Is it worth it? Greater risk aversion with lower life satisfaction among depressed individuals.

Decisions of individuals with depression are often risk-averse. Risk-aversion may also extend to decisions regarding treatment, which may cause individuals to forgo or delay treatment. It is also well established that depression is associated with lower satisfaction with life. However, whether life satisfaction is associated with risk aversion for individuals with depression is not yet known. Three groups of participants (Depressed: n = 61; Chronic pain: n = 61; Comorbid depression and pain: n = 58) completed a clinical interview and several self-report questionnaires, including the Satisfaction with Life Scale (SWLS). Participants also completed two utility elicitation tasks: time trade-off (TTO), which measures utilities of health states without implied risks, and standard gamble (SG), which measures utilities of health states in the presence of risk (presented in this study as a hypothetical clinical trial described as having both potential harms and benefits). Risk aversion is defined as the difference in the utility ratings generated via SG and via TTO. For both TTO and SG, individuals evaluated their own depression or pain. When perfect health was used as a hypothetical benefit in TTO and SG tasks, satisfaction with life was not associated with risk preferences, for either depressed participants or participants with chronic pain (all ps ns). However, for participants with depression, when the hypothetical benefit was a more ecologically valid 'mild' depression in TTO and SG tasks, lower satisfaction with life was associated with greater risk aversion (p < .005; p < .03). For depressed individuals, therefore, lower satisfaction with life may be associated with risk aversion regarding treatments when benefits are seen as minor, which may result in treatment avoidance and, consequently, further worsening of both symptoms and life satisfaction.

Increases in stress and adverse childhood experiences are associated with the co-occurrence of anxiety and depression in oncology patients.

PURPOSE: Identify subgroups of patients with distinct joint anxiety AND depression profiles and evaluate for differences in demographic and clinical characteristics, as well as stress, resilience, and coping. DESIGN: Longitudinal study. PARTICIPANTS: Patients (n = 1328) receiving chemotherapy. METHODS: Measures of state anxiety and depression were done six times over two cycles of chemotherapy. All of the other measures were completed prior to second or third cycle of chemotherapy. Latent profile analysis was used to identify the distinct joint anxiety and depression profiles. FINDINGS: Three classes were identified (i.e. Low Anxiety and Low Depression (57.5%); Moderate Anxiety and Moderate Depression (33.7%), High Anxiety and High Depression (8.8%)). For all of the stress measures, a dose response effect was seen among the profiles. Two worst profiles reported higher occurrence rates for a number of adverse childhood experiences. IMPLICATIONS FOR PROVIDERS: Patients need referrals for stress reduction techniques and mental health and social services.

A Revision of Herpes Simplex Virus Type 1 Transcription: First, Repress; Then, Express.

The herpes virus genome bears more than 80 strong transcriptional promoters. Upon entry into the host cell nucleus, these genes are transcribed in an orderly manner, producing five immediate-early (IE) gene products, including ICP0, ICP4, and ICP22, while non-IE genes are mostly silent. The IE gene products are necessary for the transcription of temporal classes following sequentially as early, leaky late, and true late. A recent analysis using precision nuclear run-on followed by deep sequencing (PRO-seq) has revealed an important step preceding all HSV-1 transcription. Specifically, the immediate-early proteins ICP4 and ICP0 enter the cell with the incoming genome to help preclude the nascent antisense, intergenic, and sense transcription of all viral genes. VP16, which is also delivered into the nucleus upon entry, almost immediately reverses this repression on IE genes. The resulting de novo expression of ICP4 and ICP22 further repress antisense, intergenic, and early and late viral gene transcription through different mechanisms before the sequential de-repression of these gene classes later in infection. This early repression, termed transient immediate-early protein-mediated repression (TIEMR), precludes unproductive, antisense, intergenic, and late gene transcription early in infection to ensure the efficient and orderly progression of the viral cascade.

Academic machine learning researchers' ethical perspectives on algorithm development for health care: a qualitative study.

