Generation of 'semi-guided' cortical organoids with complex neural oscillations.

Temporal development of neural electrophysiology follows genetic programming, similar to cellular maturation and organization during development. The emergent properties of this electrophysiological development, namely neural oscillations, can be used to characterize brain development. Recently, we utilized the innate programming encoded in the human genome to generate functionally mature cortical organoids. In brief, stem cells are suspended in culture via continuous shaking and naturally aggregate into embryoid bodies before being exposed to media formulations for neural induction, differentiation and maturation. The specific culture format, media composition and duration of exposure to these media distinguish organoid protocols and determine whether a protocol is guided or unguided toward specific neural fate. The 'semi-guided' protocol presented here has shorter induction and differentiation steps with less-specific patterning molecules than most guided protocols but maintains the use of neurotrophic factors such as brain-derived growth factor and neurotrophin-3, unlike unguided approaches. This approach yields the cell type diversity of unguided approaches while maintaining reproducibility for disease modeling. Importantly, we characterized the electrophysiology of these organoids and found that they recapitulate the maturation of neural oscillations observed in the developing human brain, a feature not shown with other approaches. This protocol represents the potential first steps toward bridging molecular and cellular biology to human cognition, and it has already been used to discover underlying features of human brain development, evolution and neurological conditions. Experienced cell culture technicians can expect the protocol to take 1 month, with extended maturation, electrophysiology recording, and adeno-associated virus transduction procedure options.

"Multiplexed screen identifies a Pseudomonas aeruginosa -specific small molecule targeting the outer membrane protein OprH and its interaction with LPS".

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa , a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT 1 , a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM ß-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target.

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

Stability-Based Proteomics for Investigation of Structured RNA-Protein Interactions.

RNA-protein interactions are essential to RNA function throughout biology. Identifying the protein interactions associated with a specific RNA, however, is currently hindered by the need for RNA labeling or costly tiling-based approaches. Conventional strategies, which commonly rely on affinity pull-down approaches, are also skewed to the detection of high affinity interactions and frequently miss weaker interactions that may be biologically important. Reported here is the first adaptation of stability-based mass spectrometry methods for the global analysis of RNA-protein interactions. The stability of proteins from rates of oxidation (SPROX) and thermal protein profiling (TPP) methods are used to identify the protein targets of three RNA ligands, the MALAT1 triple helix (TH), a viral stem loop (SL), and an unstructured RNA (PolyU), in LNCaP nuclear lysate. The 315 protein hits with RNA-induced conformational and stability changes detected by TPP and/or SPROX were enriched in previously annotated RNA-binding proteins and included new proteins for hypothesis generation. Also demonstrated are the orthogonality of the SPROX and TPP approaches and the utility of the domain-specific information available with SPROX. This work establishes a novel platform for the global discovery and interrogation of RNA-protein interactions that is generalizable to numerous biological contexts and RNA targets.

Does it add up? Educational achievement mediates child maltreatment subtypes to allostatic load.

BACKGROUND: Childhood maltreatment (CM) has been linked to higher levels of allostatic load (AL) and educational achievement is a possible pathway and may differ across gender. It is also critical to determine if CM severity or specific subtypes of CM are more or less influential. OBJECTIVE: This study examined educational achievement as a mediator linking cumulative and individual types of CM to AL and examined gender as a moderator. PARTICIPANTS AND SETTING: Using two waves of data, 897 adults from the study Midlife in the United States were analyzed. METHODS: Multiple group structural equation models stratified across gender to test were used cumulative maltreatment and maltreatment subtypes to AL and test gender as a moderator. RESULTS: Overall CM was associated with educational achievement (ß = -0.12, p < .01) and AL (ß = 0.11, p < .05) and education was inversely associated with AL (ß = -0.17, p < .001) in men but not women. The subtypes model revealed that physical abuse predicted lower level of education achievement (ß = -0.20, p < .001) and among men. Educational achievement, in turn, was associated with lower levels of AL (ß = -0.02, p = .002). Educational achievement was a possible pathway linking physical abuse to AL (ß = 0.02, 95 % CI [0.001, 0.040]) among men but was non-significant in women. Gender did not moderate any of the pathways. CONCLUSIONS: Educational achievement is a potentially modifiable social determinant of health that can be a focus of prevention and intervention efforts among men who were maltreated, particularly for those who experienced physical abuse.

