Search

An abstract of the study "Genetic Engineering of Goats for the Production of Biosimilar Antibody in Milk," by G. Laible and colleagues is presented.

Neighborhood safety is defined inconsistently across epidemiologic studies - a conceptual problem that results in incomparable measurements, hampering the design of health interventions. Using child behavior problems (measured via the Child Behavior Checklist) as the outcome of interest, this study directly compared four measures of neighborhood safety: two of experienced safety and two of perceived safety, with each one measured at family and community levels. These included children's direct experience of harm, parental perceptions, community crime statistics, and community perceptions. In a sample of 3291 ten-year-olds from the Generation R cohort (living in municipal Rotterdam, Netherlands, 2013), all four measures were correlated (χ2 ≥ 9.2, P < 0.002 in pairwise chi-square comparisons), but ultimately identified different levels of risk for behavioral health. Direct experiences of harm, parental perceptions, and community crime statistics were all associated with increased child internalizing behaviors (β = 3.12, β = 2.10, and β = 1.77, respectively), while only experiences of harm and parental perceptions were associated with increased externalizing behaviors (β = 2.75 and β = 1.31, respectively). These results provide novel evidence that the conceptual distinctions underlying different measures of neighborhood safety are meaningful for child mental health and should be considered in intervention design., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: There is widespread recognition of the importance and complexity of measuring neighborhood contexts within research on child psychopathology. In this study, we assessed the cross-sectional associations between two measures of neighborhood quality and internalizing and externalizing behaviors in preadolescence., Methods: Drawing on baseline data from the Adolescent Brain Cognitive Development Study (n = 10,577 preadolescents), we examined two multi-component assessments of neighborhood quality in relation to children's internalizing and externalizing symptoms: the Area Deprivation Index (ADI), which measures socioeconomic adversity, and the Child Opportunity Index 2.0 (COI), which measures economic, educational, and environmental opportunity. Both measures were categorized into quintiles. We then used mixed-effects linear regression models to examine bivariate and adjusted associations., Results: The bivariate associations displayed strong inverse associations between the COI and ADI and externalizing symptoms, with a graded pattern of fewer externalizing behaviors with increasing neighborhood quality. Only the ADI was associated with externalizing behaviors in models adjusted for child and family characteristics. We did not observe a clear association between either measure of neighborhood quality and internalizing behaviors in bivariate or adjusted models., Conclusions: Neighborhood quality, as measured by the COI and ADI, was associated with externalizing behaviors in preadolescent children. The association using the ADI persisted after adjustment for family-level characteristics, including financial strain. Our results indicate that different assessments of neighborhood quality display distinct associations with preadolescent behavioral health. Future research is needed to assess the association between neighborhood quality and behavior trajectories and to identify place-based intervention strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Air pollution causes premature death and disease and disproportionately harms non-white and lower-income groups in the United States. Government policies are responsible for the racial disparity in air pollution exposure and related health outcomes. Investigating complex relationships between policies, air pollution, and health requires (i) harmonized data connecting policies, environmental exposures, socioeconomic characteristics, and health at the individual and area level; (ii) interpretable estimands accounting for the complex interplay between policies and disparities in exposures and health outcomes; and (iii) data science approaches that can elucidate direct and indirect policy effects on disparities to identify effective interventions. We review statistical considerations and new data science approaches needed to scrutinize the policy impacts on disparities in air pollution exposure and health outcomes.

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS., Methods: A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures., Results: A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) C9orf72 hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ATXN2 ("ATXN2"). Flocculonodular lobule ( p adj = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura ( p adj = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients ( p adj = 0.003, t (249) = 3.04 and p adj = 0.05, t (249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline ( p adj = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline ( p adj = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection ( p adj = 0.025, t (199) = -2.26), and progressive flocculonodular lobule degeneration ( p adj = 0.017, t (249) = -2.24). C9POS patients showed progressive ventral dentate atrophy ( p adj = 0.007, t (249) = -2.75). The CSTs ( p adj < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers ( p adj < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection ( p adj = 0.001, t (190) = 6.93)., Discussion: ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.

