Separating signal from noise in wastewater data: An algorithm to identify community-level COVID-19 surges in real time.

Wastewater monitoring has provided health officials with early warnings for new COVID-19 outbreaks, but to date, no approach has been validated to distinguish signal (sustained surges) from noise (background variability) in wastewater data to alert officials to the need for heightened public health response. We analyzed 62 wk of data from 19 sites participating in the North Carolina Wastewater Monitoring Network to characterize wastewater metrics around the Delta and Omicron surges. We found that wastewater data identified outbreaks 4 to 5 d before case data (reported on the earlier of the symptom start date or test collection date), on average. At most sites, correlations between wastewater and case data were similar regardless of how wastewater concentrations were normalized and whether calculated with county-level or sewershed-level cases, suggesting that officials may not need to geospatially align case data with sewershed boundaries to gain insights into disease transmission. Although wastewater trend lines captured clear differences in the Delta versus Omicron surge trajectories, no single wastewater metric (detectability, percent change, or flow-population normalized viral concentrations) reliably signaled when these surges started. After iteratively examining different combinations of these three metrics, we developed the Covid-SURGE (Signaling Unprecedented Rises in Groupwide Exposure) algorithm, which identifies unprecedented signals in the wastewater data. With a true positive rate of 82%, a false positive rate of 7%, and strong performance during both surges and in small and large sites, our algorithm provides public health officials with an automated way to flag community-level COVID-19 surges in real time.

Rapid high-resolution size distribution protocol for adeno-associated virus using high speed SV-AUC.

Simulated SV-AUC data for an adeno-associated virus (AAV) sample consisting of four components having closely spaced sedimentation coefficients were used to develop a high-speed protocol that optimized the size distribution analysis resolution. The resulting high speed (45K rpm) SV-AUC (hs-SV-AUC) protocol poses several experimental challenges: 1) the need for rapid data acquisition, 2) increased potential for optical artifacts from steep and fast moving boundaries and 3) the increased potential for convection. To overcome these challenges the protocol uses interference detection at low temperatures and data that are confined to a limited radial-time window. In addition to providing higher resolution AAV SV-AUC data and very short run times (<20 min after temperature equilibration), the need to match the sample and reference solvent composition and meniscus positions is relaxed making interference detection as simple to employ as absorbance detection. Finally, experimental data comparing hs-SV-AUC (at 45K rpm) with standard low-speed (15K rpm) SV-AUC on the same AAV sample demonstrate the size distribution resolution improvement. These experiments also validate the use of a radial-time window and show how quickly data can be acquired using the hs-SV-AUC protocol.

Monitoring SARS-CoV-2 RNA in wastewater from a shared septic system and sub-sewershed sites to expand COVID-19 disease surveillance.

Wastewater-based epidemiology has expanded as a tool for collecting COVID-19 surveillance data, but there is limited information on the feasibility of this form of surveillance within decentralized wastewater systems (e.g., septic systems). This study assessed SARS-CoV-2 RNA concentrations in wastewater samples from a septic system servicing a mobile home park (66 households) and from two pumping stations serving a similarly sized (71 households) and a larger (1,000 households) neighborhood within a nearby sewershed over 35 weeks in 2020. Also, raw wastewater from a hospital in the same sewershed was sampled. The mobile home park samples had the highest detection frequency (39/39 days) and mean concentration of SARS-CoV-2 RNA (2.7 × 107 gene copies/person/day for the N1) among the four sampling sites. N1 gene and N2 gene copies were highly correlated across mobile home park samples (Pearson's r = 0.93, p < 0.0001). In the larger neighborhood, new COVID-19 cases were reported every week during the sampling period; however, we detected SARS-CoV-2 RNA in 12% of the corresponding wastewater samples. The results of this study suggest that sampling from decentralized wastewater infrastructure can be used for continuous monitoring of SARS-CoV-2 infections.

Expert consensus regarding indicators of a traumatic reaction in autistic youth: a Delphi survey.