Treatment trends of benign bone lesions in a suburban New York healthcare system.

Introduction: The management of benign bone lesions is controversial as it is dependent on a multitude of factors such as age, anatomic location, comorbidities, lesion metabolic activity, surgeon preferences, and goals of care, among others. Thus far, many studies have attempted to report on these lesions; however, most are heterogeneous compilations of benign and malignant lesions with nearly all failing to report patient treatment and none of which have originated from a suburban area of the United States. The goal of this study was to establish a modern database dedicated solely to benign bone tumors to reflect current diagnosis and treatment trends in suburban New York. Materials and Methods: This was a multicenter retrospective observational study with inclusion criteria limited to benign bone lesions of all ages. Malignant lesions were excluded. Patients were drawn from both primary care provider and surgeon records, with documentation of their associated management. Results: A total of 689 patients met inclusion criteria. The overall operative rate for this cohort was 71.6%. In agreement with current literature, aneurysmal bone cysts, giant cell tumors, and osteochondromas underwent surgery more frequently than enchondromas; older patients underwent surgery less frequently; benign bone lesions were more commonly found in younger males, and the distal femur and proximal tibia were the most common locations for lesions (P < .05 for all findings). Conclusion: This study demonstrates the management of a globally representative variety of benign bone lesions in a diverse suburban population of New York and should facilitate future research on how lesion type, location, management, and other factors relate to patient outcomes.

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.

Intrathoracic plates versus extrathoracic plates: a comparison of postoperative pain in surgical stabilization of rib fracture technique.

Background: Surgical stabilization of rib fractures (SSRF) has been shown to improve outcomes, yet there is an absence of studies comparing SSRF techniques. An intrathoracic system that minimizes incision length has recently been developed and adopted by multiple institutions. We hypothesized that SSRF with an intrathoracic system plus intercostal nerve cryoneurolysis (IC) leads to improved pain control compared with an extrathoracic system plus IC. Methods: A single-center, retrospective chart review was performed comparing intrathoracic SSRF versus extrathoracic SSRF, and included patients undergoing SSRF from 2015 to 2021 at a level 1 trauma center. Patients who did not undergo intercostal nerve cryoablation were excluded. The primary outcome was opioid consumption based on morphine milligram equivalent (MME) consumption. We collected Rib score, Blunt Pulmonary Contusion 18 Score, number of rib fractures, number of ribs plated, and Injury Severity Score (ISS) to compare baseline characteristics of each group. Results: A total of 112 patients were evaluated for study inclusion. Thirty-one patients were excluded due to missing outcomes data and/or lack of cryoablation. There was no difference in ISS or Rib Score between the intrathoracic (n=33) and extrathoracic (n=48) groups. At 7-day follow-up, the median MME requirement was significantly lower in the intrathoracic group (21.25) versus the extrathoracic group (46.20) (p=0.02). Conclusion: Intrathoracic SSRF was associated with a lower postoperative MME consumption compared with extrathoracic SSRF. These data support the use of intrathoracic SSRF to improve pain control compared to extrathoracic SSRF. Level of evidence: III.

Psychometric properties of the generalised version of the Screener for Substance and Behavioural Addictions (SSBA-G): A comprehensive screening tool for substance-related and behavioural addictions.

