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How did mental healthcare utilization change during the COVID-19 pandemic period among individuals with pre-existing mental disorder? Understanding utilization patterns of these at-risk individuals and identifying those most likely to exhibit increased utilization could improve patient stratification and efficient delivery of mental health services. This study leveraged large-scale electronic health record (EHR) data to describe mental healthcare utilization patterns among individuals with pre-existing mental disorder before and during the COVID-19 pandemic and identify correlates of high mental healthcare utilization. Using EHR data from a large healthcare system in Massachusetts, we identified three "pre-existing mental disorder" groups (PMD) based on having a documented mental disorder diagnosis within the 6 months prior to the March 2020 lockdown, related to: (1) stress-related disorders (e.g., depression, anxiety) (N = 115,849), (2) serious mental illness (e.g., schizophrenia, bipolar disorders) (N = 11,530), or (3) compulsive behavior disorders (e.g., eating disorder, OCD) (N = 5,893). We also identified a "historical comparison" group (HC) for each PMD (N = 113,604, 11,758, and 5,387, respectively) from the previous year (2019). We assessed the monthly number of mental healthcare visits from March 13 to December 31 for PMDs in 2020 and HCs in 2019. Phenome-wide association analyses (PheWAS) were used to identify clinical correlates of high mental healthcare utilization. We found the overall number of mental healthcare visits per patient during the pandemic period in 2020 was 10-12% higher than in 2019. The majority of increased visits was driven by a subset of high mental healthcare utilizers (top decile). PheWAS results indicated that correlates of high utilization (prior mental disorders, chronic pain, insomnia, viral hepatitis C, etc.) were largely similar before and during the pandemic, though several conditions (e.g., back pain) were associated with high utilization only during the pandemic. Limitations included that we were not able to examine other risk factors previously shown to influence mental health during the pandemic (e.g., social support, discrimination) due to lack of social determinants of health information in EHR data. Mental healthcare utilization among patients with pre-existing mental disorder increased overall during the pandemic, likely due to expanded access to telemedicine. Given that clinical correlates of high mental healthcare utilization in a major hospital system were largely similar before and during the COVID-19 pandemic, resource stratification based on known risk factor profiles may aid hospitals in responding to heightened mental healthcare needs during a pandemic., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JWS is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity), and has received grant support from Biogen, Inc. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objective: This study examined the potential influence of pre-pandemic psychological resilience on use of approach or avoidant coping styles and strategies to manage stress during the COVID-19 pandemic. We hypothesized that higher resilience would be associated with more approach coping and less avoidant coping., Design and Methods: Longitudinal cohort data were from the Nurses' Health Study II, including 13,143 female current and former healthcare professionals with pre-pandemic lifetime trauma. Pre-pandemic resilience was assessed between 2018-2019 and current coping during the outbreak of the pandemic in the United States (May-August 2020). Multiple linear regression model results identified associations between continuous pre-pandemic resilience scores and use of approach and avoidant coping styles, as well as individual coping strategies, adjusting for relevant covariates., Results: Greater resilience was associated with higher use of approach coping (ß = 0.06, 95% CI 0.05, 0.08) and lower use of avoidant coping styles (ß = -0.39, 95% CI -0.41, -0.38). Higher pre-pandemic resilience was also associated with use of eight (distraction [ß = -0.18, 95% CI -0.20, -0.16], substance use [ß = -0.15, 95% CI -0.17, -0.13], behavioral disengagement [ß = -0.29, 95% CI -0.30, -0.27], self-blame [ß = -0.44, 95% CI -0.45, -0.42], emotional support (ß = 0.03, 95% CI 0.01, 0.05), positive reframing [ß = 0.13, 95% CI 0.12, 0.15], humor [ß = 0.03, 95% CI 0.01, 0.05] and religion [ß = 0.06, 95% CI 0.04, 0.08]) of the nine coping strategies in expected directions., Conclusion: Findings have important implications for intervention or even prevention efforts to support vulnerable groups, such as women with prior trauma histories, during this and other immensely stressful times. Supporting or building psychological resilience following trauma may promote effective coping in times of future stress., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Scoglio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pregnant and postpartum women face unique challenges during the COVID-19 pandemic that may put them at elevated risk of mental health problems. However, few large-scale and no cross-national studies have been conducted to date that investigate modifiable pandemic-related behavioral or cognitive factors that may influence mental health in this vulnerable group. This international study sought to identify and measure the associations between pandemic-related information seeking, worries, and prevention behaviors on perinatal mental health during the COVID-19 pandemic. An anonymous, online, cross-sectional survey of pregnant and postpartum women was conducted in 64 countries between May 26, 2020 and June 13, 2020. The survey, available in twelve languages, was hosted on the Pregistry platform for COVID-19 studies (https://corona.pregistry.com) and advertised in social media channels and online parenting forums. Participants completed measures on demographics, COVID-19 exposure and worries, information seeking, COVID-19 prevention behaviors, and mental health symptoms including posttraumatic stress via the IES-6, anxiety/depression via the PHQ-4, and loneliness via the UCLA-3. Of the 6,894 participants, substantial proportions of women scored at or above the cut-offs for elevated posttraumatic stress (2,979 [43%]), anxiety/depression (2,138 [31%], and loneliness (3,691 [53%]). Information seeking from any source (e.g., social media, news, talking to others) five or more times per day was associated with more than twice the odds of elevated posttraumatic stress and anxiety/depression, in adjusted models. A majority of women (86%) reported being somewhat or very worried about COVID-19. The most commonly reported worries were related to pregnancy and delivery, including family being unable to visit after delivery (59%), the baby contracting COVID-19 (59%), lack of a support person during delivery (55%), and COVID-19 causing changes to the delivery plan (41%). Greater worries related to children (i.e., inadequate childcare, their infection risk) and missing medical appointments were associated with significantly higher odds of posttraumatic stress, anxiety/depression and loneliness. Engaging in hygiene-related COVID-19 prevention behaviors (face mask-wearing, washing hands, disinfecting surfaces) were not related to mental health symptoms or loneliness. Elevated posttraumatic stress, anxiety/depression, and loneliness are highly prevalent in pregnant and postpartum women across 64 countries during the COVID-19 pandemic. Excessive information seeking and worries related to children and medical care are associated with elevated symptoms, whereas engaging in hygiene-related preventive measures were not. In addition to screening and monitoring mental health symptoms, addressing excessive information seeking and women's worries about access to medical care and their children's well-being, and developing strategies to target loneliness (e.g., online support groups) should be part of intervention efforts for perinatal women. Public health campaigns and medical care systems need to explicitly address the impact of COVID-19 related stressors on mental health in perinatal women, as prevention of viral exposure itself does not mitigate the pandemic's mental health impact., Competing Interests: The authors have declared that no competing interests exist.