Background : While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods : A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72 . A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results : Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72 -positive ALS patients. Conclusions : Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

Purpose: Positive dimensions of psychological well-being in adolescence may help youth preserve cardiometabolic health (CMH) as they age, but little is known about which aspects of well-being matter most and for whom. This study examines the differential impact of five dimensions of adolescent psychological well-being on CMH maintenance in adulthood and considers social patterning in both their distribution and respective health benefits., Methods: Data were from the National Longitudinal Study of Adolescent Health (N = 3,464), five dimensions of psychological well-being were identified at baseline (1994-1995; mean age = 15 years): happiness, optimism, self-esteem, belonging, and feeling loved. CMH was measured using seven biomarkers related to chronic disease risk in 2008 (mean age = 28 years) and 2016-2018 (mean age = 38 years): high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, C-reactive protein, and body mass index. CMH maintenance in adulthood was characterized as having healthy levels of ≥6 biomarkers at each follow-up., Results: Youth who reported higher levels of belonging in the teen years were more likely to maintain CMH across young adulthood than those who reported lower levels, regardless of one's social standing (OR per 1- standard deviation  = 1.23, 95% CI = 1.03-1.46). Associations with other dimensions of well-being were heterogeneous by sex and race and ethnicity, while differences by socioeconomic factors were less apparent., Discussion: Fostering belonging through supportive social environments may help set youth on positive health trajectories and prevent chronic disease across the lifespan., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Cadherin-17 (CDH17) is a calcium-dependent cell adhesion protein that is overexpressed in several adenocarcinomas, including gastric, colorectal, and pancreatic adenocarcinoma. High levels of CDH17 have been linked to metastatic disease and poor prognoses in patients with these malignancies, fueling interest in the protein as a target for diagnostics and therapeutics. Herein, we report the synthesis, in vitro validation, and in vivo evaluation of a CDH17-targeted 89 Zr-labeled immunoPET probe., Methods: The CDH17-targeting mAb D2101 was modified with an isothiocyanate-bearing derivative of desferrioxamine (DFO) to produce a chelator-bearing immunoconjugate - DFO-D2101 - and flow cytometry and surface plasmon resonance (SPR) were used to interrogate its antigen-binding properties. The immunoconjugate was then radiolabeled with zirconium-89 (t 1/2 ~ 3.3 days), and the serum stability and immunoreactive fraction of [ 89 Zr]Zr-DFO-D2101 were determined. Finally, [ 89 Zr]Zr-DFO-D2101's performance was evaluated in a trio of murine models of pancreatic ductal adenocarcinoma (PDAC): subcutaneous, orthotopic, and patient-derived xenografts (PDX). PET images were acquired over the course of 5 days, and terminal biodistribution data were collected after the final imaging time point., Results: DFO-D2101 was produced with a degree of labeling of ~ 1.1 DFO/mAb. Flow cytometry with CDH17-expressing AsPC-1 cells demonstrated that the immunoconjugate binds to its target in a manner similar to its parent mAb, while SPR with recombinant CDH17 revealed that D2101 and DFO-D2101 exhibit nearly identical K D values: 8.2 × 10 -9 and 6.7 × 10 -9 M, respectively. [ 89 Zr]Zr-DFO-D2101 was produced with a specific activity of 185 MBq/mg (5.0 mCi/mg), remained >80% stable in human serum over the course of 5 days, and boasted an immunoreactive fraction of >0.85. In all three murine models of PDAC, the radioimmunoconjugate yielded high contrast images, with high activity concentrations in tumor tissue and low uptake in non-target organs. Tumoral activity concentrations reached as high as >60 %ID/g in two of the cohorts bearing PDXs., Conclusion: Taken together, these data underscore that [ 89 Zr]Zr-DFO-D2101 is a highly promising probe for the non-invasive visualization of CDH17 expression in PDAC. We contend that this radioimmunoconjugate could have a significant impact on the clinical management of patients with both PDAC and gastrointestinal adenocarcinoma, most likely as a theranostic imaging tool in support of CDH17-targeted therapies., (© 2024. The Author(s).)

