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Finalization of eukaryotic nuclear DNA replication relies on DNA ligase 1 (LIG1) to seal DNA nicks generated during Okazaki Fragment Maturation (OFM). Using a mutational reporter in Saccharomyces cerevisiae, we previously showed that mutation of the high-fidelity magnesium binding site of LIG1Cdc9 strongly increases the rate of single-base insertions. Here we show that this rate is increased across the nuclear genome, that it is synergistically increased by concomitant loss of DNA mismatch repair (MMR), and that the additions occur in highly specific sequence contexts. These discoveries are all consistent with incorporation of an extra base into the nascent lagging DNA strand that can be corrected by MMR following mutagenic ligation by the Cdc9-EEAA variant. There is a strong preference for insertion of either dGTP or dTTP into 3–5 base pair mononucleotide sequences with stringent flanking nucleotide requirements. The results reveal unique LIG1Cdc9-dependent mutational motifs where high fidelity DNA ligation of a subset of OFs is critical for preventing mutagenesis across the genome. DNA ligase 1 finalizes nuclear DNA replication by accurately sealing nicks generated during Okazaki Fragment Maturation. Here, Williams et al employ a low fidelity DNA ligase 1 variant to study mutation rates and specificity across the yeast genome [ABSTRACT FROM AUTHOR]

Purpose: Practical considerations precluding health-related quality of life (HRQOL) monitoring in population and clinical research have spawned development of improved items for more brief surveys of frequently measured HRQOL outcomes. The aim of this study was to validate the use of the Quality of Life General (QGEN-8), a shorter 8-item alternative to the longer 36-item short form (SF)-36 Health Survey for measuring the same eight HRQOL domains across groups of adults with varying severity of acute respiratory symptoms, such as cough and sore throat. Methods: National Opinion Research Center (NORC) representative probability (N = 1,648) and supplemental opt-in (N = 5,915) U.S. adult samples were surveyed cross-sectionally online in 2020. Parallel analyses compared QGEN-8 and SF-36 estimates of group means for each of eight matching profile domains and summary physical and mental scores across groups differing in severity of acute symptoms and chronic respiratory conditions using analysis of covariance (ANCOVAs) controlling for socio-demographics and presence of chronic respiratory conditions. Results: In support of discriminant validity, ANCOVA estimates of QGEN-8 means with SF-36 estimates revealed the same patterns of declining HRQOL with the presence and increasing severity of symptoms and chronic condition severity. Conclusion: QGEN-8® shows satisfactory validity and warrants further testing in cross-sectional and longitudinal population and clinical survey research as a more practical method for estimating group differences in SF-36 profile and summary component HRQOL scores. Summary: Upper respiratory tract infections (URTI) with symptoms such as cough and sore throat are highly prevalent and negatively impact on health-related quality of life (HRQOL). Existing instruments that comprehensively measure HRQOL are lengthy, potentially increasing respondent burden and restricting their use in clinical studies and research. The aim of this study was to evaluate whether eight newly constructed survey items, the QGEN-8®, measure the same HRQOL outcomes as the 36-item SF-36 Health Survey well enough to serve as a more practical alternative for purposes of detecting the physical and mental HRQOL effects on differing severity of acute URTI symptoms, specifically cough and sore throat. The results showed that the QGEN-8® was psychometrically sound and able to differentiate between different levels of URTI symptoms, even in cases where respondents had chronic respiratory conditions. This indicates that the briefer QGEN-8® with 75% shorter response time is able to provide HRQOL measurements comparable to those derived from lengthier instruments thereby lending itself more readily to use in clinical studies and research of URTI symptoms, such as cough and sore throat. [ABSTRACT FROM AUTHOR]

