liquid Chromatography (LC) / MS analysis. Peptide maps representing different adipocyte populations were compared and candidates that were differentially expressed were selected. Sequence-composition was resolved through tandem MS and database search. The functionality of a number of these adipokines was evaluated in a series of RNAi-based assays, established in human adipocytes, to determine the possible involvement of these secreted proteins in key metabolic transitions including: lipolysis and glucose uptake. Our systematic proteomic analysis has resulted in the identification of > 20 adipokines. A number of previously characterized secreted proteins, including visfatin and complement C1r were identified. In addition, a number of novel candidates that included: a protease inhibitor, a hydrolase and a molecule involved in cell-adhesion, were also resolved. Interestingly, subsequent comparison of the MS maps within the adipocyte samples revealed significant differences in expression of secreted / shed proteins isolated from: (i) subcutaneous and visceral depots, (ii) lean and obese subjects and (iii) normal and diabetic patients. [ABSTRACT FROM AUTHOR]

Presents an abstract for the article on the genome-wide gene expression of the malignant Reed-Sternberg cell of Hodgkin lymphoma.