The Behavior and Mind Health (BeMIND) study: Methods, design and baseline sample characteristics of a cohort study among adolescents and young adults

Objectives: The Behavior and Mind Health (BeMIND) study is a population‐based cohort study of adolescents and young adults from Dresden, Germany. The aim is to investigate psychological and behavioral factors linked to a range of mental disorders and health behaviors and their interaction with social‐environmental and genetic/biologic factors. Methods: A random sample of 14–21 year olds was drawn from the population registry in 2015. The baseline investigation was completed 11/2015–12/2016 (N = 1,180). Assessments include standardized diagnostic interview, cognitive‐affective tasks, questionnaires, biosamples, and ecologic momentary assessment in real life with combined actigraphic/geographic monitoring. In the family study component, parents completed similar assessments and provided information on child's early development. Results: The participation rate (minimum response proportion) was 21.7%; the cooperation rate was 43.4%. Acceptance and completion of study components were high. General health data indicate that more than 80% reported no or only mild impairment due to mental or somatic health problems in the past year; about 20% ever sought treatment for mental health problems or chronic somatic illnesses, respectively. Conclusions: Data from BeMIND baseline and follow‐up investigations will provide novel insights into contributors to health and disease as adolescents grow into adulthood

Nonthermal atmospheric pressure plasma enhances mouse limb bud survival, growth, and elongation.

The enhanced differentiation of mesenchymal cells into chondrocytes or osteoblasts is of paramount importance in tissue engineering and regenerative therapies. A newly emerging body of evidence demonstrates that appendage regeneration is dependent on reactive oxygen species (ROS) production and signaling. Thus, we hypothesized that mesenchymal cell stimulation by nonthermal (NT)-plasma, which produces and induces ROS, would (1) promote skeletal cell differentiation and (2) limb autopod development. Stimulation with a single treatment of NT-plasma enhanced survival, growth, and elongation of mouse limb autopods in an in vitro organ culture system. Noticeable changes included enhanced development of digit length and definition of digit separation. These changes were coordinated with enhanced Wnt signaling in the distal apical epidermal ridge (AER) and presumptive joint regions. Autopod development continued to advance for approximately 144 h in culture, seemingly overcoming the negative culture environment usually observed in this in vitro system. Real-time quantitative polymerase chain reaction analysis confirmed the up-regulation of chondrogenic transcripts. Mechanistically, NT-plasma increased the number of ROS positive cells in the dorsal epithelium, mesenchyme, and the distal tip of each phalange behind the AER, determined using dihydrorhodamine. The importance of ROS production/signaling during development was further demonstrated by the stunting of digital outgrowth when anti-oxidants were applied. Results of this study show NT-plasma initiated and amplified ROS intracellular signaling to enhance development of the autopod. Parallels between development and regeneration suggest that the potential use of NT-plasma could extend to both tissue engineering and clinical applications to enhance fracture healing, trauma repair, and bone fusion

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure

The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529

Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

Background We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing.Methods We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew’s Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for “viral infection”, “transcriptome”, “biomarker”, and “blood”. We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity.Findings We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27–47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91–0·99), sensitivity 0·84 (0·70–0·93), and specificity 0·95 (0·85–0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91–0·95).Interpretation Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge

Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response

Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination

How does your garden grow? The interface of employee and sales growth post IPO

Research Summary: Firms often succumb to a growth imperative, yet little is known about how congruence between various forms of growth affects firm value. We argue that the (in)congruence between net hiring rates (e.g., growth in the number of employees) and sales growth has significant implications for firm value, assessed via Tobin\u27s Q. We further contend that R&D expenditures and industry dynamism—factors that influence a firm\u27s ability to realize value creation—moderate the relationship between growth pattern and firm value. We use a sample of 1,181 firms that conducted their initial public offerings from 1996 to 2006 to test our conceptual model. Findings indicate that employee-dominant growth is most strongly associated with firm value, and that high levels of R&D expenditures and industry dynamism intensify these relationships. Managerial Summary: Growth is a goal and challenge for many firms, and navigating the various demands of growth represents a particularly promising opportunity for firms that recently went public. We study how firms can manage the growth process in a way that enhances firm value. Using a sample of 1,181 firms that conducted their initial public offerings from 1996 to 2006, we explore the interplay of employee and sales growth rates on value creation. We find that an employee-dominant growth pattern was more strongly related to firm value than the other patterns. Our findings also suggest that managers, especially those in firms that invest in R&D and operating in dynamic industries, should avoid a strong focus on sales growth without also ensuring growth in employees