We investigate risk factors for severe COVID-19 in persons living with HIV (PWH), including among racialized PWH, using the U.S. population-sampled National COVID Cohort Collaborative (N3C) data released from January 1, 2020 to October 10, 2022. We defined severe COVID-19 as hospitalized with invasive mechanical ventilation, extracorporeal membrane oxygenation, discharge to hospice or death. We used machine learning methods to identify highly ranked, uncorrelated factors predicting severe COVID-19, and used multivariable logistic regression models to assess the associations of these variables with severe COVID-19 in several models, including race-stratified models. There were 3 241 627 individuals with incident COVID-19 cases and 81 549 (2.5%) with severe COVID-19, of which 17 445 incident COVID-19 and 1 020 (5.8%) severe cases were among PWH. The top highly ranked factors of severe COVID-19 were age, congestive heart failure (CHF), dementia, renal disease, sodium concentration, smoking status, and sex. Among PWH, age and sodium concentration were important predictors of COVID-19 severity, and the effect of sodium concentration was more pronounced in Hispanics (aOR 4.11 compared to aOR range: 1.47–1.88 for Black, White, and Other non-Hispanics). Dementia, CHF, and renal disease was associated with higher odds of severe COVID-19 among Black, Hispanic, and Other non-Hispanics PWH, respectively. Our findings suggest that the impact of factors, especially clinical comorbidities, predictive of severe COVID-19 among PWH varies by racialized groups, highlighting a need to account for race and comorbidity burden when assessing the risk of PWH developing severe COVID-19. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR), the process of decreasing overall food consumption over an extended period of time, has been shown to increase longevity across evolutionarily diverse species and delay the onset of age-associated diseases in humans. In Caenorhabditis elegans, the Myc-family transcription factors (TFs) MXL-2 (Mlx) and MML-1 (MondoA/ChREBP), which function as obligate heterodimers, and PHA-4 (orthologous to FOXA) are both necessary for the full physiological benefits of DR. However, the adaptive transcriptional response to DR and the role of MML-1::MXL-2 and PHA-4 remains elusive. We identified the transcriptional signature of C. elegans DR, using the eat-2 genetic model, and demonstrate broad changes in metabolic gene expression in eat-2 DR animals, which requires both mxl-2 and pha-4. While the requirement for these factors in DR gene expression overlaps, we found many of the DR genes exhibit an opposing change in relative gene expression in eat-2;mxl-2 animals compared to wild-type, which was not observed in eat-2 animals with pha-4 loss. Surprisingly, we discovered more than 2000 genes synthetically dysregulated in eat-2;mxl-2, out of which the promoters of down-regulated genes were substantially enriched for PQM-1 and ELT-1/3 GATA TF binding motifs. We further show functional deficiencies of the mxl-2 loss in DR outside of lifespan, as eat-2;mxl-2 animals exhibit substantially smaller brood sizes and lay a proportion of dead eggs, indicating that MML-1::MXL-2 has a role in maintaining the balance between resource allocation to the soma and to reproduction under conditions of chronic food scarcity. While eat-2 animals do not show a significantly different metabolic rate compared to wild-type, we also find that loss of mxl-2 in DR does not affect the rate of oxygen consumption in young animals. The gene expression signature of eat-2 mutant animals is consistent with optimization of energy utilization and resource allocation, rather than induction of canonical gene expression changes associated with acute metabolic stress, such as induction of autophagy after TORC1 inhibition. Consistently, eat-2 animals are not substantially resistant to stress, providing further support to the idea that chronic DR may benefit healthspan and lifespan through efficient use of limited resources rather than broad upregulation of stress responses, and also indicates that MML-1::MXL-2 and PHA-4 may have distinct roles in promotion of benefits in response to different pro-longevity stimuli. [ABSTRACT FROM AUTHOR]

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana. [ABSTRACT FROM AUTHOR]

Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers. [ABSTRACT FROM AUTHOR]

Although Jewish people in the US are often racialized (i.e., perceived by others) as White, Jewish Americans vary in the extent to which they consider themselves White, and in how strongly they identify with being Jewish. Based on prior findings that identifying with a White ethnic subgroup (e.g., Irish, Italian) can reduce prejudice toward racial and ethnic minorities, we predicted that strongly identified Jewish Americans would exhibit less intergroup bias than weakly identified Jewish Americans. For the present research, we recruited participants whose religious affiliation was Jewish but who self-identified as racially White. In a preregistered correlational study, Jewish identification was associated with lower bias, whereas White identification was associated with greater bias, toward Whites relative to racial/ethnic minorities. The relationship between Jewish identification and intergroup bias was accounted for by high Jewish identifiers’ perceptions that they could personally contribute to diversity in groups and organizations. Across three meta-analyzed experiments, participants whose religious minority (Jewish) identity was made salient exhibited less intergroup bias than did control participants, and in one preregistered experiment, perceived personal contributions to diversity mediated the effect of condition on intergroup bias. Implications for the forms of ethnic identity that predict more versus less intergroup bias in an increasingly multicultural society are discussed. [ABSTRACT FROM AUTHOR]

Purpose of Review: To reduce pain, improve function and possibly mitigate the risk for development of osteoarthritis in patients with functionally deficient meniscus pathology, meniscal allograft transplantation (MAT) can be used to restore native joint biomechanics and increase knee joint longevity. This review explores the senior author's preferred bridge-in-slot technique and recently published long-term clinical and radiographic outcomes following MAT. Recent Findings: Recent literature demonstrates MAT to be a safe and largely successful procedure for patients with functional meniscus deficiency. A majority of patients reach established minimal clinically important difference (MCID) values. Graft survivorship is approximately 80% at 10 years, significantly delaying and in some cases, preventing the need for future joint reconstruction procedures in these young patients. Return to sport rates are over 70%, revealing meniscal allografts can withstand high impact activities. Cartilage damage at the time of MAT increases the risk for graft and clinical failure, though this may be mitigated with a concomitant cartilage restoration procedure. Summary: Meniscal allograft transplantation can provide a durable and effective long-term solution to meniscal deficiency in symptomatic patients who wish to decrease the risk of symptomatic progression and possibly further osteoarthritis and continue activities of daily life and sports with less pain and more function. By restoring more normal joint biomechanics, MAT can mitigate the potential need for future knee arthroplasty in this young active patient population. [ABSTRACT FROM AUTHOR]

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.Genomic analysis of Plasmodium DNA from 36 ancient individuals provides insight into the global distribution and spread of malaria-causing species during around 5,500 years of human history. [ABSTRACT FROM AUTHOR]

