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Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 SARS-CoV-2 antigens. In a prospective longitudinal cohort of 240 healthcare workers, composite SARS-CoV-2 IgG antibody levels did not wane significantly over a 6-month study period. In the subset of the study population previously exposed to SARS-CoV-2 based on seropositivity for nucleocapsid antibodies, higher composite anti-spike IgG levels were measured before the vaccine but no significant difference from unexposed individuals was observed at 6 months. Age, vaccine type, or worker role did not significantly impact composite IgG levels, although non-significant trends towards lower antibody levels in older participants and higher antibody levels with Moderna vaccine were observed at 6 months. A small subset of our cohort were classified as having waning antibody titers at 6 months, and these individuals were less likely to work in patient care roles and more likely to have prior exposure to SARS-CoV-2.

T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft tumor models in human T-cell reconstituted immunodeficient mice, which have a number of limitations. To explore the efficacy of human TCEs in fully immunocompetent hosts, we developed a knock-in mouse model (hCD3E-epi) in which a 5-residue N-terminal fragment of murine CD3-epsilon was replaced with an 11-residue stretch from the human sequence that encodes for a common epitope recognized by anti-human CD3E antibodies in the clinic. T cells from hCD3E-epi mice underwent normal thymic development and could be efficiently activated upon crosslinking of the T-cell receptor with anti-human CD3E antibodies in vitro. Furthermore, a TCE targeting human CD3E and murine CD20 induced robust T-cell redirected killing of murine CD20-positive B cells in ex vivo hCD3E-epi splenocyte cultures, and also depleted nearly 100% of peripheral B cells for up to 7 days following in vivo administration. These results highlight the utility of this novel mouse model for exploring the efficacy of human TCEs in vivo, and suggest a useful tool for evaluating TCEs in combination with immuno-oncology/non-immuno-oncology agents against heme and solid tumor targets in hosts with a fully intact immune system.

Background Advances in human development sciences point to tremendous possibilities to promote healthy child development and well-being across life by proactively supporting safe, stable and nurturing family relationships (SSNRs), teaching resilience, and intervening early to promote healing the trauma and stress associated with disruptions in SSNRs. Assessing potential disruptions in SSNRs, such as adverse childhood experiences (ACEs), can contribute to assessing risk for trauma and chronic and toxic stress. Asking about ACEs can help with efforts to prevent and attenuate negative impacts on child development and both child and family well-being. Many methods to assess ACEs exist but have not been compared. The National Survey of Children's Health (NSCH) now measures ACEs for children, but requires further assessment and validation. Methods We identified and compared methods to assess ACEs among children and families, evaluated the acceptability and validity of the new NSCH-ACEs measure, and identified implications for assessing ACEs in research and practice. Results Of 14 ACEs assessment methods identified, 5 have been used in clinical settings (vs public health assessment or research) and all but 1 require self or parent report (3 allow child report). Across methods, 6 to 20 constructs are assessed, 4 of which are common to all: parental incarceration, domestic violence, household mental illness/suicide, household alcohol or substance abuse. Common additional content includes assessing exposure to neighborhood violence, bullying, discrimination, or parental death. All methods use a numeric, cumulative risk scoring methodology. The NSCH-ACEs measure was acceptable to respondents as evidenced by few missing values and no reduction in response rate attributable to asking about children's ACEs. The 9 ACEs assessed in the NSCH co-occur, with most children with 1 ACE having additional ACEs. This measure showed efficiency and confirmatory factor analysis as well as latent class analysis supported a cumulative risk scoring method. Formative as well as reflective measurement models further support cumulative risk scoring and provide evidence of predictive validity of the NSCH-ACEs. Common effects of ACEs across household income groups confirm information distinct from economic status is provided and suggest use of population-wide versus high-risk approaches to assessing ACEs. Conclusions Although important variations exist, available ACEs measurement methods are similar and show consistent associations with poorer health outcomes in absence of protective factors and resilience. All methods reviewed appear to coincide with broader goals to facilitate health education, promote health and, where needed, to mitigate the trauma, chronic stress, and behavioral and emotional sequelae that can arise with exposure to ACEs. Assessing ACEs appears acceptable to individuals and families when conducted in population-based and clinical research contexts. Although research to date and neurobiological findings compel early identification and health education about ACEs in clinical settings, further research to guide use in pediatric practice is required, especially as it relates to distinguishing ACEs assessment from identifying current family psychosocial risks and child abuse. The reflective as well as formative psychometric analyses conducted in this study confirm use of cumulative risk scoring for the NSCH-ACEs measure. Even if children have not been exposed to ACEs, assessing ACEs has value as an educational tool for engaging and educating families and children about the importance of SSNRs and how to recognize and manage stress and learn resilience.