OBJECTIVES: We set out to describe academic machine learning (ML) researchers' ethical considerations regarding the development of ML tools intended for use in clinical care. MATERIALS AND METHODS: We conducted in-depth, semistructured interviews with a sample of ML researchers in medicine (N = 10) as part of a larger study investigating stakeholders' ethical considerations in the translation of ML tools in medicine. We used a qualitative descriptive design, applying conventional qualitative content analysis in order to allow participant perspectives to emerge directly from the data. RESULTS: Every participant viewed their algorithm development work as holding ethical significance. While participants shared positive attitudes toward continued ML innovation, they described concerns related to data sampling and labeling (eg, limitations to mitigating bias; ensuring the validity and integrity of data), and algorithm training and testing (eg, selecting quantitative targets; assessing reproducibility). Participants perceived a need to increase interdisciplinary training across stakeholders and to envision more coordinated and embedded approaches to addressing ethics issues. DISCUSSION AND CONCLUSION: Participants described key areas where increased support for ethics may be needed; technical challenges affecting clinical acceptability; and standards related to scientific integrity, beneficence, and justice that may be higher in medicine compared to other industries engaged in ML innovation. Our results help shed light on the perspectives of ML researchers in medicine regarding the range of ethical issues they encounter or anticipate in their work, including areas where more attention may be needed to support the successful development and integration of medical ML tools.

Herpes simplex virus 1 immediate early transcription initiation, pause-release, elongation, and termination in the presence and absence of ICP4.

IMPORTANCE: Infection with herpes simplex virus 1 (HSV-1) leads to lifelong infection due to the virus's remarkable ability to control transcription of its own genome, resulting in two transcriptional programs: lytic (highly active) and latent (restricted). The lytic program requires immediate early (IE) proteins to first repress transcription of late viral genes, which then undergo sequential de-repression, leading to a specific sequence of gene expression. Here, we show that the IE ICP4 functions to regulate the cascade by limiting RNA polymerase initiation at immediate early times. However, late viral genes that initiate too early in the absence of ICP4 do not yield mRNA as transcription stalls within gene bodies. It follows that other regulatory steps intercede to prevent elongation of genes at the incorrect time, demonstrating the precise control HSV-1 exerts over its own transcription.

Identification of distinct symptom profiles in patients with gynecologic cancers using a pre-specified symptom cluster.

PURPOSE: Pain, fatigue, sleep disturbance, and depression are four of the most common symptoms in patients with gynecologic cancer. The purposes were to identify subgroups of patients with distinct co-occurring pain, fatigue, sleep disturbance, and depression profiles (i.e., pre-specified symptom cluster) in a sample of patients with gynecologic cancer receiving chemotherapy and assess for differences in demographic and clinical characteristics, as well as the severity of other common symptoms and QOL outcomes among these subgroups. METHODS: Patients completed symptom questionnaires prior to their second or third cycle of chemotherapy. Latent profile analysis was used to identify subgroups of patients using the pre-specified symptom cluster. Parametric and nonparametric tests were used to evaluate for differences between the subgroups. RESULTS: In the sample of 233 patients, two distinct latent classes were identified (i.e., low (64.8%) and high (35.2%)) indicating lower and higher levels of symptom burden. Patients in high class were younger, had child care responsibilities, were unemployed, and had a lower annual income. In addition, these women had a higher body mass index, a higher comorbidity burden, and a lower functional status. Patients in the high class reported higher levels of anxiety, as well as lower levels of energy and cognitive function and poorer quality of life scores. CONCLUSIONS: This study identified a number of modifiable and non-modifiable risk factors associated with membership in the high class. Clinicians can use this information to refer patients to dieticians and physical therapists for tailored interventions.

Epigenetic Regulation of Inflammatory Mechanisms and a Psychological Symptom Cluster in Patients Receiving Chemotherapy.