Introduction: The potential role of pathogens, particularly vector-transmitted infectious agents, as a cause of psychosis has not been intensively investigated. We have reported a potential link between Bartonella spp. bacteremia and neuropsychiatric symptoms, including pediatric acute onset neuropsychiatric syndrome and schizophrenia. The purpose of this study was to further assess whether Bartonella spp. exposure or infection are associated with psychosis., Methods: In a blinded manner, we assessed the presence of anti- Bartonella antibodies by indirect immunofluorescence assays (IFA), and infection by amplification of bacterial DNA from blood by quantitative polymerase chain reaction (qPCR), digital PCR (dPCR), and droplet digital PCR (ddPCR) in 116 participants. Participants were categorized into one of five groups: 1) controls unaffected by psychosis ( n = 29); 2) prodromal participants ( n = 16); 3) children or adolescents with psychosis ( n = 7); 4) adults with psychosis ( n = 44); and 5) relatives of a participant with psychosis ( n = 20)., Results: There was no significant difference in Bartonella spp. IFA seroreactivity between adults with psychosis and adult controls unaffected by psychosis. There was a higher proportion of adults with psychosis who had Bartonella spp. DNA in the bloodstream (43.2%) compared to adult controls unaffected by psychosis (14.3%, p = 0.021). The Bartonella species was determined for 18 of the 31 bacteremic participants, including infection or co-infection with Bartonella henselae (11/18), Bartonella vinsonii subsp. b erkhoffii (6/18), Bartonella quintana (2/18), Bartonella alsatica (1/18), and Bartonella rochalimae (1/18)., Discussion: In conjunction with other recent research, the results of this study provide justification for a large national or international multi-center study to determine if Bartonella spp. bacteremia is more prevalent in adults with psychosis compared to adults unaffected by psychosis. Expanding the investigation to include a range of vector-borne and other microbial infections with potential CNS effects would enhance knowledge on the relationship between psychosis and infection., Competing Interests: In conjunction with Dr. S. Sontakke and North Carolina State University, EB holds US Patent No. 7,115,385 Media and Methods for Cultivation of Microorganisms, which was issued on October 3rd, 2006. He is a co-founder, shareholder and Chief Scientific Officer for Galaxy Diagnostics, a company that provides advanced diagnostic testing for the detection of Bartonella spp. infections. RM is a co-founder and the Chief Technical Officer for Galaxy Diagnostics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Delaney, Robveille, Maggi, Lashnits, Kingston, Liedig, Murray, Fallon and Breitschwerdt.)

Background: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease., Methods: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS., Results: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured., Conclusions: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect., (© 2024. The Author(s).)

Lay Abstract: Existing research has identified an increased risk of depression among autistic adults, which can negatively impact their adaptive functioning abilities and socioeconomic outcomes. Mobile app-based meditation is a feasible, accessible, and effective self-care solution for depression among neurotypical adults, but there is limited evidence for the long-term benefits of app-based meditation among autistic adults. Habits are a key behavioral strategy for maintaining behavior change, and anchoring is one effective habit formation intervention that has yet to be tested among autistic adults. This study demonstrates that it is both feasible and effective to integrate the anchoring habit formation strategy into an app-based meditation intervention for establishing meditation habits among autistic adults. In addition, the study shows that app-based meditation habits were successful at maintaining reductions in depressive symptoms over 6 months. These results demonstrate the power of anchoring-based habit formation interventions for establishing healthy habits among autistic adults, which offers a promising behavioral intervention technique for establishing other healthy habits among autistic adults. The study also shows that app-based meditation habits are an effective long-term self-care solution for managing depressive symptoms among autistic adults that should be used by mental health providers and policymakers. Future research should test this combined anchoring and app-based meditation intervention technique among larger samples of autistic adults and over longer durations to better understand the mechanisms underlying the success of this intervention., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Decisions about how to divide resources have profound social and practical consequences. Do explanations regarding the source of existing inequalities influence how children and adults allocate new resources? When 3- to 6-year-old children (N = 201) learned that inequalities were caused by structural forces (stable external constraints affecting access to resources) as opposed to internal forces (effort), they rectified inequalities, overriding previously documented tendencies to perpetuate inequality or divide resources equally. Adults (N = 201) were more likely than children to rectify inequality spontaneously; this was further strengthened by a structural explanation but reversed by an effort-based explanation. Allocation behaviors were mirrored in judgments of which allocation choices by others were appropriate. These findings reveal how explanations powerfully guide social reasoning and action from childhood through adulthood., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While the impacts of social and environmental exposure on cardiovascular risks are often reported individually, the combined effect is poorly understood., Methods and Results: Using the 2022 Environmental Justice Index, socio-environmental justice index and environmental burden module ranks of census tracts were divided into quartiles (quartile 1, the least vulnerable census tracts; quartile 4, the most vulnerable census tracts). Age-adjusted rate ratios (RRs) of coronary artery disease, strokes, and various health measures reported in the Prevention Population-Level Analysis and Community Estimates data were compared between quartiles using multivariable Poisson regression. The quartile 4 Environmental Justice Index was associated with a higher rate of coronary artery disease (RR, 1.684 [95% CI, 1.660-1.708]) and stroke (RR, 2.112 [95% CI, 2.078-2.147]) compared with the quartile 1 Environmental Justice Index. Similarly, coronary artery disease 1.057 [95% CI,1.043-1.0716] and stroke (RR, 1.118 [95% CI, 1.102-1.135]) were significantly higher in the quartile 4 than in the quartile 1 environmental burden module. Similar results were observed for chronic kidney disease, hypertension, diabetes, obesity, high cholesterol, lack of health insurance, sleep <7 hours per night, no leisure time physical activity, and impaired mental and physical health >14 days., Conclusions: The prevalence of CVD and its risk factors is highly associated with increased social and environmental adversities, and environmental exposure plays an important role independent of social factors.