This study examines whether corporate tax planning and financial reporting of income taxes vary systematically with CEO tenure. Using a CEO-firm fixed effects design, we find that the GAAP effective tax rate (ETR) is higher in the early years of the CEOs’ tenure and lowest in the last year of the CEOs’ tenure. In contrast, we find no difference in the cash ETR over the CEO’s tenure. These results suggest that the financial reporting of income taxes exhibits more variation over the CEO’s tenure than the underlying corporate tax planning and are consistent with managers being cautious in the financial reporting of income taxes early in their tenure. Further analysis shows that CEOs achieve these financial reporting outcomes in part by designating earnings as permanently reinvested and by using discretion in the reserve for uncertain tax benefits. These findings should be of interest to compensation committees and boards of directors, responsible for incentivizing and evaluating CEOs.

Recombinant adeno-associated viral (rAAV) vectors are frequently used for gene delivery to the central nervous system and are capable of transducing neurons and glia in vitro. In this study, seven serotypes of a rAAV vector expressing green fluorescent protein (GFP) were characterized for tropism and toxicity in primary cortical cells derived from embryonic rat brain. At 2 days after transduction, serotypes 1 and 5 through 8 expressed GFP predominately in glia, but by 6 days post-transduction expression was neuronal except for AAV5. AAV2 and 9 produced minimal GFP expression. Using cell viability assays, toxicity was observed at higher multiplicities of infection (MOI) for all serotypes except AAV2 and 9. The toxicity of AAV1 and 5–8 affected mostly glia as indicated by a loss of glial-marker immunoreactivity. A frameshift mutation in the GFP gene reduced overall toxicity for serotypes 1, 5 and 6, but not 7 and 8 suggesting that the toxicity was not solely due to the overexpression of GFP. Collectively, a differential tropism and toxicity was observed among the AAV serotypes on primary cortical cultures with an overall preferential glial transduction and toxicity.

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine-mediated neurodegeneration in a rodent model of Parkinson’s disease. In this study, we examined the neuroprotective effects of BMP7 against MA-mediated toxicity in dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase immunoreactivity (THir) while increasing terminal deoxynucleotidyl transferase–mediated dNTP nick end labeling. These toxicities were significantly antagonized by BMP7. Interaction of BMP7 and MA in vivo was first examined in CD1 mice. High doses of MA (10 mg/kg ×4 s.c.) significantly reduced locomotor activity and THir in striatum. I.c.v. administration of BMP7 antagonized these changes. In BMP7 +/− mice, MA suppressed locomotor activity and reduced TH immunoreactivity in nigra reticulata to a greater degree than in wild type BMP7 +/+ mice, suggesting that deficiency in BMP7 expression increases vulnerability to MA insults. Since BMP7 +/− mice also carry a LacZ-expressing reporter allele at the BMP7 locus, the expression of BMP7 was indirectly measured through the enzymatic activity of β-galactosidase (β-gal) in BMP7 +/− mice. High doses of MA significantly suppressed β-gal activity in striatum, suggesting that MA may inhibit BMP7 expression at the terminals of the nigrostriatal pathway. A similar effect was also found in CD1 mice in that high doses of MA suppressed BMP7 mRNA expression in nigra. In conclusion, our data indicate that MA can cause lesioning in the nigrostriatal dopaminergic terminals and that BMP7 is protective against MA-mediated neurotoxicity in central dopaminergic neurons. Published by Elsevier Ltd on behalf of IBRO.