Assessing addictive behaviours comprehensively and efficiently is a challenge in both research and clinical practice. Consequently, we tested the psychometric properties of the Generalized Screener for Substance and Behavioural Addictions (SSBA-G), a novel, brief screening tool measuring functional impairment resulting from both substance and behavioural addictions. The SSBA-G was developed from the Screener for Substance and Behavioural Addictions (Schluter et al., 2018) and tested in four samples including university students in Canada (n = 481) and the US (n = 164) as well as community adults in Canada (n = 301), and Hungary (n = 79). Confirmatory factor analysis supported the hypothesized bifactor model of the SSBA-G. Receiver-operation characteristic analyses revealed high differentiation accuracy (AUC=0.86-.95), as well as identical ideal cut points across the Substance Addiction (SSBA-G-S) and Behavioural Addiction (SSBA-G-B) Subscales. Results indicated good-to-excellent sensitivity and moderate-to-good specificity. The SSBA-G demonstrated excellent internal consistency and test-retest reliability as well as promising concurrent validity in relation to the original SSBA and additional questions regarding addiction-related impairment. The SSBA-G also showed good convergent and divergent validity with indicators of general mental health. These results indicate that the SSBA-G is a psychometrically sound and efficient measure of addiction-related impairment across substances and excessive behaviours.

The Risk of Lymphedema After Breast Cancer Surgery Should Not Restrict Necessary Hand Surgery Interventions.

BACKGROUND: The purpose of this study was to evaluate the incidence of lymphedema onset or exacerbation in patients undergoing upper extremity interventions, both nonoperative and operative, after breast cancer surgery. METHODS: The study inclusion criteria were the following: (1) prior history of breast cancer surgery or lymphedema from the cancer; (2) upper extremity intervention, ipsilateral to the breast cancer side; and (3) follow-up of at least 1 month. Patients were evaluated for demographic information, type of breast cancer procedure and hand intervention, number of lymph nodes dissected, preexisting lymphedema, exacerbation of lymphedema, and new-onset lymphedema. RESULTS: A total of 161 patients undergoing 385 hand interventions (300 injections, 85 surgeries) were reviewed. Median follow-up was 31 months (range: 1-110). Nineteen patients had preexisting lymphedema ipsilateral to the hand procedure and none experienced an exacerbation of their lymphedema. Three patients developed new-onset lymphedema ipsilateral to their hand intervention at an average follow-up of 30 months (range: 4-67). One patient had a single injection and developed lymphedema over 5 years later. One had 2 injections in the same hand on the same date and developed lymphedema 3 months later. The third patient had 2 injections in the right hand, 1 injection and 1 surgery in the left hand, and developed either lymphedema or swelling due to rheumatoid arthritis in the right hand 1 year after the injections. CONCLUSIONS: Patients who have undergone breast cancer surgery can safely undergo upper extremity intervention with low risk of lymphedema exacerbation or onset.

Expression of thioredoxin-1 in the ASJ neuron corresponds with and enhances intrinsic regenerative capacity under lesion conditioning in C. elegans.

A conditioning lesion of the peripheral sensory axon triggers robust central axon regeneration in mammals. We trigger conditioned regeneration in the Caenorhabditis elegans ASJ neuron by laser surgery or genetic disruption of sensory pathways. Conditioning upregulates thioredoxin-1 (trx-1) expression, as indicated by trx-1 promoter-driven expression of green fluorescent protein and fluorescence in situ hybridization (FISH), suggesting trx-1 levels and associated fluorescence indicate regenerative capacity. The redox activity of trx-1 functionally enhances conditioned regeneration, but both redox-dependent and -independent activity inhibit non-conditioned regeneration. Six strains isolated in a forward genetic screen for reduced fluorescence, which suggests diminished regenerative potential, also show reduced axon outgrowth. We demonstrate an association between trx-1 expression and the conditioned state that we leverage to rapidly assess regenerative capacity.

Characteristics of Canadian physicians and their associations with practice patterns: a scoping review.

Background: Physician characteristics such as education and sociodemographic attributes are associated with particular practice patterns, such as practice in rural settings. Understanding the Canadian context of such associations can inform medical school recruitment and health workforce decision-making. Objective: The objective of this scoping review was to report the nature and extent of the literature on associations between characteristics of physicians in Canada and physicians' practice patterns. Eligibility criteria: We included studies reporting associations between 1) the education or sociodemographic attributes of practicing physicians or residents in Canada and 2) practice patterns, including career choice, practice setting, and populations served. Methods: We searched five electronic databases (MEDLINE (R) ALL, Embase, ERIC, Education Source and Scopus) for quantitative primary studies and reviewed reference lists of included studies for additional studies. Data were extracted using a standardized data charting form. Results: Our search yielded 80 studies. Sixty-two examined education, evenly divided between undergraduate and postgraduate. Fifty-eight examined physicians' attributes, most focusing on sex/gender. The majority of studies focused on the outcome of practice setting. We found no studies examining race/ethnicity or socioeconomic status. Conclusion: Many studies in our review found positive associations between (i) rural training or rural background and rural practice setting and (ii) location of training or physicians' origin and practice in that location, consistent with previous literature. Associations for sex/gender were mixed, suggesting it may be a less useful target for workforce planning or recruitment aiming to address gaps in health care provision. More research is needed on the association of characteristics, particularly race/ethnicity and socioeconomic status, with career choice and populations served.