OBJECTIVE: It has been suggested that the sequelae of trauma are under-recognized in youth on the autism spectrum. We aimed to generate expert consensus regarding important trauma indicators, including but not limited to traumatic stress symptoms, in autistic youth. METHODS: We recruited 72 experts in autism and/or childhood trauma. Via a 2-round Delphi survey, experts commented on and rated the importance of 48 potential indicators, drawn from PTSD criteria and a broader literature on traumatic sequelae in autism. A revised list of 51 indicators, 18 clinical guidelines developed from expert comments, and summaries of expert qualifications and ratings from Round 1 were submitted to a second round (n = 66; 92% retention) of expert review and rating. RESULTS: Twenty-two indicators reached consensus (>75% round 2 endorsement). Many, but not all, reflected PTSD criteria, including intrusions (e.g., trauma re-enactments in perseverative play/speech), avoidance of trauma-reminders, and negative alterations in mood/cognition (e.g., diminished interest in activities) and in arousal/reactivity (e.g., exaggerated startle). Experts also identified increased reliance on others, adaptive and language regressions, self-injurious behavior, and non-suicidal self-injury as important indicators. Consensus guidelines emphasized the need for tailored measures, developmentally informed criteria, and multiple informants to increase diagnostic accuracy. CONCLUSIONS: Expert consensus emphasizes and informs a need for tailored diagnostic guidelines and measures to more sensitively assess traumatic reactions in autistic youth.

Timing and Trends for Municipal Wastewater, Lab-Confirmed Case, and Syndromic Case Surveillance of COVID-19 in Raleigh, North Carolina.

Objectives. To compare 4 COVID-19 surveillance metrics in a major metropolitan area. Methods. We analyzed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in wastewater influent and primary solids in Raleigh, North Carolina, from April 10 through December 13, 2020. We compared wastewater results with lab-confirmed COVID-19 cases and syndromic COVID-like illness (CLI) cases to answer 3 questions: (1) Did they correlate? (2) What was the temporal alignment of the different surveillance systems? (3) Did periods of significant change (i.e., trends) align? Results. In the Raleigh sewershed, wastewater influent, wastewater primary solids, lab-confirmed cases, and CLI were strongly or moderately correlated. Trends in lab-confirmed cases and wastewater influent were observed earlier, followed by CLI and, lastly, wastewater primary solids. All 4 metrics showed sustained increases in COVID-19 in June, July, and November 2020 and sustained decreases in August and September 2020. Conclusions. In a major metropolitan area in 2020, the timing of and trends in municipal wastewater, lab-confirmed case, and syndromic case surveillance of COVID-19 were in general agreement. Public Health Implications. Our results provide evidence for investment in SARS-CoV-2 wastewater and CLI surveillance to complement information provided through lab-confirmed cases. (Am J Public Health. 2023;113(1):79-88. https://doi.org/10.2105/AJPH.2022.307108).

Boundary convection during sedimentation velocity in the Optima analytical ultracentrifuge.

Analytical ultracentrifugation (AUC) provides the most widely applicable, precise, and accurate means for characterizing solution hydrodynamic and thermodynamic properties. While generally useful, boundary sedimentation velocity AUC (SV-AUC) analysis has become particularly important in assessing protein aggregation, fragmentation and conformational variants in the same solvents used during drug development and production. In early 2017 the only manufacturer of the analytical ultracentrifuge released its newest analytical ultracentrifuge, the Optima, to replace the aging second-generation XLA/I series ultracentrifuges. However, SV-AUC data from four Optima units used in the characterization of adeno-associated virus (AAV) have shown evidence of sample convection. Further investigation reveals this problem arises from the design of the temperature control system, which makes it prone to producing destabilizing temperature-induced density gradients that can lead to density inversions. The problem is intermittent and variable in severity within a given Optima unit and between Optima units. This convection appears to be associated mainly with low rotor speeds and dilute concentration of solvent components, i.e., AAV analysis conditions. Data features diagnostic for this problem and strategies for its elimination or minimization are provided.