BACKGROUND: A psychological symptom cluster is the most common cluster identified in oncology patients. Although inflammatory mechanisms are hypothesized to underlie this cluster, epigenetic contributions are unknown. OBJECTIVES: This study's purpose was to evaluate associations between the occurrence of a psychological symptom cluster and levels of DNA methylation for inflammatory genes in a heterogeneous sample of patients with cancer receiving chemotherapy. METHODS: Prior to their second or third cycle of chemotherapy, 1,071 patients reported the occurrence of 38 symptoms using the Memorial Symptom Assessment Scale. A psychological cluster was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using Illumina Infinium 450K and EPIC microarrays. Expression-associated CpG (eCpG) loci in the promoter region of 114 inflammatory genes on the 450K and 112 genes on the EPIC microarray were evaluated for associations with the psychological cluster. Robust rank aggregation was used to identify differentially methylated genes across both samples. Significance was assessed using a false discovery rate of 0.05 under the Benjamini-Hochberg procedure. RESULTS: Cluster of differentiation 40 ( CD40 ) was differentially methylated across both samples. All six promoter eCpGs for CD40 that were identified across both samples were hypomethylated in the psychological cluster group. CONCLUSIONS: This study is the first to suggest associations between a psychological symptom cluster and differential DNA methylation of a gene involved in tissue inflammation and cell-mediated immunity. Our findings suggest that increased CD40 expression through hypomethylation of promoter eCpG loci is involved in the occurrence of a psychological symptom cluster in patients receiving chemotherapy. These findings suggest a direction for mechanistic studies.

Reactivation of Epstein-Barr Virus from Latency Involves Increased RNA Polymerase Activity at CTCF Binding Sites on the Viral Genome.

The ability of Epstein-Barr virus (EBV) to switch between latent and lytic infection is key to its long-term persistence, yet the molecular mechanisms behind this switch remain unclear. To investigate transcriptional events during the latent-to-lytic switch, we utilized Precision nuclear Run On followed by deep Sequencing (PRO-Seq) to map cellular RNA polymerase (Pol) activity to single-nucleotide resolution on the host and EBV genome in three different models of EBV latency and reactivation. In latently infected Mutu-I Burkitt lymphoma (BL) cells, Pol activity was enriched at the Qp promoter, the EBER region, and the BHLF1/LF3 transcripts. Upon reactivation with phorbol ester and sodium butyrate, early-phase Pol activity occurred bidirectionally at CTCF sites within the LMP-2A, EBER-1, and RPMS1 loci. PRO-Seq analysis of Akata cells reactivated from latency with anti-IgG and a lymphoblastoid cell line (LCL) reactivated with small molecule C60 showed a similar pattern of early bidirectional transcription initiating around CTCF binding sites, although the specific CTCF sites and viral genes were different for each latency model. The functional importance of CTCF binding, transcription, and reactivation was confirmed using an EBV mutant lacking the LMP-2A CTCF binding site. This virus was unable to reactivate and had disrupted Pol activity at multiple CTCF binding sites relative to the wild-type (WT) virus. Overall, these data suggest that CTCF regulates the viral early transcripts during reactivation from latency. These activities likely help maintain the accessibility of the viral genome to initiate productive replication. IMPORTANCE The ability of EBV to switch between latent and lytic infection is key to its long-term persistence in memory B cells, and its ability to persist in proliferating cells is strongly linked to oncogenesis. During latency, most viral genes are epigenetically silenced, and the virus must overcome this repression to reactivate lytic replication. Reactivation occurs once the immediate early (IE) EBV lytic genes are expressed. However, the molecular mechanisms behind the switch from the latent transcriptional program to begin transcription of the IE genes remain unknown. In this study, we mapped RNA Pol positioning and activity during latency and reactivation. Unexpectedly, Pol activity accumulated at distinct regions characteristic of transcription initiation on the EBV genome previously shown to be associated with CTCF. We propose that CTCF binding at these regions retains Pol to maintain a stable latent chromosome conformation and a rapid response to various reactivation signals.