Age-related osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes in nearly every intra- and peri-articular tissue that contributes to disability in older adults. Studying the etiology of age-related OA in humans is difficult due to an unpredictable onset and insidious nature. A barrier in developing OA modifying therapies is the lack of translational models that replicate human joint anatomy and age-related OA progression. The purpose of this study was to determine whether the common marmoset is a faithful model of human age-related knee OA. Semi-quantitative microCT scoring revealed greater radiographic OA in geriatric versus adult marmosets, and the age-related increase in OA prevalence was similar between marmosets and humans. Quantitative assessments indicate greater medial tibial cortical and trabecular bone thickness and heterogeneity in geriatric versus adult marmosets which is consistent with an age-related increase in focal subchondral bone sclerosis. Additionally, marmosets displayed an age-associated increase in synovitis and calcification of the meniscus and patella. Histological OA pathology in the medial tibial plateau was greater in geriatric versus adult marmosets driven by articular cartilage damage, proteoglycan loss, and altered chondrocyte cellularity. The age-associated increase in medial tibial cartilage OA pathology and meniscal calcification was greater in female versus male geriatric marmosets. Overall, marmosets largely replicate human OA as evident by similar 1) cartilage and skeletal morphology, 2) age-related progression in OA pathology, and 3) sex differences in OA pathology with increasing age. Collectively, these data suggest that the common marmoset is a highly translatable model of the naturally occurring, age-related OA seen in humans. [ABSTRACT FROM AUTHOR]

Electric grids with buses that are mapped to geographic latitude and longitude are useful for a growing number of applications, such as data visualization, geomagnetically induced current calculations, and multi-energy coupled infrastructure simulations. This paper presents a methodology for validating the quality of geographic coordinates for a power system model, and to assign coordinates to buses with missing or low-quality coordinates. This method takes advantage of geographic indicators already intrinsic to a grid model, such as branch length as implied by impedance and susceptance parameters. The coordinate assignment process uses an approach inspired by graph drawing, that lays out the vertices (buses) and edges (transmission lines), formulated as a nonlinear programming problem with soft edge length constraints. The layout method is very computationally fast and scalable to large power system cases. The method is demonstrated in this paper using a 37-bus test case and a 6717-bus test case, both publicly available, along with a large actual grid model. The results show that, for cases with only a few errors in the coordinates, cases with no coordinates known beforehand, and others in between, this method is able to assign reasonable geographic coordinates to best match known data about the grid. [ABSTRACT FROM AUTHOR]

Purpose: Trochleoplasty has become increasingly utilised to address patellar instability in the setting of severe trochlear dysplasia. There remains a paucity of literature on the outcomes of 'thick'‐ versus 'thin'‐osteochondral flap trochleoplasty. The purpose of this study is to compare clinical and radiographic outcomes between patients with patellar instability with symptomatic trochlear dysplasia treated using a 'thick' versus 'thin' osteochondral flap trochleoplasty. Methods: A systematic review and meta‐analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines using a PRISMA checklist. Quality assessment of final articles was conducted by two blinded reviewers. Articles were separated based on the use of a 'thick' versus 'thin' flap trochleoplasty. Data collection consisted of recording the following variables: patient demographics, indications for trochleoplasty, mean follow‐up time, additional procedures performed during trochleoplasty, patient‐reported outcome measures (PROMs), radiographic outcomes (tibial tubercle‐trochlear groove [TT‐TG] distance, Caton–Deschamps Index [CDI] and sulcus angle [SA]) and the incidence of any postoperative complications and patellar redislocation rates. Results: A total of 24 studies, consisting of 927 patients, were identified as meeting inclusion criteria. A total of five papers described a 'thick' flap technique, while 19 papers described the use of a 'thin' flap technique. No significant difference in the mean improvement of Kujala scores was appreciated when comparing 'thick' versus 'thin' techniques (p > 0.05). Improvements in mean radiographic outcomes based on TT‐TG, CDI and SA were observed in both 'thick' and 'thin' flap trochleoplasty groups. The overall redislocation rate was 0.35%. Conclusion: No significant difference in Kujala scores was observed in patients undergoing trochleoplasty utilising 'thick' versus 'thin' technique, while improvements in mean TT‐TG, CDI and SA were noted in both technique groups, with an overall redislocation rate of 0.35%. Level of Evidence: Level IV. [ABSTRACT FROM AUTHOR]

Hypersonic vehicles must withstand extreme conditions during flights that exceed five times the speed of sound. These systems have the potential to facilitate rapid access to space, bolster defense capabilities, and create a new paradigm for transcontinental earth-to-earth travel. However, extreme aerothermal environments create significant challenges for vehicle materials and structures. This work addresses the critical need to develop resilient refractory alloys, composites, and ceramics. We will highlight key design principles for critical vehicle areas such as primary structures, thermal protection, and propulsion systems; the role of theory and computation; and strategies for advancing laboratory-scale materials to manufacturable flight-ready components. Hypersonic vehicles experience extreme temperatures, high heat fluxes, and aggressive oxidizing environments. Here, the authors highlight key materials design principles for critical vehicle areas and strategies for advancing laboratory-scale materials to flight-ready components. [ABSTRACT FROM AUTHOR]