We examine the determinants of negative media coverage of corporate taxes as well as whether and how firms respond to media scrutiny. Prior literature demonstrates that the business press can act as an information intermediary and/or an entertainment provider. We test which of these roles the media primarily serve in their coverage of corporate income taxes by developing a selection model to identify which firm characteristics increase the probability of negative coverage. Our analysis reveals that negative media coverage is increasing in firms’ tax aggressiveness and in the extent of firms’ foreign operations, which suggests the media serve at least some role as information intermediaries. We find no evidence that firms reduce their level of tax avoidance following negative media attention but do find they report smaller reserves for uncertain tax positions. We also test for changes in disclosure quality and document an increase in passive voice and ambiguous language in income tax footnote disclosures. Thus, it appears firms’ primary response to negative media coverage is a decrease in disclosure readability rather than a change in economic activity. Our findings suggest that the media do not influence firms’ tax avoidance activity, which should be of interest to boards and shareholders.

We propose that investors rely on tax rate heuristics to reduce information processing costs associated with understanding complex income tax information and examine which rate investors use to impound income taxes into firm value. We find that the top U.S. statutory rate is more associated with firm value than the firm’s prior year effective tax rate (ETR), prior three-year average ETR or prior-year industry-average ETR. However, we find that investors rely less on the statutory tax rate when the benefits (costs) of doing so are higher (lower). Specifically, when firms have more opportunities for long-term tax savings or when information processing costs are lower investors rely less on the statutory tax rate. Our findings have implications for management in communicating tax information to investors and for standard setters in understanding which tax information investors use.

We examine how different accounting metrics used to evaluate CEO performance for annual bonuses affect the level of corporate tax planning as well as financial reporting for income taxes. We predict and find that firms using cash flow metrics report lower GAAP and cash effective tax rates (ETR) than firms using earnings metrics. We also find that firms using after-tax earnings metrics report lower GAAP ETRs but similar cash ETRs as firms using pre-tax earnings metrics. Further analyses show that firms using after-tax earnings metrics are more likely to designate foreign earnings as permanently reinvested and have lower discretionary reserves for tax uncertainty. Hence, it appears that both types of firms engage in similar levels of tax planning, but firms evaluating CEOs with after tax-earnings metrics incentivize different financial reporting choices.

Thromboelastography (TEG) presents a novel testing environment to detect functional antibodies associated with heparin-induced thrombocytopenia (HIT). TEG is considered a qualitative and qualitative method for assess global hemostasis in a test environment that includes shear stresses. In this study we explore the sensitivity of TEG to detect a HIT-associated reaction when whole blood or platelet rich plasma (PRP) is mixed with heat inactivated positive HIT sera in the presence of low dose (0.2U/mL) or high dose (100U/mL) sodium heparin. TEG is designed to record the kinetic changes in whole blood or plasma-based samples during clot initiation, propagation and fibrinolysis. Here we show that HIT positive sera can cause a reaction in both whole blood and PRP when exposed to reactive normal donor whole blood or PRP. Curiously, whole blood was shown to be more sensitive to the presence of HIT positive sera than PRP. The ration of heat-inactivated sera to donor whole blood or PRP was 1 to 2 parts. HIT positive sera was obtained from a patient that was clinical diagnosed with HIT type II and had a clinically significant positive ELISA with an optical density of 1.735 ± 0.032. HIT positive sera with ELISA optical densities above 1.000 or associated with an enhanced likelihood of developing thrombosis. Additionally, the HIT positive sera was functionally positive with 13 qualified, reactive HIT normal platelet donors with a washed-platelet heparin-induced platelet activation (wp-HIPA) average result of 66 ± 11%. The wp-HIPA is an established reference method or GOLD STANDARD assay for the diagnosis of HIT. The positive TEG detection of this functional HIT antibody may reveal another, more rapid test approach for the hospital and reference laboratory diagnosis of HIT. Additional studies are warranted to further characterize the comparative sensitivities of TEG and wp-HIPA and other reference methods for the diagnosis of HIT. Disclosures No relevant conflicts of interest to declare.

We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, we report the stable allotopic expression, import and function of two mitochondria encoded genes, ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.

Between May 1875 and December 1879, Vincent van Gogh's life was marked by a devout evangelical piety, distinctly different from what had gone before. Although raised in a religious family, his father a Dutch Reformed minister in the Groningen tradition, van Gogh barely mentions religion in his early letters.l His religious fervor deepened considerably, however, sometime during 1875, while he was living in Paris. Van Gogh's letters dating from May 1875 are increasingly filled with biblical quotations and religious reflections.2 His sister-in-law, Jo van Gogh-Bonger, in describing van Gogh's character during this period wrote, "that was Vincent's aim-to humble himself, to forget himself, 'mourir a soi-meme,' (to sacrifice every personal desire), that was the ideal he tried to reach as long as he sought his refuge in religion, and he never did a thing by halves."3 She argues that this change in van Gogh's character occurred when he returned home from London in July, 1874. "From that time on there was a change in his character: he inclined more and more toward religious fanaticism and led a secluded life."4 Van Gogh's sister-in-law attributed this change to an unrequited love for Ursula (actually Eugenie) Loyer, in whose boarding house van Gogh lived while in London. Most of van Gogh's biographers

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet β-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine–induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD.

Viral vector toxicity is a primary concern in choosing an optimal gene delivery vehicle for either studying biological phenomena or evaluating potential therapeutic strategies. Generally, adenoassociated viral vectors are thought to be among the least toxic viral vectors. Currently, over 100 serotypes of AAV have been identified or produced and the tropism of the serotypes varies. In the central nervous system, studies have shown serotypes 1, 2, 5, 6, 7, 8, 9 and 10 are capable of transduction. We have previously reported the transduction of primary neuronal cultures by serotypes 1, 2, 5, and 6. Here, we compare the toxicity of serotypes 1, 2, 5, 6, 7, 8 and 9 and tropism of serotypes 7, 8 and 9 on primary cortical cultures derived from rat embryonic brain tissue. A self-complementing AAV vector containing modified AAV2 terminal repeats flanking a green fluorescent protein expressed from the CMV promoter was packaged using the cap gene from AAV serotypes 1, 2, 5, 6, 7, 8, or 9. All vectors were purified by CsCl centrifugation. Cultures were infected on DIV6 then examined for GFP fluorescence, toxicity and immunoreactivity on DIV8 and 12. At 48 hours after infection at a comparable MOI of 10000, only serotype 1 showed significant toxicity as determined by LDH assay. Using an MTS assay, similar toxicity was observed at an MOI of 100000; however, at a higher MOI, serotypes 1, 6, 7 and 8 exhibited greater toxicity than serotypes 2, 5 and 9. One week after infection, serotypes 7 and 8 resulted in primarily NeuN+ colocalized with GFP fluorescence, however, GFAP+ fibers expressing GFP were detected. Serotype 9 infected both NeuN+ and GFAP+ cells. Overall, AAV serotypes 1, 2, 5, 6, 7, 8 and 9 transduce rat neurons and glia in vitro with varied efficiency and toxicity.

Competence to stand trial is a constitutional prerequisite to adjudication of criminal cases and essential to preserving the fairness, accuracy, dignity, and autonomy of criminal proceedings. Psychologists are called upon to address the issue of competence more often than any other issue in the criminal law. Increasingly, case law developments and psychological formulations of the concept of trial competence have focused on not only the knowledge-based or foundational aspects of competence, but the decisional aspects as well. Competency assessment instruments, multiple sources of data, and psychological measures of cognitive functions, personality, and malingering contribute to the evaluation of competency. The task is complicated by the need to consider the relationship between psycho-legal impairments and symptoms of psychopathology and by the fluid nature of competency across time and across specific case demands. The empirical literature on correlates and factors associated with competence provides some support for the validity of psychological opinions regarding trial competence. Treatment, the needs of special populations, competency assistance strategies, and the problem of the permanently incompetent defendant are further considerations in the evaluation of competence. Psychology makes a significant contribution to the understanding of trial competence through the development of measures, theoretical and empirical research, assessment and treatment, and consultation with courts and attorneys. Keywords: assessment; attorneys; competence; court; crime; defendant; trial