Associations Between Demographic, Clinical, and Symptom Characteristics and Stress in Oncology Patients Receiving Chemotherapy.

BACKGROUND: Patients undergoing cancer treatment experience global stress and cancer-specific stress. Both types of stress are associated with a higher symptom burden. OBJECTIVE: In this cross-sectional study, we used a comprehensive set of demographic, clinical, and symptom characteristics to evaluate their relative contribution to the severity of global and cancer-specific stress. METHODS: Patients (N = 941) completed study questionnaires before their second or third cycle of chemotherapy. RESULTS: Consistent with our a priori hypothesis, we found both common and distinct characteristics associated with higher levels of global stress and cancer-specific stress. A significant proportion of our patients had scores on the Impact of Event Scale-Revised suggestive of subsyndromal (29.4%) or probable (13.9%) posttraumatic stress disorder. Four of the 5 stepwise linear regression analyses for the various stress scales explained between 41.6% and 54.5% of the total variance. Compared with various demographic and clinical characteristics, many of the common symptoms associated with cancer and its treatments uniquely explained a higher percentage of the variance in the various stress scales. Symptoms of depression made the largest unique contribution to the percentage of total explained variance across all 5 scales. CONCLUSION: Clinicians need to assess for global stress, cancer-specific stress, and depression in patients receiving chemotherapy. IMPLICATIONS FOR PRACTICE: Patients may benefit from integrative interventions (eg, mindfulness-based stress reduction, cognitive behavioral therapy, acupuncture) that simultaneously address stress and symptoms commonly associated with cancer and its treatments.

Physicians' and Machine Learning Researchers' Perspectives on Ethical Issues in the Early Development of Clinical Machine Learning Tools: Qualitative Interview Study.

BACKGROUND: Innovative tools leveraging artificial intelligence (AI) and machine learning (ML) are rapidly being developed for medicine, with new applications emerging in prediction, diagnosis, and treatment across a range of illnesses, patient populations, and clinical procedures. One barrier for successful innovation is the scarcity of research in the current literature seeking and analyzing the views of AI or ML researchers and physicians to support ethical guidance. OBJECTIVE: This study aims to describe, using a qualitative approach, the landscape of ethical issues that AI or ML researchers and physicians with professional exposure to AI or ML tools observe or anticipate in the development and use of AI and ML in medicine. METHODS: Semistructured interviews were used to facilitate in-depth, open-ended discussion, and a purposeful sampling technique was used to identify and recruit participants. We conducted 21 semistructured interviews with a purposeful sample of AI and ML researchers (n=10) and physicians (n=11). We asked interviewees about their views regarding ethical considerations related to the adoption of AI and ML in medicine. Interviews were transcribed and deidentified by members of our research team. Data analysis was guided by the principles of qualitative content analysis. This approach, in which transcribed data is broken down into descriptive units that are named and sorted based on their content, allows for the inductive emergence of codes directly from the data set. RESULTS: Notably, both researchers and physicians articulated concerns regarding how AI and ML innovations are shaped in their early development (ie, the problem formulation stage). Considerations encompassed the assessment of research priorities and motivations, clarity and centeredness of clinical needs, professional and demographic diversity of research teams, and interdisciplinary knowledge generation and collaboration. Phase-1 ethical issues identified by interviewees were notably interdisciplinary in nature and invited questions regarding how to align priorities and values across disciplines and ensure clinical value throughout the development and implementation of medical AI and ML. Relatedly, interviewees suggested interdisciplinary solutions to these issues, for example, more resources to support knowledge generation and collaboration between developers and physicians, engagement with a broader range of stakeholders, and efforts to increase diversity in research broadly and within individual teams. CONCLUSIONS: These qualitative findings help elucidate several ethical challenges anticipated or encountered in AI and ML for health care. Our study is unique in that its use of open-ended questions allowed interviewees to explore their sentiments and perspectives without overreliance on implicit assumptions about what AI and ML currently are or are not. This analysis, however, does not include the perspectives of other relevant stakeholder groups, such as patients, ethicists, industry researchers or representatives, or other health care professionals beyond physicians. Additional qualitative and quantitative research is needed to reproduce and build on these findings.