Contexte: Il existe un lien entre les caractéristiques des médecins, comme leur formation et leur profil sociodémographique, et des cadres de pratique particuliers, comme la pratique en milieu rural. La compréhension de ces liens dans le contexte canadien peut éclairer les stratégies d'admission dans les facultés de médecine et la planification de la main-d'œuvre dans le secteur de la santé. Objectif: L'objectif de cette revue exploratoire était de faire état de la nature et de l'étendue de la littérature sur les liens entre les caractéristiques des médecins au Canada et leurs cadres de pratique. Critères de sélection : Nous avons inclus les études établissant des liens entre 1) la formation ou le profil sociodémographique des médecins ou des résidents en exercice au Canada et 2) les cadres de pratique, y compris le choix de carrière, le milieu de pratique et les populations desservies. Méthodes: Nous avons effectué des recherches dans cinq bases de données électroniques (MEDLINE (R) ALL, Embase, ERIC, Education Source et Scopus) pour trouver des études quantitatives primaires et avons examiné les listes de références bibliographiques des articles retenus pour repérer d'autres études. Les données ont été extraites à l'aide d'un formulaire normalisé. Résultats: Notre recherche a permis de recenser 80 études. Soixante-deux d'entre elles portaient sur l'éducation, réparties de manière égale entre le premier cycle et le cycle de spécialisation. Cinquante-huit examinaient les caractéristiques des médecins, la plupart portant sur le sexe/genre. La majorité des études étaient focalisées sur le critère du milieu de pratique. Nous n'avons trouvé aucune étude portant sur la race/ethnicité ou le statut socio-économique. Conclusion: En accord avec des travaux antérieurs de nombreuses études de notre revue trouvent des associations positives entre (i) la formation en milieu rural ou l'origine rurale et un cadre de pratique rural et entre (ii) le lieu de formation ou l'origine du médecin et une pratique dans ce lieu. Les associations relatives au sexe/genre étaient mitigées, ce qui porte à croire qu'il s'agit peut-être d'une cible moins utile pour la planification ou le recrutement d'une main-d'œuvre visant à combler les lacunes dans la prestation des soins de santé. Des travaux supplémentaires sont nécessaires sur les liens entre le profil des médecins, en particulier la race/ethnie et le statut socio-économique, d'une part, et le choix de carrière et les populations desservies d'autre part.

Marital quality and depression as mediators linking childhood maltreatment to adult physical health.

BACKGROUND: Childhood maltreatment is known to influence adult physical health among midlife adults. Evidence suggests that depressive symptoms mediate the association. However, research has discounted the role of marital quality in understanding health outcomes among adults maltreated in childhood. OBJECTIVE: To advance this line of inquiry, we examined the relationship between marital quality and depressive symptoms in a sequential mediation model linking childhood maltreatment to adult physical health over ten years. PARTICIPANTS AND SETTING: Our sample consisted of midlife adults (n = 550) from three waves of the Midlife Development in the United States (MIDUS) study. The majority (n = 91.4 %) were white. At MIDUS 2, the mean age was 54.84 (SD = 10.78) and the mean age at MIDUS 3 was 63.96 (SD = 10.81). METHODS: Structural equation modeling was used to examine the degree to which marital quality and depressive symptoms mediated the relationship between childhood maltreatment and adult physical outcomes. Bootstrapping procedures were used to estimate the indirect effects. RESULTS: The serial mediation effects from maltreatment to adult physical health through marital quality and depressive symptoms were significant. Likewise, the simple indirect effects from maltreatment to subjective evaluations and the number of chronic health conditions through depressive symptoms were also significant. CONCLUSIONS: Childhood maltreatment is linked to adult physical health problems through marital quality and depressive symptoms, suggesting that the quality of adult marriages may play a critical role in health outcomes. Improving the quality of marriages may reduce risk factors, such as depression, that potentate future physical health problems.