Regulation of cell junctions is crucial for the integrity of epithelial tissues and organs. Cell junctions also play roles in controlling cell proliferation for organ growth. Translationally controlled tumor protein (TCTP) is a conserved protein involved in growth control, but its role in cell junctions is unknown. Here we show that Drosophila Tctp directly interacts with the septate junction protein Coracle (Cora) to regulate epithelial integrity and organ growth. Tctp localizes together with Cora in the epidermis of the embryo. Loss of Cora reduces the level of Tctp in the epidermis but not vice versa. cora/+ or Tctp/+ single heterozygotes develop normally to adulthood. However, double heterozygotes for cora and Tctp mutations show severe disruption of epithelia causing synthetic lethality in the embryo. Double knockdown of Cora and Tctp in eye imaginal disc synergistically leads to disruption of the eye disc, resulting in a severe reduction or loss of eye and head. Conversely, double knockdown of Cora and Tctp in wing disc causes overgrowth as well as cell death. Inhibition of cell death under this condition causes hyperplastic growth of the wing disc. Tctp also shows direct and functional interaction with Cora-associated factors like Yurt and Na+/K+-ATPase. This study suggests that proper levels of Tctp and Cora are essential for the maintenance of the Cora complex and the integrity of epithelia. Our data also provide evidence that both Cora and Tctp are required to suppress overgrowth in developing wing., Competing Interests: The authors have declared that no competing interests exist.