Oral health plays a significant role in the quality of life and overall well-being of the aging population. However, age-related changes in oral health are not well understood due to challenges with current animal models. In this study, we analyzed the oral health and microbiota of a short-lived non-human primate (i.e., marmoset), as a step towards establishing a surrogate for studying the changes that occur in oral health during human aging. We investigated the oral health of marmosets using cadaveric tissues in three different cohorts: young (aged ≤6 years), middle-aged, and older (>10 years) and assessed the gingival bacterial community using analyses of the V3–V4 variable region of 16S rRNA gene. The oldest cohort had a significantly higher number of dental caries, increased dental attrition/erosion, and deeper periodontal pocket depth scores. Oral microbiome analyses showed that older marmosets had a significantly greater abundance of Escherichia-Shigella and Propionibacterium, and a lower abundance of Agrobacterium/Rhizobium at the genus level. Alpha diversity of the microbiome between the three groups showed no significant differences; however, principal coordinate analysis and non-metric multidimensional scaling analysis revealed that samples from middle-aged and older marmosets were more closely clustered than the youngest cohort. In addition, linear discriminant analysis effect size (LEFSe) identified a higher abundance of Esherichia-Shigella as a potential pathogenic biomarker in older animals. Our findings confirm that changes in the oral microbiome are associated with a decline in oral health in aging marmosets. The current study suggests that the marmoset model recapitulates some of the changes in oral health associated with human aging and may provide opportunities for developing new preventive strategies or interventions which target these disease conditions. [ABSTRACT FROM AUTHOR]

Purpose: One plausible mechanistic hypothesis is the potential contribution of inflammatory mechanisms to shortness of breath. This study was aimed to evaluate for associations between the occurrence of shortness of breath and perturbations in inflammatory pathways. Methods: Patients with cancer reported the occurrence of shortness of breath six times over two cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath occurrence profiles (i.e., none (70.5%), decreasing (8.2%), increasing (7.8%), high (13.5%)). Using an extreme phenotype approach, whole transcriptome differential gene expression and pathway impact analyses were performed to evaluate for perturbed signaling pathways associated with shortness of breath between the none and high classes. Two independent samples (RNA-sequencing (n = 293) and microarray (n = 295) methodologies) were evaluated. Fisher’s combined probability method was used to combine these results to obtain a global test of the null hypothesis. In addition, an unweighted knowledge network was created using the specific pathway maps to evaluate for interconnections among these pathways. Results: Twenty-nine Kyoto Encyclopedia of Genes and Genomes inflammatory signaling pathways were perturbed. The mitogen-activated protein kinase signaling pathway node had the highest closeness, betweenness, and degree scores. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related shortness of breath, were perturbed. Conclusions: Findings provide preliminary support for the hypothesis that inflammation contribute to the occurrence of shortness of breath in patients with cancer. In addition, the mechanisms that underlie shortness of breath in oncology patients may be similar to other respiratory diseases. [ABSTRACT FROM AUTHOR]

A family of parsimonious contaminated shifted asymmetric Laplace mixtures is developed for unsupervised classification of asymmetric clusters in the presence of outliers and noise. A series of constraints are applied to a modified factor analyzer structure of the component scale matrices, yielding a family of twelve models. Application of the modified factor analyzer structure and these parsimonious constraints makes these models effective for the analysis of high-dimensional data by reducing the number of free parameters that need to be estimated. A variant of the expectation-maximization algorithm is developed for parameter estimation with convergence issues being discussed and addressed. Popular model selection criteria like the Bayesian information criterion and the integrated complete likelihood (ICL) are utilized, and a novel modification to the ICL is also considered. Through a series of simulation studies and real data analyses, that includes comparisons to well-established methods, we demonstrate the improvements in classification performance found using the proposed family of models. [ABSTRACT FROM AUTHOR]

With the beginning of the Early Bronze Age in Central Europe ~ 2200 BC, a regional and supra-regional hierarchical social organization emerged with few individuals in positions of power (chiefs), set apart by rich graves with extensive burial constructions. However, the social organization and stratification within the majority of people, who represent the non-elite, remain unclear. Here, we present genome-wide data of 46 individuals from the Early Bronze Age burial ground of Leubingen in today's Germany, integrating archaeological, genetic and strontium isotope data to gain new insights into Early Bronze Age societies. We were able to reconstruct five pedigrees which constitute the members of close biological kinship groups (parents and their offspring), and also identify individuals who are not related to individuals buried at the site. Based on combined lines of evidence, we observe that the kinship structure of the burial community was predominantly patrilineal/virilocal involving female exogamy. Further, we detect a difference in the amount of grave goods among the individuals buried at Leubingen based on genetic sex, age at death and locality but see no difference in the types of grave goods. [ABSTRACT FROM AUTHOR]

Global meaning systems help people make sense of their experiences, but suffering can violate global meaning and create distress. One type of potential violation is conflict between one's experience of suffering and one's deeply-held beliefs about God as loving, powerful, and just. The problem of theodicy—why an all-powerful and all-loving God would allow suffering—has long been an important theological and philosophical concern, but little is known about how theodicy plays out psychologically for religious individuals facing serious life difficulties. To address this issue within a specific religious tradition, Christianity, we drew upon philosophy, Christian theology, and psychology to develop the construct of theodical struggling. Through theological and philosophical input, we generated a 28-item pool and conducted 10 cognitive interviews with a diverse sample of Christian adults. In three consecutive online studies of Christian adult samples, we reduced the scale to 11 items through PCA, found a strong one-factor solution using EFA, and found support for the one-factor solution along with preliminary reliability and validity. This newly-developed Theodical Struggling Scale represents an important advance in understanding individuals' experiences of ruptures in their beliefs regarding God's goodness and paves the way for future research on this topic. [ABSTRACT FROM AUTHOR]

Opinion statement: PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility. [ABSTRACT FROM AUTHOR]