Sociodemographic characteristics of youth in a trauma focused-cognitive behavioral therapy effectiveness trial in the city of Philadelphia.

While randomized controlled trials of trauma-focused cognitive behavioral therapy (TF-CBT) have demonstrated efficacy for youth with posttraumatic stress disorder, TF-CBT effectiveness trials typically show attenuated outcomes. This decrease in effectiveness may be due to the differences in sociodemographic characteristics of youth in these trials; youth in efficacy trials are more often white and middle-income, whereas youth in effectiveness trials are more often racial/ethnic minorities, of low socioeconomic status (SES) and live in high crime neighborhoods. In this study-drawn from an effectiveness trial of TF-CBT in community mental health clinics across Philadelphia-we describe the sociodemographic characteristics of enrolled youth. We measured neighborhood SES by matching participants' addresses to American Community Survey data from their Census tracts, housing stability using the National Outcomes Measurement System, and neighborhood violence using police department crime statistics. Our results suggest that the majority of youth presenting for TF-CBT in mental health clinics in the City of Philadelphia live in poor and high-crime neighborhoods, experience substantial housing instability, and are predominantly ethnic and racial minorities. Thus, youth presenting for treatment experience significant racial and socioeconomic adversity. We also explored the association between these characteristics and youth symptom severity upon presenting for treatment. These factors were not associated with youth symptom severity or overall mental health functioning in our sample (with small effect sizes and p > .05 for all). Implications for future research, such as the need for efficacy and effectiveness trials to more fully characterize their samples and the need for pragmatic trials are discussed.

Benchmarking Treatment Effectiveness of Community-Delivered Trauma-Focused Cognitive Behavioral Therapy.

It is critical for urban youth with post-traumatic stress disorder (PTSD) living in poverty to have access to evidence-based interventions for their traumatic stress. However, there is limited research on the effectiveness of these interventions when provided in urban, community settings. The objectives of the current study are to (a) evaluate the effectiveness of trauma-focused cognitive behavioral therapy delivered from 2013 to 2016 in 15 behavioral health agencies on youth (N = 114) PTSD as well as  general mental health symptoms and  functioning, and (b) benchmark these clinical outcomes against other published efficacy and effectiveness trials. Effectiveness data are from the Philadelphia County Community Behavioral Health System, a system that has invested significantly in the training and ongoing support of clinicians providing high-quality trauma services to youth since 2012. From baseline to last assessment, youth PTSD symptom severity (d = 0.34), PTSD functional impairment (d = 0.38), and overall mental health problem severity (d = 0.29) improved. The effect sizes of  improvements were smaller than effect sizes observed in efficacy and effectiveness studies. This study is the first benchmarking study of TF-CBT and provides preliminary findings with regard to the effectiveness, and transportability, of TF-CBT to urban community settings that serve youth in poverty.

Evaluation and treatment of childhood physical abuse and neglect: a review.

According to 2010 CDC estimates, 1 in 5 US children have experienced maltreatment. Risk factors for child maltreatment include child characteristics such as non-compliance and diagnostic conditions that increase caregiver burden. Parent characteristic risk factors include parental mental illness and low social support. New developments in radiologic evaluation of child maltreatment will be reviewed. New findings in evidence based psychotherapies for childhood maltreatment will be discussed. A review of the role of pharmacotherapy in child maltreatment cases will also be presented. New evidence from prevention models targeting young mothers and families are also reviewed.

Editorial: Chronicity of Maltreatment and the Importance of Attachment and Peer Relationships on Youth Mental Health Trajectory.