Introduction: Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts., Methods: We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClim TM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers' residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C)., Results: Weekly temperatures ranged from -5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1-28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: -1.6 SDS [95 %CI -2.0; -0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1-7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: -0.1 cm/week [-0.2; -0.04]), with a susceptibility period from weeks 4-12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes., Conclusions: Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Immunoglobulins, both full-length antibodies and smaller antibody fragments, have long been regarded as effective platforms for diagnostic and therapeutic radiopharmaceuticals. The construction of radiolabeled immunoglobulins (i.e., radioimmunoconjugates) requires the manipulation of the biomolecule through the attachment of a radiohalogen or the bioconjugation of a chelator that is subsequently used to coordinate a radiometal. Both synthetic approaches have historically relied upon the stochastic modification of amino acids within the immunoglobulin, a process which poses a risk to the structural and functional integrity of the biomolecule itself. Not surprisingly, radioimmunoconjugates with impaired antigen binding capacity will inevitably exhibit suboptimal in vivo performance. As a result, the biological characterization of any newly synthesized radioimmunoconjugate must include an assessment of whether it has retained its ability to bind its antigen. Herein, we provide straightforward and concise protocols for three assays that can be used to determine the immunoreactivity of a radioimmunoconjugate: (1) a cell-based linear extrapolation assay; (2) a cell-based antigen saturation assay; and (3) a resin- or bead-based assay. In addition, we will provide a critical analysis of the relative merits of each assay, an examination of the inherent limitations of immunoreactivity assays in general, and a discussion of other approaches that may be used to interrogate the biological behavior of radioimmunoconjugates., (© 2024. The Author(s).)

Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy's 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [ 89 Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLC─i.e., orthotopic, metastatic, and patient-derived xenografts─with the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the β-emitting radiometal 177 Lu─[ 177 Lu]Lu-DTPA-A″-CHX-αCD133─was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.