Vascular rings may cause respiratory or gastrointestinal symptoms due to compression of the trachea and/or esophagus. Advances in imaging have enabled early detection in asymptomatic patients posing new management dilemmas. Surgery is expected to relieve symptoms, although this has not been well studied. We sought to evaluate the presence and pattern of symptoms associated with vascular rings before surgical intervention and to detail symptom resolution after surgery. A 10-year retrospective review of patients diagnosed with an isolated vascular ring was performed between January 2010 and December 2019. 100 patients were identified; 35 double aortic arch (DAA) and 65 right aortic arch and left ligamentum arteriosum (RALL). 73 patients were symptomatic on presentation; 47 had respiratory, 5 had gastrointestinal, and 21 had both types of symptoms. Surgical repair was performed in 75 patients; 74 were symptomatic. Respiratory symptoms were more likely in patients with preoperative tracheal narrowing (p < 0.001). Moderate-severe respiratory symptoms led to surgery in RALL patients (OR 10.6, p = 0.0001). DAA patients were more likely to undergo surgery (p < 0.001) irrespective of symptom severity. At a median post-surgical follow-up of 4 months, there was a significant reduction in symptom burden (p < 0.001), except for asthma symptoms (p = 0.131). Symptom resolution was not dependent on the vascular ring anatomy (p = 0.331) or the age at operation (p = 0.158). Vascular rings are typically accompanied by respiratory symptoms and less commonly GI symptoms, both of which resolve in most patients after surgery. Those who present predominantly with asthma-like symptoms may not achieve resolution after surgery. [ABSTRACT FROM AUTHOR]

Aims: Mixed communities of plant species with different functional traits or microbial associations can more fully utilize soil nutrient pools. However, there is a gap in our understanding of the synergistic influences of arbuscular mycorrhizal (AM) fungi in nutrient capture and resource partitioning across different soil depths in mixed plant communities, as well as their possible effects on plant coexistence. To address these knowledge gaps, we assessed the effect of AM fungi on nutrient uptake and competition between shallow- and deep-rooted pairs of grass and legume species. Methods: To quantify the mycorrhizal mediation of N uptake at different soil depths, 15N tracer was injected into soil at 3- and 25-cm depths of microcosms planted with monoculture or bi-species mixtures, with or without AM fungi. Results: AM symbioses reduced plant competition by equalizing access to N and subsequently increasing shoot N and P concentrations of plant species on mixed communities. Niche differentiation had minimal effects on grass and legume competitive interactions. Both deep-rooted plant species, i.e., Medicago sativa and Dactylis glomerata, and shallow-rooted species, i.e., Lolium perenne and Trifolium repens, primarily acquired nutrients from shallow soil layers. However, AM fungi significantly enhanced nutrient uptake and facilitated N2 fixation in legumes at 3 and 25 cm soil depths. Conclusion: Our results suggest AM fungi strongly influence host-plant competitiveness and vertical nutrient capture in mixed plant communities, underscoring that microbial mutualist-mediated nutrient acquisition is a key driver of gains in productivity of grass–legume mixtures. [ABSTRACT FROM AUTHOR]

Myogenous temporomandibular disorders is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), and lateral pterygoid muscles (LPM). This study aimed to examine sensory nerve types innervating MM, TM and LPM of adult non-human primate—common marmosets. Sensory nerves were localized in specific regions of these muscles. Pgp9.5, marker for all nerves, and NFH, a marker for A-fibers, showed that masticatory muscles were primarily innervated with A-fibers. The proportion of C- to A-fibers was highest in LPM, and lowest in MM. All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked mrgprD and CHRNA3, a silent nociceptive marker. TrpV1 was register in 17% of LPM nerves. All fibers in masticatory muscles were labeled with GFAP+, a myelin sheath marker. There were substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. MM, TM and LPM NFH+ fibers contained different percentages of trkC+ and parvalbumin+, but not trkB+ fibers. Tyrosine hydroxylase antibodies, which did not label TG, highlighted sympathetic fibers around blood vessels of the masticatory muscles. Overall, masticatory muscle types of marmosets have similarities and differences in innervation patterns. [ABSTRACT FROM AUTHOR]

The Iron Age of highland Pang Mapha, northwestern Thailand, is characterised by a mortuary practice known as Log Coffin culture. Dating between 2300 and 1000 years ago, large coffins carved from individual teak trees have been discovered in over 40 caves and rock shelters. While previous studies focussed on the cultural development of the Log Coffin-associated sites, the origins of the practice, connections with other wooden coffin-using groups in Southeast Asia, and social structure within the region remain understudied. Here, we present genome-wide data from 33 individuals from five Log Coffin culture sites to study genetic ancestry profiles and genetic interconnectedness. The Log Coffin-associated genomes can be modelled as an admixture between Hòabìnhian hunter-gatherer-, Yangtze River farmer-, and Yellow River farmer-related ancestry. This indicates different influence spheres from Bronze and Iron Age individuals from northeastern Thailand as reflected by cultural practices. Our analyses also identify close genetic relationships within the sites and more distant connections between sites in the same and different river valleys. In combination with high mitochondrial haplogroup diversity and genome-wide homogeneity, the Log Coffin-associated groups from northwestern Thailand seem to have been a large, well-connected community, where genetic relatedness played a significant role in the mortuary ritual. Large log coffins placed on stilts in natural caves characterize the Iron Age of northwestern Thailand. Here, the authors conduct archaeogenetic analyses of 33 individuals, identifying a large, well-connected community, where genetic relatedness played a significant role in the mortuary ritual. [ABSTRACT FROM AUTHOR]