Childhood maltreatment impacts human development across the life span in most areas of functioning, particularly the onset of mental health symptoms. As our understanding of the biological underpinnings of the effects of maltreatment on childhood development continues to grow, it becomes even more salient to delineate and understand potential variance associated with timing and chronicity of maltreatment. Moreover, as family and peer relationships are known to mediate effects of stress on childhood mental health outcomes,1,2 it is important to acknowledge and specifically explore the potential effects of the relational context of a child when stress and trauma are being investigated. By gaining understanding of these complexities of the interplay between maltreatment, attachment/relational patterns, and mental health symptoms, we can most effectively focus efforts on formulation, prevention, and treatment. Duprey et al.3 begin to directly address this need by performing a longitudinal follow-up study on participants who participated in a 1-week research summer camp (at the time of participation: N = 697; mean [SD] age = 11.29 [0.97] years; 71.3% Black or African American; 50.5% male; at the time of contact for second wave of assessment: n = 427; mean [SD] age = 19.67 [1.16] years; 78.0% Black or African American; 48.9% male) examining the indirect effects of child maltreatment timing and chronicity to young adult internalizing and externalizing symptomatology via childhood attachment security and peer problems.

An interaction between DNA polymerase and helicase is essential for the high processivity of the bacteriophage T7 replisome.

Synthesis of the leading DNA strand requires the coordinated activity of DNA polymerase and DNA helicase, whereas synthesis of the lagging strand involves interactions of these proteins with DNA primase. We present the first structural model of a bacteriophage T7 DNA helicase-DNA polymerase complex using a combination of small angle x-ray scattering, single-molecule, and biochemical methods. We propose that the protein-protein interface stabilizing the leading strand synthesis involves two distinct interactions: a stable binding of the helicase to the palm domain of the polymerase and an electrostatic binding of the carboxyl-terminal tail of the helicase to a basic patch on the polymerase. DNA primase facilitates binding of DNA helicase to ssDNA and contributes to formation of the DNA helicase-DNA polymerase complex by stabilizing DNA helicase.

Identifying youth at risk for difficulties following a traumatic event: pre-event factors are associated with acute symptomatology.

This study examined factors related to children's acute symptoms following a potentially traumatic event (PTE) to more clearly identify domains that should be included in screenings of youth exposed to a PTE. In particular, the authors examined whether trauma category (i.e., sexual abuse/disclosure of abuse, intentionally perpetrated traumas other than sexual abuse, and unintentional traumas) was related to symptoms after controlling for other relevant factors. Participants were 112 youth presenting for clinical evaluation within a month of a PTE and their nonoffending caregivers. Using data from baseline assessments collected as part of a randomized controlled trial of a secondary prevention program, the following factors were tested in 3 hierarchical regression models: index PTE category, history of traumatic exposure, preindex event functioning, and parenting behaviors. Prior trauma exposure, preindex event functioning, and hostile parenting were uniquely related to children's symptoms in the acute posttraumatic period after controlling for time since the event and child age, but trauma category was not. Implications for identifying and referring children at high risk for poor outcomes in the early aftermath of a PTE are discussed. An exclusive focus on the event is insufficient and more comprehensive understanding of the child and family is required.

A Developmentally Informed Approach to Address Mass Firearm Violence.

Pediatric medical providers have an important role to play in response to mass gun violence events. Although mass gun violence events are rare, the rate of mass shootings is unfortunately increasing, and such events are shown to have significant and far-reaching psychological impact on children and adolescents. Recommendations from the behavioral health and pediatric fields are consolidated along with developmental considerations to support pediatric provider response in the aftermath of a mass gun violence event. Gun violence prevention strategies are also discussed.

Past the Pandemic: a virtual intervention supporting the well-being of healthcare workers through the COVID-19 pandemic.