Risk factors for worse anxiety trajectories among patients undergoing cancer chemotherapy.

PURPOSE: Patients undergoing chemotherapy for cancer often experience heightened anxiety. While receipt of chemotherapy occurs over multiple cycles, limited research has examined anxiety longitudinally. The purposes of this study, in a large sample of patients with breast, gynecological, gastrointestinal, or lung cancer, were to evaluate, over the course of two cycles of chemotherapy, for inter-individual differences in the trajectories of anxiety and identify associations between demographic, clinical, symptom, and psychological adjustment characteristics and initial levels and trajectories of anxiety. METHODS: Patients with breast, gynecologic, lung, or gastrointestinal cancer (n = 1323) were assessed with the Spielberger State Anxiety Inventory (STAI-S) six times over two cycles of chemotherapy. At enrollment, patients completed self-report instruments assessing demographic, symptom, stress, and coping characteristics. We used hierarchical linear modeling to identify risk factors associated with initial levels and trajectories of state anxiety. RESULTS: Inter-individual differences in initial levels of anxiety were associated with functional status, sleep disturbance, morning fatigue, cognitive function, global and cancer-specific stress, resilience, and several coping characteristics (i.e., sense of coherence, acceptance, using emotional support, self-distraction, denial, venting, and self-blame). Demographic and clinical characteristics associated with interindividual differences in anxiety trajectories were age, employment status, and MAX-2 score. CONCLUSION: This study provides novel data on the course and predictors of anxiety during two cycles of chemotherapy among a large sample of patients with varied cancer types. Further research focused on risk factors for heightened levels of anxiety during chemotherapy may help point toward more effective interventions for this commonly experienced symptom.

Anxiety trajectories: An observational study of women undergoing chemotherapy for breast or gynecological cancer.

BACKGROUND: While anxiety is prevalent among women who undergo chemotherapy for breast or gynecologic cancer, research on its predictors has focused primarily on cross-sectional evaluations or on assessments of anxiety prior to and after receipt of chemotherapy. Few studies have evaluated for predictors of inter-individual variability in levels of anxiety during chemotherapy. This study evaluated for inter-individual differences in anxiety across two cycles of chemotherapy and identified demographic, clinical, symptom, and psychological adjustment (e.g., stress, coping) characteristics associated with initial levels and trajectories of anxiety. METHODS: Patients with breast (n = 530) or gynecologic (n = 233) cancer completed the Spielberger State Anxiety Inventory six times over two cycles of chemotherapy. At enrollment, self-report measures were used to assess demographic, symptom, stress, and coping characteristics. Hierarchical linear modeling was used to evaluate for risk factors associated with initial levels and trajectories of state anxiety. RESULTS: At enrollment, demographic, clinical, symptom, and psychological adjustment characteristics associated with inter-individual differences of anxiety were: marital status, functional status, sleep disturbance, cognitive function, global stress, cancer-specific stress, resilience, sense of coherence, and the coping strategies of venting and self-blame. Employment status and morning fatigue were the only characteristics associated with inter-individual differences in the trajectories of anxiety. Denial was the only characteristic associated with both initial levels and the trajectories of anxiety. CONCLUSIONS: A variety of patient characteristics predicted initial levels of anxiety. Fewer characteristics predicted trajectories of anxiety. Identification of specific risk factors, such as avoidant coping, suggests the need for targeted interventions among higher-risk patients.

Immediate Early Proteins of Herpes Simplex Virus Transiently Repress Viral Transcription before Subsequent Activation.