Age and sex have a profound effect on cytosine methylation levels in humans and many other species. Here we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R = 0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. Using the primate data, we characterize the effect of age and sex on individual cytosines in highly conserved regions. We identify 11 sex-related CpGs on autosomes near genes (POU3F2, CDYL, MYCL, FBXL4, ZC3H10, ZXDC, RRAS, FAM217A, RBM39, GRIA2, UHRF2). Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers of aging for all primates. [ABSTRACT FROM AUTHOR]

Objectives: Evidence is lacking for trait mindfulness as a longitudinal protective factor following bereavement and other stressful life events. This study aimed to determine whether trait mindfulness predicted better mental health adjustment (i.e., decreased distress and greater positive states of mind) in young adults following the recent loss of a loved one. This study also examined cognitive (e.g., intrusive and deliberate thoughts) and somatic (e.g., sleep disturbance) processes as possible underlying mechanisms linking trait mindfulness to mental health consequent to bereavement. Method: Recently-bereaved undergraduate students (n = 117) completed questionnaires evaluating multifaceted aspects of mental health adjustment following their loss at three time points (T1: baseline, T2: 3 weeks, T3: 6 weeks). Results: Trait mindfulness significantly predicted reduced distress symptoms (i.e., anxiety, depression, and stress) and increased positive states of mind over time. Trait mindfulness significantly impacted mental health following loss indirectly through its effect on sleep disturbance, but it had no significant indirect effects through intrusive or deliberate thoughts. Conclusions: Trait mindfulness may be a key protective factor for young adults who experience highly stressful events. Findings underscore the importance of sleep disturbance as a critical factor linking trait mindfulness and mental health adjustment consequent to bereavement. This study contributes to our understanding of risk and resilience factors following loss, which can also inform targeted mindfulness-based interventions as well as future studies to eventually establish causal pathways between trait mindfulness and mental health consequent to bereavement. Preregistration: This study was not preregistered. [ABSTRACT FROM AUTHOR]

Versions of cognitive behavioral therapy (Coping Cat, CC; Behavioral Interventions for Anxiety in Children with Autism, BIACA) have shown efficacy in treating anxiety among youth with autism spectrum disorder. Measures of efficacy have been primarily nomothetic symptom severity assessments. The current study examined idiographic coping outcomes in the Treatment of Anxiety in Autism Spectrum Disorder study (N = 167). Longitudinal changes in coping with situations individualized to youth fears (Coping Questionnaire) were examined across CC, BIACA and treatment as usual (TAU) in a series of multilevel models. CC and BIACA produced significantly greater improvements than TAU in caregiver-reported coping. Youth report did not reflect significant differences. Results show the efficacy of CC and BIACA in improving idiographic caregiver-, but not youth-, reported youth coping. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess the validity, floor and ceiling effects, and dimensionality of PROMIS Physical Function (PF) and Pain compared to legacy patient reported outcome (PRO) measures in patients undergoing medial patellofemoral ligament (MPFL) reconstruction. Methods: Patients who underwent MPFL reconstruction between 2018 to 2020 were retrospectively reviewed. Preoperatively, patients completed the IKDC, VR-12, Kujala, SF-12, KOOS JR, PROMIS PF and Pain surveys. Inter-survey convergence was assessed with Spearman correlations. Psychometric analysis included investigations of inter-survey convergent validity, intra-survey floor and ceiling effects, and Rasch analyses with person–item fit and iterative question elimination model fit testing. Results: A total of 76 patients (mean age: 22.6 ± 8.4 years) who completed preoperative surveys were included (compliance: 91.7–96.2%). Preoperatively, age was significantly associated with both PROMIS PF (coefficient: – 0.291, P = 0.005) and Pain scores (coefficient: 0.294, P = 0.002). PROMIS PF had a Very Good correlation with IKDC and PROMIS Pain had a Very Good correlation with KOOS JR. Other correlations ranged from Poor to Good. No significant floor or ceiling effects were observed for any PRO. On iterative question elimination Rasch modelling, only two questions from PROMIS PF remained after 6 rounds of elimination while PROMIS Pain had no questions remaining after 3 rounds of elimination. Conclusion: Preoperative PROMIS PF and Pain provided only Fair to Good correlations with most legacy PROs. Although no significant floor and ceiling effects were observed, PROMIS PF and Pain did not perform well psychometrically in this population of patients undergoing MPFL reconstruction. These results suggest PROMIS questionnaires should be used with caution in this population, especially if used in isolation, when discussing clinical expectations with patients. The authors recommend continued use of legacy PROs specific to assessment of patellar instability and function that have established validity in patellar instability populations. Level of evidence: Level IV. [ABSTRACT FROM AUTHOR]

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing. Exercise has positive effects on the brain during aging. Here the authors show that in mice, platelet-released exerkine PF4 mediates the effects of exercise on the brain. [ABSTRACT FROM AUTHOR]

Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span. [ABSTRACT FROM AUTHOR]