To decrease burnout and improve mental health and resiliency among doctors, nurses, and hospital staff during the COVID-19 pandemic, the University of Colorado partnered with ECHO Colorado to offer the state's healthcare workforce an interactive, psychoeducational, and online intervention that encouraged connection and support. The series utilized the Stress Continuum Model as its underlying conceptual framework. Between July 2020 and February 2022, 495 healthcare workers in Colorado participated in the series across eight cohorts. One-way repeated measures ANOVAs were performed to test for differences in pretest and posttest scores on series' objectives. Healthcare workers showed significant improvement from pretest to posttest in (1) knowing when and how to obtain mental health resources, F(1, 111) = 46.497, p < 0.001, (2) recognizing of the importance of being socially connected in managing COVID-related stress, F(1, 123) = 111.159, p < 0.001, (3) managing worries, F(1, 123) = 94.941, p < 0.001, (4) feeling prepared to manage stressors related to the pandemic, F(1, 111) = 100.275, p < 0.001, (5) feeling capable in dealing with challenges that occur daily, F(1, 111) = 87.928, p < 0.001, and (6) understanding the Stress Continuum Model F(1, 123) = 271.049, p < 0.001. This virtual series showed efficacy in improving the well-being of healthcare workers during a pandemic and could serve as a model for mental health support for healthcare workers in other emergency response scenarios.

Stable IgG-like bispecific antibodies directed toward the type I insulin-like growth factor receptor demonstrate enhanced ligand blockade and anti-tumor activity.

Bispecific antibodies (BsAbs) target multiple epitopes on the same molecular target or different targets. Although interest in BsAbs has persisted for decades, production of stable and active BsAbs has hindered their clinical evaluation. Here, we describe the production and characterization of tetravalent IgG-like BsAbs that combine the activities of allosteric and competitive inhibitors of the type-I insulin-like growth factor receptor (IGF-1R). The BsAbs, which were engineered for thermal stability, express well, demonstrate favorable biophysical properties, and recognize both epitopes on IGF-1R. Only one BsAb with a unique geometry, denoted BIIB4-5scFv, was capable of engaging all four of its binding arms simultaneously. All the BsAbs (especially BIIB4-5scFv) demonstrated enhanced ligand blocking over the single monoclonal antibodies (mAbs), particularly at high ligand concentrations. The pharmacokinetic profiles of two IgG-like BsAbs were tested in nude mice and shown to be comparable with that of the parental mAbs. The BsAbs, especially BIIB4-5scFv, demonstrated an improved ability to reduce the growth of multiple tumor cell lines and to inhibit ligand-induced IGF-1R signaling in tumor cells over the parental mAbs. BIIB4-5scFv also led to superior tumor growth inhibition over its parental mAbs in vivo. In summary, BsAbs that bridge multiple inhibitory mechanisms against a single target may generally represent a more effective strategy for intervention in oncology or other indications compared with traditional mAb therapy.

Treatment of childhood sexual abuse: an updated review.

Childhood sexual abuse (CSA) involves multiple complex factors that make the evaluation of therapeutic interventions especially complicated. PTSD prevalence rates of CSA are approximately 37 % -53 %. Several other psychiatric sequelae of CSA exist. CSA appears to disrupt brain and body physiology. One co-located service delivery model reported a 52 % linkage rate of CSA survivors with mental health treatment. This article reviews current literature on the treatment of CSA, including psychosocial interventions, pharmacotherapy, and early preventative interventions. It also provides an update on the short- and long-term sequelae of CSA and implications for future research directions. A literature search of papers published in the last 3 years was conducted using the keywords treatment, sexual abuse, childhood, epigenetics, resilience and review, and searching the following databases: PsycInfo, PubMed, Substance Abuse and Mental Health Services Administration, and Centers for Disease Control.

Post-translational modifications differentially affect IgG1 conformation and receptor binding.

Post-translational modifications (PTMs) can have profound effects on protein structure and protein dynamics and thereby can influence protein function. To understand and connect PTM-induced functional differences with any resulting conformational changes, the conformational changes must be detected and localized to specific parts of the protein. We illustrate these principles here with a study of the functional and conformational changes that accompany modifications to a monoclonal immunoglobulin gamma1 (IgG1) antibody. IgG1s are large and heterogeneous proteins capable of incorporating a multiplicity of PTMs both in vivo and in vitro. For many IgG1s, these PTMs can play a critical role in affecting conformation, biological function, and the ability of the antibody to initiate a potential adverse biological response. We investigated the impact of differential galactosylation, methionine oxidation, and fucosylation on solution conformation using hydrogen/deuterium exchange mass spectrometry and probed the effects of IgG1 binding to the FcgammaRIIIa receptor. The results showed that methionine oxidation and galactosylation both impact IgG1 conformation, whereas fucosylation appears to have little or no impact to the conformation. FcgammaRIIIa binding was strongly influenced by both the glycan structure/composition (namely galactose and fucose) and conformational changes that were induced by some of the modifications.