Objective: To develop an in-depth understanding of how people with COPD exercise power in the self-management of their illness., Methods: This was a narrative inquiry using Foucault's concepts of power, knowledge and agency as a conceptual framework. Up to three unstructured interviews were conducted with 31 people with COPD in the Republic of Ireland. Thematic template analysis was used to analyse the data. The COREQ checklist was used to report this qualitative study., Results: The findings of the study show that participants exercised power through mobilising agency in two main ways. They resisted the imposition of power by leveraging different types of knowledge. They also engaged in practices designed to operate on the self and the body in order to achieve happiness and health. However, this agency was constrained by the imposition of power by health care professionals., Conclusion: The findings expand the understanding of self-management as a complex and multi-dimensional concept that is negotiated and constructed by people with COPD, using their own knowledge and agency., Practice Implications: Honouring the considerable skills and resources that people with COPD mobilise to self-manage should form the heart of person-centred self-management support., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Microplastics and nanoplastics have become ubiquitous environmental pollutants. The threat these plastics pose to human health has fueled research focused on their pathophysiology and toxicology, yet many of their fundamental properties - for example, their in vivo pharmacokinetics - remain poorly understood. In this investigation, we have harnessed positron emission tomography (PET) to track the in vivo fate of micro- and nanoplastics administered to mice intratracheally and intravenously. To this end, 1 μm and 20 nm diameter amine-functionalized polystyrene particles were modified with an isothiocyanate-bearing variant of desferrioxamine (DFO) and radiolabeled with the positron-emitting radiometal [ 89 Zr]Zr 4+ . Both radioplastics - [ 89 Zr]Zr-DFO-PS1000 and [ 89 Zr]Zr-DFO-PS20 - were produced in ∼95% radiochemical yield and found to be >85% stable to demetallation over one week at 37 °C in human serum and simulated lung fluid. The incubation of [ 89 Zr]Zr-DFO-PS1000 and [ 89 Zr]Zr-DFO-PS20 with MH-S cells revealed that the majority of the former were phagocytosed by alveolar macrophages within 4 h, while the latter largely evaded consumption. Finally, the in vivo behavior of the radioplastics was interrogated in mice upon intravenous and intratracheal administration. PET imaging and biodistribution experiments revealed that the intravenously injected plastics accumulated primarily in the liver and spleen, yielding hepatic radioactivity concentrations of 101 ± 48 %ID/g and 92 ± 22 %ID/g at 168 h post-injection for [ 89 Zr]Zr-DFO-PS1000 and [ 89 Zr]Zr-DFO-PS20 , respectively. In contrast, the mice that received the radioplastics via intratracheal installation displayed the highest uptake in the lungs at the end of one week: 4 ± 2 %ID/g for [ 89 Zr]Zr-DFO-PS1000 and 32 ± 6 %ID/g for [ 89 Zr]Zr-DFO-PS20. Ultimately, this work illustrates the critical role that the route of exposure plays in the bioaccumulation of plastic particles, reveals that size dramatically influences the pulmonary retention of inhaled particles, and underscores the value of PET imaging as a tool for studying the pharmacokinetics of environmental pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The objective of this review is to explore critical illness survivors' experiences of attending an intensive care unit (ICU) follow-up service., Introduction: A significant proportion of critical illness survivors will require ICU follow-up care to support adverse symptoms in health domains, including cognition, mental health, and physical and social function. While there is consensus on the need for ICU follow-up services, systematic reviews to date have not identified any significant impact of ICU follow-up services on clinical health outcomes. An understanding of survivors' experiences of attending an ICU follow-up service may improve the effectiveness and design of such services., Inclusion Criteria: This review will include studies that explore the experiences of adult ( 18 years of age) critical illness survivors who attended an ICU follow-up service following discharge from an ICU, regardless of the admitting diagnosis or ICU length of stay., Methods: This review will be conducted in line with the JBI methodological framework for qualitative systematic reviews. Electronic databases, including MEDLINE, CINAHL, PsycINFO, Embase, and Web of Science Core Collection, will be searched to identify relevant studies for inclusion in the review. Studies will be screened by 2 independent reviewers. Critical appraisal, data extraction, and data synthesis will be completed by 2 independent reviewers using a meta-aggregation method for data synthesis. Confidence in the research findings will be assessed and assigned a ConQual score., Review Registration: PROSPERO CRD42023404585., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 JBI.)