Every animal secretes mucus, placing them among the most diverse biological materials. Mucus hydrogels are complex mixtures of water, ions, carbohydrates, and proteins. Uncertainty surrounding their composition and how interactions between components contribute to mucus function complicates efforts to exploit their properties. There is substantial interest in commercializing mucus from the garden snail, Cornu aspersum, for skincare, drug delivery, tissue engineering, and composite materials. C. aspersum secretes three mucus—one shielding the animal from environmental threats, one adhesive mucus from the pedal surface of the foot, and another pedal mucus that is lubricating. It remains a mystery how compositional differences account for their substantially different properties. Here, we characterize mucus proteins, glycosylation, ion content, and mechanical properties that could be used to provide insight into structure-function relationships through an integrative "mucomics" approach. We identify macromolecular components of these hydrogels, including a previously unreported protein class termed Conserved Anterior Mollusk Proteins (CAMPs). Revealing differences between C. aspersum mucus shows how considering structure at all levels can inform the design of mucus-inspired materials. Mucus are ubiquitous natural materials, but little is known about their structures or properties. Here, the authors identify the components of three functional mucus from snails, which are the focus of a rapidly growing number of biomedical and cosmetic applications. [ABSTRACT FROM AUTHOR]

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.Platelet factors transfer the benefits of young blood to the ageing brain in mice through CXCR3, which mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. [ABSTRACT FROM AUTHOR]

Archaeogenetic studies have described two main genetic turnover events in prehistoric western Eurasia: one associated with the spread of farming and a sedentary lifestyle starting around 7000–6000 bc (refs. 1–3) and a second with the expansion of pastoralist groups from the Eurasian steppes starting around 3300 bc (refs. 4,5). The period between these events saw new economies emerging on the basis of key innovations, including metallurgy, wheel and wagon and horse domestication6–9. However, what happened between the demise of the Copper Age settlements around 4250 bc and the expansion of pastoralists remains poorly understood. To address this question, we analysed genome-wide data from 135 ancient individuals from the contact zone between southeastern Europe and the northwestern Black Sea region spanning this critical time period. While we observe genetic continuity between Neolithic and Copper Age groups from major sites in the same region, from around 4500 bc on, groups from the northwestern Black Sea region carried varying amounts of mixed ancestries derived from Copper Age groups and those from the forest/steppe zones, indicating genetic and cultural contact over a period of around 1,000 years earlier than anticipated. We propose that the transfer of critical innovations between farmers and transitional foragers/herders from different ecogeographic zones during this early contact was integral to the formation, rise and expansion of pastoralist groups around 3300 bc.Archaeogenetic analysis of 135 individuals from the zone between southeastern Europe and the northwestern Black Sea region indicates contacts between farming and pastoralist populations at the end of the Copper Age. [ABSTRACT FROM AUTHOR]

A growing number of pharmaceutical and small molecule interventions are reported to extend the lifespan of laboratory animals including Caenorhabditis, Drosophila, and mouse. However, the degree to which these pro-longevity interventions are conserved across species is unclear. Here, we took two approaches to ask the question: to what extent do longevity intervention studies in Caenorhabditis and Drosophila recapitulate effects on mouse lifespan? The first approach analyzes all published reports on longevity in the literature collated by the DrugAge database, and the second approach focused on results designed for reproducibility as reported from the NIA-supported Interventions Testing Program (ITP) and the Caenorhabditis Interventions Testing Program (CITP). Using published data sources, we identify only modest sensitivity and specificity of Drosophila interventional studies for identifying pro-longevity compounds in mouse lifespan studies. Surprisingly, reported studies in C. elegans show little predictive value for identifying drugs that extend lifespan in mice. The results therefore suggest caution should be used when making assumptions about the translatability of lifespan-extending compounds across species, including human intervention. [ABSTRACT FROM AUTHOR]

Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein hepatocyte-directed AAV transgene expression is silenced using the clinically validated modality of chemically modified small interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies. Here the authors propose an RNA interference-based switch for dynamic control of AAV transgene expression. In this approach, transgene expression may be silenced by RNAi and subsequently recovered using REVERSIR oligonucleotides. [ABSTRACT FROM AUTHOR]

Purpose: Upper respiratory tract infections (URTI) and related symptoms are widespread and a common reason for visiting primary care with cough and sore throat being most prevalent. Despite their impact on daily activities, no studies have explored the impact on health-related quality of life (HRQOL) in representative general populations. We aimed to understand the short-term impact of the two most prevalent URTI symptoms on HRQOL. Methods: Online 2020 surveys including acute (≤ 4 weeks) respiratory symptoms (sore throat and cough) and SF-36® health survey (all with 4-week recall) were analysed using analysis of covariance (ANCOVA) in comparison with adult US population norms. Linear T-score transformation of SF-6D utility (ranging from 0 to 1) enabled direct comparisons with SF-36. Results: In total, 7563 US adults responded (average age: 52 years; range: 18–100 years). Sore throat and cough lasting at least several days were experienced by 14% and 22% participants, respectively. Chronic respiratory conditions were reported by 22% of the sample. A clear and consistent pattern of group HRQOL means declining significantly (p < 0.001) for acute cough and sore throat symptom presence and severity. Declines were observed on SF-36 physical (PCS) and mental component (MCS) and health utility (SF-6D) scores controlling for covariates. Those reporting respiratory symptoms 'most days' declined ≥ 0.5 standard deviation (minimal important difference [MID]) worse with averages at the 19th and 34th centiles for cough on the PCS and MCS, and 21st to 26th centile for sore throat. Conclusion: Declines in HRQOL with acute cough and sore throat symptoms consistently exceeded MID standards and should not be ignored as self-limiting without intervention. Future studies on early self-care for symptom relief and its implications on HRQOL and health economics would be valuable to understand the benefits on healthcare burden and need for updating treatment guidelines. [ABSTRACT FROM AUTHOR]