Pharmacological secondary prevention of PTSD in youth: challenges and opportunities for advancement.

Child and adolescent posttraumatic stress disorder (PTSD) is associated with an increased risk for a number of deleterious mental and physical health outcomes that if untreated may persist throughout the life course. Efficacious interventions applied soon after trauma exposure have the potential to reduce or prevent the development of PTSD symptoms and their associated impact on behavior and physical health. We review extant research related to treatment-modifiable peritraumatic predictors of pediatric PTSD, which have informed an emerging field of pharmacologic secondary prevention (i.e., occurring shortly following trauma exposure) of PTSD. Challenges and opportunities for early posttrauma PTSD prevention are described. Finally, we offer new models for biologically informed integration of pharmacologic and psychosocial secondary prevention intervention strategies for children and adolescents.

Exploring potential sources of childhood trauma: A qualitative study with autistic adults and caregivers.

LAY ABSTRACT: The stressors autistic individuals encounter and experience as traumatic may vary from those not on the spectrum and typically measured. We conducted in-depth interviews with autistic adults and caregivers of children and adults on the spectrum to identify potential sources of trauma for autistic individuals and evaluate the ability of a standard trauma measure to capture those experiences. Fourteen autistic adults and 15 caregivers with varied backgrounds, clinical profiles, and histories of adversity were interviewed. Participants also completed standard measures of autism, traumatic exposures, and stress. Interviews were analyzed to record both traditional sources of trauma, for comparison with the standard measure, and distinct sources, described as traumatic only in the narratives of participants. Participants described varied experiences as traumatic. Whereas some reflected traditional traumas (e.g. maltreatment) and forms of social marginalization, others reflected conflicts between autistic characteristics and the environment (e.g. sensory trauma). All adults and most caregivers described sources of trauma in interviews not reported on the standard measure. Results have implications for assessing traumatic events in autism and for understanding their contribution to the mental health of this group.

A Qualitative Study of Self and Caregiver Perspectives on How Autistic Individuals Cope With Trauma.

Background: Coping can moderate the relationship between trauma exposure and trauma symptoms. There are many conceptualisations of coping in the general population, but limited research has considered how autistic individuals cope, despite their above-average rates of traumatic exposure. Objectives: To describe the range of coping strategies autistic individuals use following traumatic events. Methods: Fourteen autistic adults and 15 caregivers of autistic individuals, recruited via stratified purposive sampling, completed semi-structured interviews. Participants were asked to describe how they/their child attempted to cope with events they perceived as traumatic. Using an existing theoretical framework and reflexive thematic analysis, coping strategies were identified, described, and organized into themes. Results: Coping strategies used by autistic individuals could be organized into 3 main themes: (1) Engaging with Trauma, (2) Disengaging from Trauma, and (3) Self-Regulatory Coping. After the three main themes were developed, a fourth integrative theme, Diagnostic Overshadowing, was created to capture participants' reports of the overlap or confusion between coping and autism-related behaviors. Conclusions: Autistic individuals use many strategies to cope with trauma, many of which are traditionally recognized as coping, but some of which may be less easily recognized given their overlap with autism-related behaviors. Findings highlight considerations for conceptualizing coping in autism, including factors influencing how individuals cope with trauma, and how aspects of autism may shape or overlap with coping behavior. Research building on these findings may inform a more nuanced understanding of how autistic people respond to adversity, and how to support coping strategies that promote recovery from trauma.