Protein Folding Stability Profiling of Colorectal Cancer Chemoresistance Identifies Functionally Relevant Biomarkers.

Reported here is the application of three protein folding stability profiling techniques (including the stability of proteins from rates of oxidation, thermal protein profiling, and limited proteolysis approaches) to identify differentially stabilized proteins in six patient-derived colorectal cancer (CRC) cell lines with different oxaliplatin sensitivities and eight CRC patient-derived xenografts (PDXs) derived from two of the patient derived cell lines with different oxaliplatin sensitivities. Compared to conventional protein expression level analyses, which were also performed here, the stability profiling techniques identified both unique and novel proteins and cellular components that differentiated the sensitive and resistant samples including 36 proteins that were differentially stabilized in at least two techniques in both the cell line and PDX studies of oxaliplatin resistance. These 36 differentially stabilized proteins included 10 proteins previously connected to cancer chemoresistance. Two differentially stabilized proteins, fatty acid synthase and elongation factor 2, were functionally validated in vitro and found to be druggable protein targets with biological functions that can be modulated to improve the efficacy of CRC chemotherapy. These results add to our understanding of CRC oxaliplatin resistance, suggest biomarker candidates for predicting oxaliplatin sensitivity in CRC, and inform new strategies for overcoming chemoresistance in CRC.

Temporal transcriptional control of neural induction in human induced pluripotent stem cells.

Introduction: Neural induction of human induced pluripotent stem cells represents a critical switch in cell state during which pluripotency is lost and commitment to a neural lineage is initiated. Although many of the key transcription factors involved in neural induction are known, we know little of the temporal and causal relationships that are required for this state transition. Methods: Here, we have carried out a longitudinal analysis of the transcriptome of human iPSCs undergoing neural induction. Using the temporal relationships between the changing profile of key transcription factors and subsequent changes in their target gene expression profiles, we have identified distinct functional modules operative throughout neural induction. Results: In addition to modules that govern loss of pluripotency and gain of neural ectoderm identity, we discover other modules governing cell cycle and metabolism. Strikingly, some of these functional modules are retained throughout neural induction, even though the gene membership of the module changes. Systems analysis identifies other modules associated with cell fate commitment, genome integrity, stress response and lineage specification. We then focussed on OTX2, one of the most precociously activated transcription factors during neural induction. Our temporal analysis of OTX2 target gene expression identified several OTX2 regulated gene modules representing protein remodelling, RNA splicing and RNA processing. Further CRISPRi inhibition of OTX2 prior to neural induction promotes an accelerated loss of pluripotency and a precocious and aberrant neural induction disrupting some of the previously identified modules. Discussion: We infer that OTX2 has a diverse role during neural induction and regulates many of the biological processes that are required for loss of pluripotency and gain of neural identity. This dynamical analysis of transcriptional changes provides a unique perspective of the widespread remodelling of the cell machinery that occurs during neural induction of human iPSCs.

Serial indirect effects from childhood maltreatment to adult chronic health conditions through contemporary family relationships and mental health problems: Inquiry into sleep disturbances and stress.