A multitude of natural and synthetic chemicals are present in our environment.Through the study of a compound's cytotoxicity, researchers can carefully set regulations regarding how much of a certain chemical in the ambient environment is tolerable. In the past, research has focused on point measurements such as the LD50. Instead, we consider entire time-dependent cellular response curves through the application of functional mixed effects models. We identify differences in such curves corresponding to the chemical's mode of action—i.e. how the compound attacks human cells. Through such analysis, we identify curve features to be used for cluster analysis via application of both k-means and self organizing maps. The data is analyzed by making use of functional principal components as a data driven basis and separately by considering B-splines for identifying local-time features. Our analysis can be used to drastically speed up future cytotoxicity research. [ABSTRACT FROM AUTHOR]

Modern humans have populated Europe for more than 45,000 years1,2. Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period3. Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe4, but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants.Combined analysis of new genomic data from 116 ancient hunter-gatherer individuals together with previously published data provides insights into the genetic structure and demographic shifts of west Eurasian forager populations over a period of 30,000 years. [ABSTRACT FROM AUTHOR]

The utility of symptom (SVT) and performance (PVT) validity tests has been independently established in neuropsychological evaluations, yet research on the relationship between these two types of validity indices is limited to circumscribed populations and measures. This study examined the relationship between SVTs on the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and PVTs in a mixed neuropsychiatric setting. This cross-sectional study included data from 181 diagnostically and demographically diverse patients with neuropsychiatric conditions referred for outpatient clinical neuropsychological evaluation at an academic medical center. All patients were administered a uniform neuropsychological battery, including the MMPI-2-RF and five PVTs (i.e., Dot Counting Test; Medical Symptom Validity Test; Reliable Digit Span; Test of Memory Malingering-Trial 1; Word Choice Test). Nonsignificant associations emerged between SVT and PVT performance. Although the Response Bias Scale was most predictive of PVT performance, MMPI-2-RF SVTs generally had low classification accuracy for predicting PVT performance. Neuropsychological test performance was related to MMPI-2-RF SVT status only when overreporting elevations were at extreme scores. The current study further supports that SVTs and PVTs measure unique and dissociable constructs among diverse patients with neuropsychiatric conditions, consistent with literature from other clinical contexts. Therefore, objective evidence of symptom overreporting on MMPI-2-RF SVTs cannot be interpreted as definitively indicating invalid performance on tests of neurocognitive abilities. As such, clinicians should include both SVTs and PVTs as part of a comprehensive neuropsychological evaluation as they provide unique information regarding performance and symptom validity. [ABSTRACT FROM AUTHOR]

Purpose of Review: Multimodality therapy including radical prostatectomy, radiation therapy, and hormone therapy are frequently deployed in the management of localized prostate cancer. We sought to perform a critical appraisal of the most contemporary literature focusing on the multimodality management of localized prostate cancer. Recent Findings: Men who are ideal candidates for multimodality therapy include those with unfavorable intermediate-risk disease, high-risk disease, and very high-risk disease. Enhancements in both systemic agents (including second-generation antiandrogens) as well as localized therapies (such as stereotactic body radiotherapy and brachytherapy) are refining the optimal balance between the use of systemic and local therapies for localized prostate cancer. Genomic predictors are emerging as critical tools for more precisely allocating treatment intensification with multimodality therapies as well as treatment de-intensification. Summary: Close collaboration among medical oncologists, surgeons, and radiation oncologists will be critical for coordinating evidence-based multimodality therapies when clearly indicated and for supporting shared decision-making in areas where the evidence is mixed. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C) after COVID-19 is commonly associated with cardiac involvement. Studies found myocardial dysfunction, as measured by decreased ejection fraction and abnormal strain, to be common early in illness. However, there is limited data on longitudinal cardiac outcomes. We aim to describe the evolution of cardiac findings in pediatric MIS-C from acute illness through at least 2-month follow-up. A retrospective single-center review of 36 patients admitted with MIS-C from April 2020 through September 2021 was performed. Echocardiographic data including cardiac function and global longitudinal strain (GLS) were analyzed at initial presentation, discharge, 2–4-week follow-up, and at least 2-month follow-up. Patients with mild and severe disease, normal and abnormal left ventricular ejection fraction (LVEF), and normal and abnormal GLS at presentation were compared. On presentation, 42% of patients with MIS-C had decreased LVEF < 55%. In patients in whom GLS was obtained (N = 18), 44% were abnormal (GLS < |− 18|%). Of patients with normal LVEF, 22% had abnormal GLS. There were no significant differences in troponin or brain natriuretic peptide between those with normal and abnormal LVEF. In most MIS-C patients with initial LVEF < 55% (90%), LVEF normalized upon discharge. At 2-month follow-up, all patients had normal LVEF with 21% having persistently abnormal GLS. Myocardial systolic dysfunction and abnormal deformation were common findings in MIS-C at presentation. While EF often normalized by 2 months, persistently abnormal GLS was more common, suggesting ongoing subclinical dysfunction. Our study offers an optimistic outlook for recovery in patients with MIS-C and carditis, however ongoing investigation for longitudinal effects is warranted. [ABSTRACT FROM AUTHOR]