Depressive symptoms are related to abnormalities in the autonomic nervous system (ANS), and physiological signals that can be used to measure and evaluate such abnormalities have previously been used as indicators for diagnosing mental disorder, such as major depressive disorder (MDD). In this study, we investigate the feasibility of developing an objective measure of depressive symptoms that is based on examining physiological abnormalities in individuals when they are experiencing mental stress. To perform this, we recruited 30 patients with MDD and 31 healthy controls. Then, skin conductance (SC) was measured during five 5-min experimental phases, comprising baseline, mental stress, recovery from the stress, relaxation, and recovery from the relaxation, respectively. For each phase, the mean amplitude of the skin conductance level (MSCL), standard deviations of the SCL (SDSCL), slope of the SCL (SSCL), mean amplitude of the non-specific skin conductance responses (MSCR), number of non-specific skin conductance responses (NSCR), and power spectral density (PSD) were evaluated from the SC signals, producing 30 parameters overall (six features for each phase). These features were used as input data for a support vector machine (SVM) algorithm designed to distinguish MDD patients from healthy controls based on their physiological responses. Statistical tests showed that the main effect of task was significant in all SC features, and the main effect of group was significant in MSCL, SDSCL, SSCL, and PSD. In addition, the proposed algorithm achieved 70% accuracy, 70% sensitivity, 71% specificity, 70% positive predictive value, 71% negative predictive value in classifying MDD patients and healthy controls. These results demonstrated that it is possible to extract meaningful features that reflect changes in ANS responses to various stimuli. Using these features, detection of MDD was feasible, suggesting that SC analysis has great potential for future diagnostics and prediction of depression based on objective interpretation of depressive states., Competing Interests: The authors have declared that no competing interests exist.

Background: A family history can be a valuable tool in the era of precision medicine. Although a few studies have described an association of family history of lung cancer with EGFR activating mutation, their impact on survival of lung cancer patients is unclear., Methods: The study included consecutive 829 non-small-cell lung cancer patients who received analysis of EGFR mutation in a prospective lung cancer cohort. Family history of lung cancer was obtained by face-to-face interviews at the time of diagnosis. An association of EGFR activating mutation with a family history of lung cancer in first-degree relatives was evaluated with multivariate logistic regression analysis, and its association with survival was estimated with Cox's proportional hazards model., Results: Seventy five (9.0%) patients had family history of lung cancer. The EGFR mutation was commonly observed in patients with positive family history compared to those with no family history (46.7% v 31.3%, χ2 p = 0.007). The family history was significantly associated with the EGFR mutation (aOR and 95% CI: 2.01 and 1.18-3.60, p = 0.011). Patients with the positive family history survived longer compared to those without (MST, 17.9 v 13.0 months, log-rank p = 0.037). The presence of the EGFR mutation was associated with better survival in patients without the family history (aHR and 95% CI: 0.72 and 0.57-0.90, p = 0.005). However, this prognostic impact was not observed in patients with the positive family history (aHR and 95% CI: 1.01 and 0.50-2.36, p = 0.832)., Conclusions: In comparison to patients without the family history, EGFR activating mutation was common, and it did not affect prognosis in patients with positive family history.

Background: We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1) / Receptor-for-Advanced-Glycation-End-products (RAGE) signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB)., Methods: A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80); age-and-sex matched asymptomatic individuals (tested for latent TB) were used for comparison (n = 45). Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA) of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients' PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan) for cytokine induction ex vivo., Results: In active PTB, plasma IL-8/CXCL8 [median(IQR), 6.0(3.6-15.1) vs 3.6(3.6-3.6) pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001), severity-score (rs +0.317, P = 0.004), and fever and hospitalization durations (rs +0.407, P<0.001). IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02-1.23 per unit increase, P = 0.021) and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08-1.87, P = 0.012) concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2-2.8 fold). Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1) and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034). Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α) when combined with lipoarabinomannan., Conclusion: In patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important roles in pathogenesis and disease manifestations. Our clinico-immunological data can provide basis for the development of new strategies for disease monitoring, management and control.