Herpes simplex virus 1 (HSV-1) utilizes cellular RNA polymerase II (Pol) to transcribe its genes in one of two phases. In the latent phase, viral transcription is highly restricted, but during the productive lytic phase, more than 80 genes are expressed in a temporally coordinated cascade. In this study, we used Precision nuclear Run On followed by deep Sequencing (PRO-Seq) to characterize early viral transcriptional events using HSV-1 immediate early (IE) gene mutants, corresponding genetically repaired viruses, and wild-type virus. Unexpectedly, in the absence of the IE genes ICP4, ICP22, and ICP0 at 1.5 hours postinfection (hpi), we observed high levels of aberrant transcriptional activity across the mutant viral genomes but substantially less on either wild-type or the congenic repaired virus genomes. This feature was particularly prominent in the absence of ICP4 expression. Cycloheximide treatment during infection with both the ICP4 and ICP22 mutants and their respective genetic repairs did not alter the relative distribution of Pol activity, but it increased overall activity across both viral genomes, indicating that both virion components and at least some de novo protein synthesis were required for full repression. Overall, these data reveal that prior to their role in transcriptional activation, IE gene products and virion components first repress transcription and that the HSV-1 lytic transcriptional cascade is mediated through subsequent derepression steps. IMPORTANCE HSV-1 transcription during productive replication is believed to comprise a series of activation steps leading to a specific sequence of gene expression. Here, we show that virion components and IE gene products ICP0, ICP4, and ICP22 first repress viral gene transcription to various degrees before subsequently activating specific gene subsets. It follows that the entire HSV transcriptional program involves a series of steps to sequentially reverse this repression. This previously uncharacterized repressive activity of IE genes very early in infection may represent an important checkpoint allowing HSV-1 to orchestrate either the robust lytic transcriptional cascade or the more restricted transcriptional program during latency.

Oncology outpatients with worse depression and sleep disturbance profiles are at increased risk for a higher symptom burden and poorer quality of life outcomes.

OBJECTIVE: /Background - Depression and sleep disturbance are significant problems during chemotherapy. Study purposes were to identify subgroups of patients with distinct joint depression AND sleep disturbance profiles and evaluate for differences in demographic and clinical characteristics, severity of symptoms, and quality of life (QOL) outcomes among these subgroups. PATIENTS/METHODS: Oncology outpatients (n = 1331) completed measures of depression and sleep disturbance six times over two chemotherapy cycles. Latent profile analysis, that modeled the two symptoms together, was done to identify the distinct joint depression and sleep disturbance profiles. RESULTS: Five distinct profiles were identified (i.e., no depression or sleep disturbance (None, 21.4%); no depression and moderate sleep disturbance (32.3%); subsyndromal depression and very high sleep disturbance (20.4%); moderate depression and moderate sleep disturbance (17.7%); and high depression and very high sleep disturbance (8.2%)). Compared to the None class, the other four classes were more likely to be female; less likely to be employed; had a higher comorbidity burden; and had a lower functional status. Patients in the two very high sleep disturbance classes had problems with both sleep initiation and maintenance. These patients reported higher levels of depressive symptoms, trait and state anxiety, and fatigue as well as lower levels of energy, cognitive function, and poorer QOL. CONCLUSIONS: Over 45% of the patients had subsyndromal to high levels of depression AND moderate or very high levels of sleep disturbance. Characteristics associated with the higher risk profiles can be used to screen patients at increased risk for both symptoms.

Influence of Dispositional Optimism on Ethically Salient Research Perspectives: A Pilot Study.

Research participants should be drawn as fairly as possible from the potential volunteer population. Underlying personality traits are underexplored as factors influencing research decision-making. Dispositional optimism, known to affect coping, physical health, and psychological well-being, has been minimally studied with respect to research-related attitudes. We conducted an exploratory, online survey with 151 individuals (with self-reported mental illness [n = 50], physical illness [n = 51], or neither [n = 50]) recruited via MTurk. We evaluated associations between dispositional optimism (assessed with the Life Orientation Test-Revised) and general research attitudes, perceived protectiveness of five research safeguards, and willingness to participate in research using safeguards. Strongly optimistic respondents expressed more positive research attitudes and perceived four safeguards as more positively influencing willingness to participate. Optimism was positively associated with expressed willingness to participate in clinical research. Our findings add to a limited literature on the influence of individual traits on ethically salient research perspectives.