Hair androgen concentrations and depressive disorders in adolescents from the general population

Although the link between androgens and depression is well established in adults, the effects of cofactors on this association are less clearly understood, particularly in youth. Epidemiological cohort study of adolescents in Dresden, Germany. Analyses comprised data of 985 individuals assessed at baseline and of 512 individuals at 1-year follow-up. We investigated multivariable regression models for cross-sectional and longitudinal associations of hair testosterone, dehydroepiandrosterone (DHEA), and their cortisol ratios with 12-month diagnoses of major depressive disorder (MDD) and MDD without any anxiety disorder assessed with standardized diagnostic interview (DIA-X-5), and with dimensional depression scores (PHQ-9, PROMIS), separately for males and females. The potential moderating effect of social support was determined. Cross-sectional analyses yielded inverse associations of testosterone and DHEA with MDD and MDD without any anxiety disorders in males. In cross-sectional and longitudinal analyses, baseline ratio cortisol/DHEA was significantly, inversely associated to PROMIS-depression in males. Only cross-sectional associations for ratio cortisol/DHEA and PROMIS-depression remained significant after Bonferroni-Holm correction. No robust associations were observed in female participants. Social support exerted no consistent moderating effect on the investigated association. The present observational cohort study showed no consistent association of hair androgen concentrations with depressive disorders in adolescents. However, findings provide some support for the association between the cortisol/DHEA ratio and depression in males. Longitudinal research designs in large samples are needed to understand the interplay between androgens, depression, and developmental and social factors in youth

Prevalence, Onset, and Course of Suicidal Behavior Among Adolescents and Young Adults in Germany

Suicidal behavior is a leading cause of death among adolescents and young adults. In light of the ideation-to-action framework, the delineation of frequency and temporal characteristics of such behavior during this developmental period is crucial.; To provide lifetime and 12-month prevalence estimates of suicidal behavior, including ideation, plan, and attempt, in adolescents and young adults of the general population, and to provide information about age at onset, temporal characteristics of suicidal behavior, including duration (number of years between onset and last occurrence) and frequency (number of episodes), and transition patterns across suicidal behaviors.; A cross-sectional epidemiological study was conducted in a random community sample of 1180 adolescents and young adults aged 14 to 21 years assessed in 2015 to 2016 in Dresden, Germany. Data analysis was performed from October 2018 to March 2019.; Lifetime and 12-month suicidal behavior (ideation, plan, and attempt) were assessed with a standardized diagnostic interview (Munich-Composite International Diagnostic Interview) by trained clinical interviewers. The onset, frequency, and duration of suicidal behavior were assessed by questionnaire.; Of the 1180 participants (495 male [weighted percentage, 51.7%]; mean [SD] age, 17.9 [2.3] years), 130 participants (10.7%; 95% CI, 9.0%-12.8%), 65 participants (5.0%; 95% CI, 3.9%-6.5%), and 41 participants (3.4%; 95% CI, 2.4%-4.7%) reported lifetime suicidal ideation, plan, and attempt, respectively. Any lifetime suicidal behavior was reported by 138 participants (11.5%; 95% CI, 9.7%-13.7%). Age-specific cumulative incidence estimates indicated an increase in suicidal behavior during adolescence, starting at age 10 years (<1%), increasing slightly until the age of 12 years (2.2%), and then increasing sharply thereafter until age 20 years (13.5%). There were different patterns among female and male participants for ideation, plan, and attempt, with an overall higher incidence among female participants for ideation (hazard ratio, 1.51; 95% CI, 1.02-2.22; P = .04), for plan (hazard ratio, 3.31; 95% CI, 1.72-6.36; P < .001), and, among those older than 14 years, for attempt (hazard ratio, 3.07; 95% CI, 1.11-8.49; P = .03). Of those with suicidal ideation, 66.0% reported persistent or recurrent ideation over more than 1 year with 75.0% reporting more than 1 episode. Of the participants with lifetime suicidal ideation, 47.0% reported a suicide plan and 23.9% reported a suicide attempt. The transition to suicide plan or attempt occurred mainly in the year of onset of suicidal ideation or plan; of those who transitioned, 74.9% transitioned from ideation to plan, 71.2% transitioned from ideation to attempt, and 85.4% transitioned from plan to attempt in the same year.; There is an urgent public health need for timely identification of suicidal behavior in adolescents and young adults to terminate persistent or recurrent suicidal tendencies and to interrupt the ideation-to-action transition