The Drosophila eye-antenna imaginal disc (ead) is a flattened sac of two-layered epithelia, from which most head structures are derived. Secreted morphogens like Wingless (Wg), Hedgehog (Hh), and Decapentaplegic (Dpp) are important for early patterning of ead, but the underlying mechanisms are still largely unknown. To understand how these morphogens function in the ead of early larval stages, we used wg-LacZ and dpp-Gal4 markers for the examination of wild-type and mutant eads. We found that the ead immediately after hatching was crescent-shaped with the Bolwig's nerve at the ventral edge, suggesting that it consists of dorsal domain. In a subsequent step, transcriptional induction of dpp in the cells along the Bolwig's nerve was followed by rapid growth of the ventral domain. Both Wg and Hh were required for the formation of the ventral domain. Wg was crucial for the growth of the entire ead, but Hh was essential for cell division only in the dorsal domain. In the ventral domain, Hh regulated dpp transcription. Based on these data, we propose that signaling among distinct groups of cells expressing Wg, Dpp, or Hh in the ead of the first-instar larvae are critical for coordinated growth and patterning of ead.

The coordinated regulation of cell fate and cell survival is crucial for normal pattern formation in developing organisms. In Drosophila compound eye development, crystalline arrays of hexagonal ommatidia are established by precise assembly of diverse cell types, including the photoreceptor cells, cone cells and interommatidial (IOM) pigment cells. The molecular basis for controlling the number of cone and IOM pigment cells during ommatidial pattern formation is not well understood. Here we present evidence that BarH1 and BarH2 homeobox genes are essential for eye patterning by inhibiting excess cone cell differentiation and promoting programmed death of IOM cells. Specifically, we show that loss of Bar from the undifferentiated retinal precursor cells leads to ectopic expression of Prospero and dPax2, two transcription factors essential for cone cell specification, resulting in excess cone cell differentiation. We also show that loss of Bar causes ectopic expression of the TGFβ homolog Decapentaplegic (Dpp) posterior to the morphogenetic furrow in the larval eye imaginal disc. The ectopic Dpp expression is not responsible for the formation of excess cone cells in Bar loss-of-function mutant eyes. Instead, it causes reduction in IOM cell death in the pupal stage by antagonizing the function of pro-apoptotic gene reaper. Taken together, this study suggests a novel regulatory mechanism in the control of developmental cell death in which the repression of Dpp by Bar in larval eye disc is essential for IOM cell death in pupal retina.

Perception of temperature is an important brain function for organisms to survive. Evidence suggests that temperature preference behavior (TPB) in Drosophila melanogaster, one of poikilothermal animals, is regulated by cAMP-dependent protein kinase (PKA) signaling in mushroom bodies of the brain. However, downstream targets for the PKA signaling in this behavior have not been identified. From a genome-wide search for the genes regulated by PKA activity in the mushroom bodies, we identified the cyp6a17 Cytochrome P450 gene as a new target for PKA. Our detailed analysis of mutants by genetic, molecular and behavioral assays shows that cyp6a17 is essential for temperature preference behavior. cyp6a17 expression is enriched in the mushroom bodies of the adult brain. Tissue-specific knockdown and rescue experiments demonstrate that cyp6a17 is required in the mushroom bodies for normal temperature preference behavior. This is the first study, to our knowledge, to show PKA-dependent expression of a cytochrome P450 gene in the mushroom bodies and its role as a key factor for temperature preference behavior. Taken together, this study reveals a new PKA-Cytochrome P450 pathway that regulates the temperature preference behavior., (© 2011 Kang et al.)

Background: Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis., Methods: Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed., Results: 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course., Conclusions: A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.