OBJECTIVE: Childhood maltreatment accelerates biological aging, leaving adults vulnerable to chronic health problems. There is robust evidence that social relationships, including those with family members, may influence chronic health problems through psychological pathways, but there is little research considering stress and sleep problems, especially among adults who experienced childhood maltreatment. Furthermore, longitudinal research is lacking related to maltreatment and chronic health problems. The current study examined familial support and strain and subsequent sleep problems and stress in a serial mediational model linking childhood maltreatment to chronic health problems over time. METHOD: Using three waves of data from the study of Midlife Development in the United States (N = 859; 55.8% female), structural equation modeling was used to examine familial support, strain, stress, and sleep problems in serial mediational model linking maltreatment to the number of chronic health conditions over a 9-year period. RESULTS: Childhood maltreatment was indirectly associated with a number of chronic health conditions through familial support and strain through subsequent reports of stress. Although family support was associated with fewer sleep problems, the bootstrapped indirect effect was not significant. Simple indirect effects from maltreatment to the number of chronic health problems were significant through both sleep problems and stress. CONCLUSION: Contemporary family relationships and psychological problems are possible points of prevention and intervention reducing the number of chronic health conditions among adults who were maltreated in childhood. Focusing on familial relationships and stress processes may be particularly fruitful. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Does Forgiveness Enhance Or Detract From Relationship Quality Among Sexual Abuse Survivors?

Many women experience childhood sexual abuse (CSA) during their childhood and CSA often negatively impacts adult's romantic relationships. Consequently, it is important to understand the protective factors that buffer against the detrimental impact of CSA on the quality of women's romantic relationships. Forgiveness may be one such factor. The current study looked at trait forgiveness as a moderator of CSA and overall relationship quality, positive relationship quality, and negative relationship quality. A sample of 171 women completed an online survey. Using hierarchical regression, forgiveness was found to moderate the association between CSA and overall relationship quality and negative relationship quality, but not positive relationship quality. Findings indicate that the interaction between CSA and forgiveness was significant, but higher levels of forgiveness actually decreased overall relationship quality and increased negative relationship quality. The relationship between CSA and overall reports of relationship quality and negative relationship quality were stable at low levels of forgiveness, but when forgiveness was high overall relationship quality decreased and negative relationship quality increased. CSA was also directly associated with lower levels of positive relationship quality. Findings from the study indicate continued conceptual refinement when considering CSA, forgiveness, and relationship quality.

High-Throughput Neutralization and Serology Assays Reveal Correlated but Highly Variable Humoral Immune Responses in a Large Population of Individuals Infected with SARS-CoV-2 in the US between March and August 2020.

The ability to measure neutralizing antibodies on large scale can be important for understanding features of the natural history and epidemiology of infection, as well as an aid in determining the efficacy of interventions, particularly in outbreaks such as the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Because of the assay's rapid scalability and high efficiency, serology measurements that quantify the presence rather than function of serum antibodies often serve as proxies of immune protection. Here, we report the development of a high-throughput, automated fluorescence-based neutralization assay using SARS-CoV-2 virus to quantify neutralizing antibody activity in patient specimens. We performed large-scale testing of over 19,000 COVID-19 convalescent plasma (CCP) samples from patients who had been infected with SARS-CoV-2 between March and August 2020 across the United States. The neutralization capacity of the samples was moderately correlated with serological measurements of anti-receptor-binding domain (RBD) IgG levels. The neutralizing antibody levels within these convalescent-phase serum samples were highly variable against the original USA-WA1/2020 strain with almost 10% of individuals who had had PCR-confirmed SARS-CoV-2 infection having no detectable antibodies either by serology or neutralization, and ~1/3 having no or low neutralizing activity. Discordance between neutralization and serology measurements was mainly due to the presence of non-IgG RBD isotypes. Meanwhile, natural infection with the earliest SARS-CoV-2 strain USA-WA1/2020 resulted in weaker neutralization of subsequent B.1.1.7 (alpha) and the B.1.351 (beta) variants, with 88% of samples having no activity against the BA.1 (omicron) variant. IMPORTANCE The ability to directly measure neutralizing antibodies on live SARS-CoV-2 virus in individuals can play an important role in understanding the efficacy of therapeutic interventions or vaccines. In contrast to functional neutralization assays, serological assays only quantify the presence of antibodies as a proxy of immune protection. Here, we have developed a high-throughput, automated neutralization assay for SARS-CoV-2 and measured the neutralizing activity of ~19,000 COVID-19 convalescent plasma (CCP) samples collected across the United States between March and August of 2020. These data were used to support the FDA's interpretation of CCP efficacy in patients with SARS-CoV-2 infection and their issuance of emergency use authorization of CCP in 2020.