A high stress profile is associated with severe pain in oncology patients receiving chemotherapy.

PURPOSE: Oncology patients receiving chemotherapy can experience both cancer and non-cancer pain. In addition, oncology patients face numerous stressors and their responses are highly variable. Stress and pain are intricately linked. The purpose of this study was to evaluate for differences in pain characteristics and mood disturbance among oncology patients with distinct stress profiles. METHODS: From a sample of 957 patients with and without pain, latent profile analysis identified three groups of patients with distinct stress profiles (i.e., Stressed, Normative, Resilient). In the subset of 671 patients with pain, receiving chemotherapy for breast, lung, gastrointestinal, or gynecologic cancer, we evaluated for differences among the stress profiles in terms of pain characteristics (e.g., intensity, qualities, interference) and mood disturbance (anxiety, depressive symptoms). RESULTS: Compared to Normative patients (n = 333; 49.6%), Stressed patients (n = 305; 45.5%) reported higher levels of pain intensity, pain interference, anxiety, and depressive symptoms and more commonly described pain as throbbing, shooting, burning, exhausting, tiring, penetrating, nagging, miserable, and unbearable. Compared to Resilient patients (n = 33; 4.9%), Stressed patients reported significantly higher mood-related pain interference scores and more severe anxiety and depressive symptoms. CONCLUSIONS: A high stress profile is common (45.5%) and is associated with more severe pain and associated symptoms. Efforts to identify and target this group for interventions may improve patient outcomes.

Higher stress and symptom severity are associated with worse depressive symptom profiles in patients receiving chemotherapy.

PURPOSE: In a sample of oncology patients, identify subgroups of patients with distinct depressive symptom profiles and evaluate for differences in demographic and clinical characteristics, levels of stress and resilience, and the severity of common co-occurring symptoms. METHODS: Patients (n = 1327) had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; and were scheduled to receive at least two additional cycles of chemotherapy. Demographic and clinical characteristics, stress, resilience, and co-occurring symptoms were evaluated at enrollment. Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CES-D) scale a total of six times over two cycles of chemotherapy. Latent profile analysis (LPA) was used to identify subgroups of patients (i.e., latent classes) with distinct depressive symptom profiles using the six CES-D scores. RESULTS: Based on the findings from the LPA, 47.3% of the patients were classified as "None"; 33.6% as "Subsyndromal"; 13.8% as "Moderate"; and 5.3% as "High". Compared to None class, patients in the Subsyndromal, Moderate, and High classes had a lower functional status, a higher comorbidity burden, and a self-reported diagnosis of depression or back pain. Those patients with higher levels of depressive symptoms reported higher levels of stress, lower levels of resilience, and increased severity of co-occurring symptoms. CONCLUSIONS: Inter-individual variability in depressive symptoms was associated with demographic and clinical characteristics, multiple types of stress and levels of resilience, as well as with the increased severity of multiple co-occurring symptoms. The risk factors associated with worse depressive symptom profiles can assist clinicians to identify high risk patients and initiate more timely supportive care interventions.

Stem cell-derived porcine macrophages as a new platform for studying host-pathogen interactions.

BACKGROUND: Infectious diseases of farmed and wild animals pose a recurrent threat to food security and human health. The macrophage, a key component of the innate immune system, is the first line of defence against many infectious agents and plays a major role in shaping the adaptive immune response. However, this phagocyte is a target and host for many pathogens. Understanding the molecular basis of interactions between macrophages and pathogens is therefore crucial for the development of effective strategies to combat important infectious diseases. RESULTS: We explored how porcine pluripotent stem cells (PSCs) can provide a limitless in vitro supply of genetically and experimentally tractable macrophages. Porcine PSC-derived macrophages (PSCdMs) exhibited molecular and functional characteristics of ex vivo primary macrophages and were productively infected by pig pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV), two of the most economically important and devastating viruses in pig farming. Moreover, porcine PSCdMs were readily amenable to genetic modification by CRISPR/Cas9 gene editing applied either in parental stem cells or directly in the macrophages by lentiviral vector transduction. CONCLUSIONS: We show that porcine PSCdMs exhibit key macrophage characteristics, including infection by a range of commercially relevant pig pathogens. In addition, genetic engineering of PSCs and PSCdMs affords new opportunities for functional analysis of macrophage biology in an important livestock species. PSCs and differentiated derivatives should therefore represent a useful and ethical experimental platform to investigate the genetic and molecular basis of host-pathogen interactions in pigs, and also have wider applications in livestock.