Purpose: Site-specific approaches to bioconjugation produce well-defined and homogeneous immunoconjugates with potential for superior in vivo behavior compared to analogs synthesized using traditional, stochastic methods. The possibility of incorporating photoaffinity chemistry into a site-specific bioconjugation strategy is particularly enticing, as it could simplify and accelerate the preparation of homogeneous immunoconjugates for the clinic. In this investigation, we report the synthesis, in vitro characterization, and in vivo evaluation of a site-specifically modified, 89 Zr-labeled radioimmunoconjugate created via the reaction between an mAb and an Fc-binding protein bearing a photoactivatable 4-benzoylphenylalanine residue., Procedures: A variant of the Fc-binding Z domain of protein A containing a photoactivatable, 4-benzoylphenylalanine residue - Z(35BPA) - was modified with desferrioxamine (DFO), combined with the A33 antigen-targeting mAb huA33, and irradiated with UV light. The resulting immunoconjugate - DFO Z(35BPA) -huA33 - was purified and characterized via SDS-PAGE, MALDI-ToF mass spectrometry, surface plasmon resonance, and flow cytometry. The radiolabeling of DFO Z(35BPA) -huA33 was optimized to produce [ 89 Zr]Zr-DFO Z(35BPA) -huA33, and the immunoreactivity of the radioimmunoconjugate was determined with SW1222 human colorectal cancer cells. Finally, the in vivo performance of [ 89 Zr]Zr-DFO Z(35BPA) -huA33 in mice bearing subcutaneous SW1222 xenografts was interrogated via PET imaging and biodistribution experiments and compared to that of a stochastically labeled control radioimmunoconjugate, [ 89 Zr]Zr-DFO-huA33., Results: HuA33 was site-specifically modified with Z(35BPA)-DFO, producing an immunoconjugate with on average 1 DFO/mAb, high in vitro stability, and high affinity for its target. [ 89 Zr]Zr-DFO Z(35BPA) -huA33 was synthesized in 95% radiochemical yield and exhibited a specific activity of 2 mCi/mg and an immunoreactive fraction of ~ 0.85. PET imaging and biodistribution experiments revealed that high concentrations of the radioimmunoconjugate accumulated in tumor tissue (i.e., ~ 40%ID/g at 120 h p.i.) but also that the Z(35BPA)-bearing immunoPET probe produced higher uptake in the liver, spleen, and kidneys than its stochastically modified cousin, [ 89 Zr]Zr-DFO-huA33., Conclusions: Photoaffinity chemistry and an Fc-binding variant of the Z domain were successfully leveraged to create a novel site-specific strategy for the synthesis of radioimmunoconjugates. The probe synthesized using this method - DFO Z(35BPA) -huA33 - was well-defined and homogeneous, and the resulting radioimmunoconjugate ([ 89 Zr]Zr-DFO Z(35BPA) -huA33) boasted high specific activity, stability, and immunoreactivity. While the site-specifically modified radioimmunoconjugate produced high activity concentrations in tumor tissue, it also yielded higher uptake in healthy organs than a stochastically modified analog, suggesting that optimization of this system is necessary prior to clinical translation., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

The use of race in maternal serum screening is problematic because race is a social construct rather than a distinct biological classifier. Nevertheless, laboratories offering this testing are encouraged to use race-specific cutoff values for maternal serum screening biomarkers to determine the risk of fetal abnormalities. Large cohort studies examining racial differences in maternal serum screening biomarker concentrations have yielded conflicting results, which we postulate may be explained by genetic and socioeconomic differences between racial cohorts in different studies. We recommend that the use of race in maternal serum screening should be abandoned. Further research is needed to identify socioeconomic and environmental factors that contribute to differences in maternal serum screening biomarker concentrations observed between races. A better understanding of these factors may facilitate accurate race-agnostic risk estimates for aneuploidy and neural tube defects., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: To examine how self-management is conceptualised in the research literature on chronic obstructive pulmonary disease (COPD)., Methods: A narrative review was undertaken to search the research literature on COPD self-management. Ten databases (2000-2021) were searched for published texts. Sixty-two articles met the inclusion criteria. A thematic analysis was conducted of the literature., Results: Three conceptualisations of COPD self-management were identified: 1) a dominant medicocentric conceptualisation which represented self-management as medical in focus; 2) a less dominant experiential conceptualisation that viewed it as arising from the experiences of people living with COPD; and 3) a smaller body of literature that attempted to integrate medicocentric and experiential conceptualisations of self-management., Discussion: The dominance of the medicocentric conceptualisation of self-management and the polarisation of medicocentric and experiential perspectives were striking. An integrated conceptualisation of self-management has the potential to unite these competing perspectives and promote collaborative relationships between individuals and professionals, so long as the underlying values informing it are made explicit. However, there is a dearth of literature on this approach and it would benefit from more attention. Methods such as Co-production and the Personal Outcomes Approach offer the potential to support an integrated perspective in clinical practice.