Summer flounder, Paralichthys dentatus, culture is becoming increasingly popular in the United States because of high market prices and consumer demand. In addition, flounder is a marine fish species that can tolerate a wide range of salinities, allowing for inland intensive fish culture. Oxytetracycline (OTC) is one of two available FDA-approved antibiotics for use in foodfish in the United States. Oxytetracycline was chosen for these studies because it is excreted primarily unchanged through the urine and the absorption, distribution and elimination of this drug may be influenced by environmental and physiological conditions. Four experiments were conducted to investigate: 1) pharmacokinetic parameters of oxytetracycline (50 mg/kg) following intravascular (IV), intraperitoneal (IP), intramuscular (IM) and per os (PO) administration in summer flounder maintained at 28 ppt salinity and 20°C; 2) pharmacokinetic parameters of OTC (50 mg/kg) following IM and PO administration in summer flounder maintained at three different salinity levels of 0 ppt, 15 ppt and 32 ppt and the physiological adjustments summer flounder make to acclimate to environmental salinity; 3) OTC retention times in muscle tissue from summer flounder maintained at three different salinity levels (0 ppt, 15 ppt, 32 ppt) and treated with a single 50 mg/kg OTC dose via IM and PO administration; and 4) pharmacokinetic parameters of OTC (50 mg/kg) following IM and PO administration in clinically healthy and clinically diseased summer flounder maintained at 28 ppt and 20°C. Oxytetracycline plasma concentrations were determined using high performance liquid chromatography (HPLC) and analyzed using a non-compartmental pharmacokinetic model for all routes of drug administration. Statistical comparisons were not made between the different routes of OTC exposure, but results from experiment one indicated that IV administration of OTC resulted in the largest area under the curve (AUC) value (8147.9 µg·h/ml) and the highest maximum plasma concentration (Cmax) of 1173.2 µg/ml OTC at 5 min post-injection. Intramuscular injections of OTC resulted in prolonged total body elimination half-life (T ½) of 301.3 h and high fish-to-fish variability (0.6). Per os administration resulted in low Cmax (0.2 µg/ml OTC) and poor systemic bioavailability (0.2 %). Results from experiment two demonstrated that when OTC is administered IM AUC estimates are significantly (p

Skin tests and in vitro histamine-release reactions were used to evaluate 130 patients observed in an employee allergy clinic at a biomedical research facility. The allergens used included extracts from pollens (ragweed, grasses, trees, weeds), molds, mixed feathers, house dust, cat, dog, mouse, rat, rabbit, guinea pig, and hamster. Of all patients, 66% complained of allergic symptoms on laboratory animal exposure, although only 52% worked directly with animals. Among patients with symptoms, 91% were positive by skin test to at least one laboratory animal, and 46% had asthma. The median length of exposure to laboratory animals before onset of symptoms was 2.8 yr with 60% of the patients developing their symptoms within 3 yr. Among patients who had allergic symptoms before exposure to laboratory animals, 79% were skin test positive to laboratory animals when they were evaluated in this study. There was a close association found between the skin test and histamine-release results with the laboratory animal allergens: 91% of the 4+ skin reactors had leukocytes positive for histamine release versus 5% of the leukocyte donors with less than 1+ skin reactions. A close relationship in positive reactions to different laboratory animal allergens was also found. For example, individuals positive to mouse were positive also to rat (95%), rabbit (79%), guinea pig (83%), and hamster (88%). Patients who reacted to laboratory animals also reacted to some extent to house dust and cat and dog allergens, and about one half of the animal-allergic individuals reacted to pollens. Although nonpollen-allergic individuals can develop sensitivity to laboratory animals, the group at higher risk are allergic individuals, especially those sensitive to house dust, cats, or dogs.