ICP22 of Herpes Simplex Virus 1 Decreases RNA Polymerase Processivity.

To determine the role of ICP22 in transcription, we performed precise nuclear run-on followed by deep sequencing (PRO-seq) and global nuclear run-on with sequencing (GRO-seq) in cells infected with a viral mutant lacking the entire ICP22-encoding α22 (US1/US1.5) gene and a virus derived from this mutant bearing a restored α22 gene. At 3 h postinfection (hpi), the lack of ICP22 reduced RNA polymerase (Pol) promoter proximal pausing (PPP) on the immediate early α4, α0, and α27 genes. Diminished PPP at these sites accompanied increased Pol processivity across the entire herpes simplex virus 1 (HSV-1) genome in GRO-seq assays, resulting in substantial increases in antisense and intergenic transcription. The diminished PPP on α gene promoters at 3 hpi was distinguishable from effects caused by treatment with a viral DNA polymerase inhibitor at this time. The ICP22 mutant had multiple defects at 6 hpi, including lower viral DNA replication, reduced Pol activity on viral genes, and increased Pol activity on cellular genes. The lack of ICP22 also increased PPP release from most cellular genes, while a minority of cellular genes exhibited decreased PPP release. Taken together, these data indicate that ICP22 acts to negatively regulate transcriptional elongation on viral genes in part to limit antisense and intergenic transcription on the highly compact viral genome. This regulatory function directly or indirectly helps to retain Pol activity on the viral genome later in infection. IMPORTANCE The longstanding observation that ICP22 reduces RNA polymerase II (Pol II) serine 2 phosphorylation, which initiates transcriptional elongation, is puzzling because this phosphorylation is essential for viral replication. The current study helps explain this apparent paradox because it demonstrates significant advantages in negatively regulating transcriptional elongation, including the reduction of antisense and intergenic transcription. Delays in elongation would be expected to facilitate the ordered assembly and functions of transcriptional initiation, elongation, and termination complexes. Such limiting functions are likely to be important in herpesvirus genomes that are otherwise highly transcriptionally active and compact, comprising mostly short, intronless genes near neighboring genes of opposite sense and containing numerous 3'-nested sets of genes that share transcriptional termination signals but differ at transcriptional start sites on the same template strand.

Stakeholders' Perspectives regarding Participation in Neuromodulation-Based Dementia Intervention Research.

This study evaluated stakeholders' perspectives regarding participation in two hypothetical neuromodulation trials focused on individuals with Alzheimer's disease and related disorders (ADRDs). Stakeholders (i.e., individuals at risk for ADRDs [n = 56], individuals with experience as a caregiver for someone with a cognitive disorder [n = 60], and comparison respondents [n = 124]) were recruited via MTurk. Primary outcomes were willingness to enroll (or enroll one's loved one), feeling lucky to have the opportunity to enroll, and feeling obligated to enroll in two protocols (transcranial magnetic stimulation, TMS; deep brain stimulation, DBS). Relative to the Comparison group, the At Risk group endorsed higher levels of "feeling lucky" regarding both research protocols, and higher willingness to participate in the TMS protocol. These findings provide tentative reassurance regarding the nature of decision making regarding neurotechnology-based research on ADRDs. Further work is needed to evaluate the full range of potential influences on research participation.