Objectives: We evaluate the potential of paired isotopic analysis of bone carbonate and collagen to examine the diet of post-medieval human and animal populations from England (17th-19th c.), including, for the first time, manufacturing towns in northern England. The potential for identifying C 4 crop consumption is explored alongside regional and local patterning in diet by sex and socioeconomic status., Materials and Methods: Humans (n = 216) and animals (n = 168) were analyzed from sites in London and northern England for both carbon and nitrogen isotopes of bone collagen (𝛿 13 C coll , 𝛿 15 N coll ). Isotopic analysis of bone carbonates (𝛿 13 C carb , 𝛿 18 O carb ) was carried out on all humans and 27 animals, using Fourier transform infrared spectroscopy-attenuated total reflectance to assess diagenesis., Results: Variations in diet were observed between and within different populations by geographical location and socioeconomic status. Three pigs and one cow consumed C 4 resources, indicating the availability of C 4 -fed animal protein. Londoners consumed more animal and marine protein and C 4 resources. Middle- and upper-class populations from both London and northern populations also had greater access to these foods compared to those of lower status in the same regions., Discussion: This substantial multi-isotope dataset deriving from bone carbonate and collagen combined from diverse post-medieval urban communities enabled, for the first time, the biomolecular identification of the dynamics of C 4 consumption (cane sugar/maize) in England, providing insight into the dynamics of food globalization during this period. We also add substantially to the animal dataset for post-medieval England, providing further insight into animal management during a key moment of agricultural change., (© 2023 The Authors. American Journal of Biological Anthropology published by Wiley Periodicals LLC.)

DNA in eukaryotic cells is packaged into the compact and dynamic structure of chromatin. This packaging is a double-edged sword for DNA repair and genomic stability. Chromatin restricts the access of repair proteins to DNA lesions embedded in nucleosomes and higher order chromatin structures. However, chromatin also serves as a signaling platform in which post-translational modifications of histones and other chromatin-bound proteins promote lesion recognition and repair. Similarly, chromatin modulates the formation of DNA damage, promoting or suppressing lesion formation depending on the chromatin context. Therefore, the modulation of DNA damage and its repair in chromatin is crucial to our understanding of the fate of potentially mutagenic and carcinogenic lesions in DNA. Here, we survey many of the landmark findings on DNA damage and repair in chromatin over the last 50 years (i.e., since the beginning of this field), focusing on excision repair, the first repair mechanism studied in the chromatin landscape. For example, we highlight how the impact of chromatin on these processes explains the distinct patterns of somatic mutations observed in cancer genomes., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Complicated grief is a debilitating condition that individuals may experience after losing a loved one. General practitioners (GPs) are well positioned to provide patients with support for grief-related issues. Traditionally, Irish GPs play an important role in providing patients with emotional support regarding bereavement. However, GPs have commonly reported not being aptly trained to respond to bereavement-related issues. This study explores GPs' current knowledge of and practice regarding complicated grief., Methods: A qualitative study adopting a phenomenological approach to explore the experiences of GPs on this issue. Semi-structured interviews were carried out with a purposive sample of nine GPs (five men and four women) in Ireland. Potential participants were contacted via email and phone. Interviews were audio-recorded, transcribed and analysed using Braun & Clarke's () model of thematic analysis., Results: GPs had limited awareness of the concept of complicated grief and were unfamiliar with relevant research. They also reported that their training was either non-existent or outdated. GPs formed their own knowledge of grief-related issues based on their intuition and experiences. For these reasons, there was not one agreed method of how to respond to grief-related issues reported by patients, though participants recognised the need for intervention, onward referral and review., Conclusions: The research highlighted that GPs felt they required training in complicated grief so that they would be better able to identify and respond to complicated grief.

Objectives: Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW., Participants: Undergraduate students ( N  = 300) from a Midwestern university during Fall 2019., Method: Participants completed questionnaires assessing STMO, DPW, and RSB frequency., Results: A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW., Conclusions: Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention.