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Objective: To assess the relationship between MRI-derived changes in whole-brain and ventricular volume with change in cognitive scores in Alzheimer's disease (AD), mild cognitive impairment (MCI) and control subjects.Material and Methods: In total 131 control, 231 MCI and 99 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with T1-weighted volumetric MRIs from baseline and 12-month follow-up were used to derive volume changes. Mini mental state examination (MMSE), Alzheimer's disease assessment scale (ADAS)-cog and trails test changes were calculated over the same period.Results: Brain atrophy rates and ventricular enlargement differed between subject groups (p < 0.0005) and in MCI and AD were associated with MMSE changes. Both measures were additionally associated with ADAS-cog and trails-B in MCI patients, and ventricular expansion was associated with ADAS-cog in AD patients. Brain atrophy (p < 0.0005) and ventricular expansion rates (p = 0.001) were higher in MCI subjects who progressed to AD within 12 months of follow-up compared with MCI subjects who remained stable. MCI subjects who progressed to AD within 12 months had similar atrophy rates to AD subjects.Conclusion: Whole-brain atrophy rates and ventricular enlargement differed between patient groups and healthy controls, and tracked disease progression and psychological decline, demonstrating their relevance as biomarkers. [ABSTRACT FROM AUTHOR]

Background: Most patients with primary hyperparathyroidism are postmenopausal women. The presence of osteopenia in persons with mild primary hyperparathyroidism is considered an indication for parathyroidectomy. No prospective, controlled trials have assessed medical therapies for osteopenia in primary hyperparathyroidism.Objective: To examine the effects of estrogen-progestin therapy (hormone replacement therapy) on bone mineral density and biochemical indices in postmenopausal women with mild primary hyperparathyroidism.Design: Double-blind, randomized, placebo-controlled trial.Setting: University teaching hospital.Patients: 42 postmenopausal women with mild primary hyperparathyroidism.Intervention: Patients were randomly assigned to receive either conjugated estrogens, 0.625 mg/d, and medroxyprogesterone, 5 mg/d, or placebo.Measurements: Bone mineral densities of the total body, lumbar spine, proximal femur (femoral neck, Ward triangle, trochanter), and proximal forearm were measured every 6 months using dual-energy x-ray absorptiometry. Biochemical indices of bone turnover and calcium metabolism were measured at baseline, 6 months, and 2 years.Results: In the placebo group, bone mineral densities of the total body and the proximal forearm decreased significantly from baseline (mean +/- SE, -2.3% +/- 0.7% [p = 0.005] and -3.5% +/- 1.2% [p = 0.01], respectively). At the other sites, bone mineral density also tended to decline. In the hormone replacement therapy group, bone mineral density increased from baseline in the total body (1.3% +/- 0.4%; P = 0.004), lumbar spine (5.2% +/- 1.4%; p = 0.002), and femoral neck (3.4% +/- 1.5%; p = 0.05). The between-group differences in bone mineral density at the end of the study ranged from 3.6% to 6.6% and were significant at all sites (P > 0.001 and P < 0.05) except for the Ward triangle (p = 0.06). In the hormone replacement therapy group, serum alkaline phosphatase levels decreased by 22% (p = 0.0004 compared with baseline), urinary hydroxyproline excretion decreased by 42% (p = 0.0004), urinary N-telopeptide excretion decreased by 54% (p = 0.001), and urinary calcium excretion decreased by 45% (p = 0.007). Hormone replacement therapy did not change levels of serum ionized calcium or intact parathyroid hormone.Conclusions: Although hormone replacement therapy has little effect on serum calcium levels, it suppresses bone turnover, reduces urinary calcium excretion, and increase bone mineral density throughout the skeleton in postmenopausal women with mild primary hyperparathyroidism. This therapy is thus an important management option for these patients. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common cancer in younger adults. In patients undergoing liver resection with RAS-altered CRCs, there is evidence suggesting younger patients have worse outcomes than older patients. To explain this pattern, differences in associations between RAS status and other cancer-related biomarkers in tumors from younger versus older patients with CRC were evaluated in a cohort of 925 patients with CRC, 277 (30.0%) of whom were ≤50 years old, and 454 (49.1%) who had RAS-altered tumors. For 3 biomarkers, RNF43, APC, and microsatellite instability (MSI), the association with RAS status was significantly modified by age after adjustment for multiple testing. Specifically, younger patients with RAS-altered tumors were more likely to be MSI-high, RNF43 mutated, and APC wild type. These differences might contribute to the observed pattern of diminished survival in younger versus older patients with CRC with RAS-mutated tumors undergoing liver metastasis resection., (© The Author(s) 2024. Published by Oxford University Press.)

Cardiac fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) material resulting in cardiac tissue scarring and dysfunction. While it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains debated. By combining lineage tracing and RNA sequencing, our group made the paradigm-shifting discovery that a subpopulation of resident vascular stem cells residing within the aortic, carotid artery, and femoral aartery adventitia (termed AdvSca1-SM cells) originate from mature vascular smooth muscle cells (SMCs) through an in situ reprogramming process. SMC-to-AdvSca1-SM reprogramming and AdvSca1-SM cell maintenance is dependent on induction and activity of the transcription factor, KLF4. However, the molecular mechanism whereby KLF4 regulates AdvSca1-SM phenotype remains unclear. In the current study, leveraging a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomic approaches, we demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in the setting of Angiotensin II (AngII)-induced cardiac fibrosis. Differentiation was characterized by loss of stemness-related genes, including Klf4 , but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of profibrotic transition of AdvSca1-SM-like cells in human cardiomyopathy. Surprisingly and paradoxically, AdvSca1-SM-specific genetic knockout of Klf4 prior to AngII treatment protected against cardiac inflammation and fibrosis, indicating that Klf4 is essential for the profibrotic response of AdvSca1-SM cells. Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells, but also orchestrates their response to profibrotic stimuli, and may serve as a therapeutic target in cardiac fibrosis.

Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole-room calorimetry and is expressed as a respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. The clinical, metabolic, and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (β-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (β-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (β-coefficient 0.447, p = 0.02) directly correlated with the severity of weight gain. No statistically significant relationship between peak RQ, trough RQ, and weight change was demonstrated. Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity after LT with the potential to develop new diagnostics and therapeutics., (Copyright © 2023 American Association for the Study of Liver Diseases.)

We previously established that vascular smooth muscle-derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM cell lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM-derived cells localized throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMC), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared with WT mice. Additionally, Klf4 deletion drastically modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMC and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potentially unstable atherosclerotic plaques.

Reproductive function is critical for species survival; however, it is energetically costly and physically demanding. Reproductive suppression is therefore a physiologically appropriate adaptation to certain ecological, environmental, and/or temporal conditions. This 'allostatic' suppression of fertility enables individuals to accommodate unfavorable reproductive circumstances and safeguard survival. The mechanisms underpinning this reproductive suppression are complex, yet culminate with the reduced secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn suppresses gonadotropin release from the pituitary, thereby impairing gonadal function. The focus of this review will be on the role of RFamide-related peptide (RFRP) neurons in different examples of allostatic reproductive suppression. RFRP neurons release the RFRP-3 peptide, which negatively regulates GnRH neurons and thus appears to act as a 'brake' on the neuroendocrine reproductive axis. In a multitude of predictable (e.g., pre-puberty, reproductive senescence, and seasonal or lactational reproductive quiescence) and unpredictable (e.g., metabolic, immune and/or psychosocial stress) situations in which GnRH secretion is suppressed, the RFRP neurons have been suggested to act as modulators. This review examines evidence for and against these roles.

Background: Pediatric hospital resources including critical care faculty (intensivists) redeployed to provide care to adults in adult ICUs or repurposed PICUs during wave 1 of the coronavirus disease 2019 (COVID-19) pandemic., Objectives: To determine the magnitude of pediatric hospital resource redeployment and the experience of pediatric intensivists who redeployed to provide critical care to adults with COVID-19., Methods: A mixed methods study was conducted at 9 hospitals in 8 United States cities where pediatric resources were redeployed to provide care to critically ill adults with COVID-19. A survey of redeployed pediatric hospital resources and semistructured interviews of 40 redeployed pediatric intensivists were simultaneously conducted. Quantitative data were summarized as median (interquartile range) values., Results: At study hospitals, there was expansion in adult ICU beds from a baseline median of 100 (86-107) to 205 (108-250). The median proportion (%) of redeployed faculty (88; 66-100), nurses (46; 10-100), respiratory therapists (48; 18-100), invasive ventilators (72; 0-100), and PICU beds (71; 0-100) was substantial. Though driven by a desire to help, faculty were challenged by unfamiliar ICU settings and culture, lack of knowledge of COVID-19 and fear of contracting it, limited supplies, exhaustion, and restricted family visitation. They recommended deliberate preparedness with interprofessional collaboration and cross-training, and establishment of a robust supply chain infrastructure for future public health emergencies and will redeploy again if asked., Conclusions: Pediatric resource redeployment was substantial and pediatric intensivists faced formidable challenges yet would readily redeploy again., (Copyright © 2023 by the American Academy of Pediatrics.)

Bacterial meningitis is a catastrophic nervous system disorder with high mortality and wide range of morbidities. Some of the meningitis-causing bacteria occupy cholesterol dependent cytolysins (CDCs) to increase their pathogenicity and arrange immune-evasion strategy. Studies have observed that the relationship between CDCs and pathogenicity in these meningitides is complex and involves interactions between CDC, blood-brain barrier (BBB), glial cells and neurons. In BBB, these CDCs acts on capillary endothelium, tight junction (TJ) proteins and neurovascular unit (NVU). CDCs also observed to elicit intriguing effects on brain inflammation which involves microglia and astrocyte activations, along with neuronal damage as the end-point of pathological pathways in bacterial meningitis. As some studies mentioned potential advantage of CDC-targeted therapeutic mechanisms to combat CNS infections, it might be a fruitful avenue to deepen our understanding of CDC as a candidate for adjuvant therapy to combat bacterial meningitis., Competing Interests: Conflict of interest: The authors declare that there were no financial or commercial ties that might be viewed as potential conflicts of interest during the conduct of this manuscript., (© 2023 the Author(s), licensee AIMS Press.)

The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Pediatric spinal cord injury and dysfunction (SCI/D) can result from atypical embryologic development or be acquired as the result of trauma, infection, autoimmune conditions, and tumors. The age of onset and causal mechanism of SCI/D has dramatic implications for function and risk of comorbidities throughout the lifespan. Optimal care of children with SCI/D is multidisciplinary and the pediatrician is a very important member of this team. This review highlights functional prognosis and important health maintenance issues to prevent complications and maximize independence. It is intended to assist the pediatrician in the care of this unique patient population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-β1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits.

Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Combining bioclinical parameters with liver stiffness measurement (LSM) has improved the diagnostic performance of vibration-controlled transient elastography (VCTE) for detection of advanced fibrosis in patients with chronic liver disease. However, this approach has not yet been tested in liver transplantation (LT) recipients. Thus, the aim of this study was to evaluate the diagnostic performance of combining LSM-based scores with LSM alone for the detection of advanced fibrosis in LT recipients. Adult LT recipients with a liver biopsy, VCTE, and clinical data necessary to construct LSM-based fibrosis models (FibroScan-AST [FAST], AGILE-3+, and AGILE-4) were included ( n = 132). The diagnostic statistics for advanced fibrosis (fibrosis stage 0-2 vs. 3-4) were determined by optimal cut-off using the Youden index. The area under the receiver operating characteristic curve (AUROC) for LSM was 0.94 (95% confidence interval [95% CI], 0.89-0.99), FAST was 0.65 (95% CI, 0.50-0.79), AGILE-3+ was 0.90 (95% CI, 0.83-0.97), and AGILE-4 was 0.90 (95% CI, 0.83-0.97). No statistically significant differences were noted between the AUROC of LSM versus LSM-based scores. The false-positive rates for AGILE-3+ and AGILE-4 were 14.5% and 11.8% compared with 8.3% for LSM alone. The false-positive rates in LSM-based scores were higher among patients with diabetes mellitus, higher AST levels, and lower platelet counts. The LSM-based scores did not improve the diagnostic performance of LSM alone in LT recipients for the detection of advanced fibrosis. This lack of improvement in diagnostic performance results from the impact of immunosuppression on bioclinical profile and underscores the importance of developing LSM-based scores that are specific to LT patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Exposure to community violence (ECV) poses a prevalent threat to the health and development of adolescents. Research indicates those who have more Adverse Childhood Experiences (ACEs) are at higher risk for ECV, which further exacerbates risk of negative mental and physical health impacts. Additionally, those with more ACEs are more likely to exhibit conduct problems, which has also been linked to risk for ECV. Despite the prevalence and impact of ECV, there is limited longitudinal research on the risk factors that precede this exposure as well as family-level factors that may prevent it. The current study examined conduct problems as a potential mediator between ACEs and future indirect (i.e. witnessing) ECV in adolescents. Additionally, this study included caregiver factors, such as caregiver knowledge about their adolescent, caregiver involvement, and caregiver-adolescent relationship quality as potential protective moderators. Participants included (N = 1137) caregiver-adolescent dyads identified as at-risk for child maltreatment prior to child's age four for inclusion in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). Conduct problems at age 14 mediated the relationship between ACEs from ages 0-12 and indirect ECV at age 16 (standardized indirect effect = .03, p = .005). Caregiver knowledge moderated the indirect relationship (b = -.40, p = .030), and caregiver involvement moderated the direct relationship between ACEs and indirect ECV (b = -.03, p = .033). Findings expand our knowledge about the longitudinal pathways that increase risk of violence exposure over the course of adolescent development, as well as the protective benefits caregivers can offer to disrupt these pathways and reduce risk of future traumatization. Implications are discussed for interventions that aim to address and prevent trauma and adverse outcomes among youth exposed to child maltreatment, household dysfunction, and community violence.

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function., Competing Interests: Declaration of competing interest Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Children's exposure to family conflict is associated with the development of behavior problems. However, it remains unclear whether this association (1) functions bidirectionally and (2) exists independent of more severe forms of violent victimization., Objective: The present study aimed to examine bidirectional and transactional associations between family conflict and children's behavioral problems, controlling for time-varying violent victimization experiences. Invariance testing examined whether these models differed by gender and by maltreatment status prior to initial recruitment., Participants and Setting: Participants were caregiver-child dyads identified prospectively as being at risk for maltreatment and family violence exposure prior to age four (N = 1281; 51.4 % female; 74.6 % persons of color)., Methods: Caregivers were interviewed prospectively about family conflict, children's aggressive and delinquent behavior, and children's victimization experiences at child ages 6, 8, and 10., Results: After controlling for prior victimization, significant cross-lagged bidirectional associations were identified between family conflict and child behavior problems. Indirect effects from age 6 to age 10 externalizing problems through age 8 family conflict were not supported. Several bidirectional paths were stronger among boys than girls. Results revealed little evidence for moderation by prerecruitment maltreatment status., Conclusions: Findings support a conceptualization of the family-child relationship that is reciprocal in nature and highlight the importance of non-violent, everyday negative family processes. Interventions aiming to improve child behavior problems by targeting severely dysfunctional family processes should also address non-violent, lower-level patterns of negative family interactions, such as everyday instances of blame, criticism, nonacceptance, and favoritism., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare. This study was based upon secondary data analysis using publicly available data from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). These data can be accessed at https://www.ndacan.acf.hhs.gov/datasets/dataset-details.cfm?ID=158. LONGSCAN was supported by grants from the Children's Bureau, Office on Child Abuse and Neglect, and Administration for Children, Youth, and Families. The current study was not funded externally. This study was not preregistered., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of the p53 protein have been studied extensively, structural information for full-length p53 remains incomplete. Functionalized microprocessor chips (microchips) with properties amenable to electron microscopy permitted us to visualize complete p53 assemblies for the first time. The new structures revealed p53 in an inactive dimeric state independent of DNA binding. Residues located at the protein-protein interface corresponded with modification sites in cancer-related hot spots. Changes in these regions may amplify the toxic effects of clinical mutations. Taken together, these results contribute advances in technology and imaging approaches to decode native protein models in different states of activation., (© 2022 Wiley-VCH GmbH.)

Background: Although researchers have found an increased risk for psychopathology among maltreated adolescents placed in out-of-home care, different trajectories of psychopathology by out-of-home placements have not been previously studied., Objective: The current study is built on previous investigation of youth in different long-term out-of-home placements and examined the trajectories of adolescent psychopathology by out-of-home placement classes., Participants and Setting: We leveraged data from the Southwestern site of the Longitudinal Studies of Child Abuse and Neglect. Participants included caregiver-youth dyads (N = 273), who had substantiated reports of child maltreatment (CM) prior to children's age four and were placed in out-of-home care., Methods: Five out-of-home placement classes from ages 4 to 12 (i.e., stable adopted, stable reunified, stable kinship care, stable non-kin foster care, and unstable placement) were identified from previous study and participants were interviewed at youth ages 12, 14, and 16 to assess adolescent psychopathology. Latent Growth Curve Analysis was used to examine trajectories of psychopathology by placement classes., Results: Adolescents in unstable placement and stable adopted classes had higher intercepts and more positive or less negative slopes for psychopathology compared to those in stable kinship care and stable reunified classes., Conclusions: Adolescents in unstable placement and stable adopted classes were at similarly elevated risk for psychopathology, whereas adolescents in stable kinship care and stable reunified classes were at lower risk for psychopathology. We discuss the clinical implication to preventing and intervening risks for psychopathology among maltreated youth in unstable and adopted placements., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reproductive dysfunction in women has been linked to high caloric diet (HCD)-feeding and obesity. Central resistance to leptin and insulin have been shown to accompany diet-induced infertility in rodent studies, and we have previously shown that deleting suppressor of cytokine signaling 3, which is a negative regulator of leptin signaling, from all forebrain neurons partially protects mice from HCD-induced infertility. In this study, we were interested in exploring the role of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of both leptin and insulin signaling, in the pathophysiology of HCD-induced obesity and infertility. To this end, we generated male and female neuron-specific PTP1B knockout mice and compared their body weight gain, food intake, glucose tolerance, and fertility relative to control littermates under both normal calorie diet and HCD feeding conditions. Both male and female mice with neuronal PTP1B deletion exhibited slower body weight gain in response to HCD feeding, yet only male knockout mice exhibited improved glucose tolerance compared with controls. Neuronal PTP1B deletion improved the time to first litter in HCD-fed mice but did not protect female mice from eventual HCD-induced infertility. While the mice fed a normal caloric diet remained fertile throughout the 150-day period of assessment, HCD-fed females became infertile after producing only a single litter, regardless of their genotype. These data show that neuronal PTP1B deletion is able to partially protect mice from HCD-induced obesity but is not a critical mediator of HCD-induced infertility., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The goal of this study was to demonstrate the range in effective orifice area (EOA) values that may be possible given the ISO 5840 definition of EOA and the practical limits in the accurate measurement of pressure differential across large diameter valves., Methods: A 31 mm mechanical valve was tested on a commercially available pulse duplicator configured for mitral valve testing and tuned to nominal conditions. The experimental data was used as a basis for performing Monte Carlo analyses with published specifications for commonly used pressure sensors as well as measurement equipment accuracy requirements described in ISO 5840. The sources of error were modeled as normally distributed random variables and the simulation was iterated 1,000,000 times., Results: Experimentally-derived EOAs ranged from 2.7 to 5.0 cm 2 , while the Monte Carlo simulation provided results ranging from approximately 0.4 to 6.7 cm 2 . Many of these results are clearly non-physical with EOAs larger than the valve's geometric orifice area and exceedingly short positive pressure differential periods, yet they align with other published results for the same valve model., Conclusions: The volatility of the standard EOA formulation at low mean gradients combined with the difficulty in accurately measuring such small differentials with industry-standard fluid pressure transducers results in a performance metric which is very sensitive to test execution, particularly for low-gradient prostheses., (© 2021. Biomedical Engineering Society.)

Background: Knowledge about the impacts of child abuse and neglect (CAN) experiences on late adolescent psychopathology has been limited by a failure to consider the frequent co-occurrence of CAN types and potential unique impacts of specific combinations., Objective: Using person-centered analyses, we aimed to identify unobserved groups of youth with similar patterns of lifetime CAN experiences before age 16 and differences in psychopathology symptom counts between groups two years later., Participants and Setting: Participants were 919 adolescent-caregiver dyads (56% female; 56% Black, 7% Latina/o, 13% mixed/other)., Methods: Prospective, multi-informant data, including child protective services records and caregiver and youth reports were collected, and youth completed a diagnostic interview at age 18., Results: Latent Class Analyses classified adolescents into four distinct groups based on patterns of physical neglect, supervisory neglect, and physical, sexual, and psychological abuse: "Low-Risk" (37%), "Neglect" (19%), "Abuse" (11%), and "Multi-type CAN" (33%). The Multi-type CAN class had significantly more major depressive, generalized anxiety, and nicotine use symptoms than the Low-Risk class, and more post-traumatic stress, antisocial personality, and illicit substance use symptoms, than Low-Risk and Neglect classes. The Abuse class had significantly more generalized anxiety and attention deficit/hyperactivity symptoms than the Low-Risk class, and more major depressive, antisocial personality, and illicit substance use symptoms, than Low-Risk and Neglect classes. The Neglect class did not have elevated psychopathology symptoms., Conclusion: Findings highlight important differences in the associations between lifetime CAN experience patterns and psychopathology. Researchers should explore mechanisms underlying psychopathology that are impacted by different CAN experience patterns., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.

Distal embolization of thrombus can lead to impairment of microvascular perfusion, and measures of abnormal microvascular perfusion have been associated with increased mortality and worsened clinical outcomes. Large multicenter randomized controlled trials and multiple meta-analyses have failed to demonstrate an improvement in clinical outcomes with the routine use of manual aspiration thrombectomy, with some studies suggesting an increased incidence of stroke, likely owing to thrombus dislodgement during retrieval leading to cerebral vessel embolization. In patients with high thrombus burden who do not respond to balloon predilation, the use of manual aspiration thrombectomy as a bailout treatment strategy can be considered., Competing Interests: Disclosure The authors have no relevant disclosures regarding this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Trauma Symptom Checklist for Children (TSCC) is a widely used youth assessment of broad, transdiagnostic symptomatology following trauma. However, its factor structure has not been thoroughly tested in diverse samples. Youth ( N = 738) exposed to interpersonal violence, including physical and sexual abuse, completed the TSCC. Confirmatory factor analysis was used to test one-, six-, and eight-factor models of the TSCC clinical scales, based on previous literature and the TSCC manual. We examined measurement invariance across boys and girls and Black and non-Black participants, as well as convergent and discriminant validity. An eight-factor structure, consisting of posttraumatic stress, anxiety, depression, anger, overt dissociation, fantasy dissociation, sexual preoccupation, and sexual distress, demonstrated the best fit, with two items removed. Invariance tests supported configural and metric (but not scalar) invariance. This research highlights the need for further testing before differences between gender and racial groups can be accurately compared.

Parents who were abused as children are at increased risk for perpetuating maladaptive parenting practices, yet the mechanisms underlying this relationship remain unclear. This study prospectively examined maternal distress (a latent variable consisting of depressive symptoms and daily stress) and family violence as potential mediators in the intergenerational transmission of abusive (i.e., psychologically aggressive and physically assaultive) parenting. Participants included ( N = 768) mother-child dyads identified as being at-risk for family violence and maltreatment prior to children's age four. More maternal childhood abuse was associated with more distress and increased risk for family violence exposure in adulthood. However, only maternal distress mediated the association between mothers' history of abuse and their use of abusive parenting strategies. This study provides critical information about ecological mechanisms underlying the intergenerational transmission of abusive parenting and suggests the importance of targeting depression and stress management among mothers with abuse histories to curtail the cycle of violence.

Abstract: We previously reported the mean 4-year outcomes of anatomic total shoulder replacement using an all-polyethylene, pegged, hybrid-fixation (bone ingrowth and cement) glenoid component. In the present study, we report on that patient cohort after another 4 years of follow-up (mean, 101 months; range, 77 to 146 months). At that time, the median American Shoulder and Elbow Surgeons (ASES) score was 92 points (interquartile range [IQR], 81.7 to 98.3) and the median Oxford Shoulder Score was 47 points (IQR, 41 to 48). Osseointegration, demonstrated by bone ingrowth between the flanges on the central peg as seen on coronal computed tomography (CT), was complete in 75% of the shoulders, partial in 21%, and absent in 4%. There were radiolucent lines at the bone-prosthesis interface on CT, with a median Yian score of 1 (IQR, 0 to 2; range, 0 to 18). The conclusion in the present study was that shoulder arthroplasty with an all-polyethylene, hybrid-fixation (bone ingrowth and cement) pegged glenoid component has durable clinical and radiographic outcomes at medium-term follow-up., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: Funding for CT scans was provided by the Melbourne Orthopaedic Group Research Fund. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/G223)., (Copyright © 2020 by The Journal of Bone and Joint Surgery, Incorporated.)

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin-resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin-responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player., (© 2021 British Society for Neuroendocrinology.)

RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 the authors.)

Background: Healthy parenting attitudes are foundational for positive parenting and child well-being. However, few studies explore their formation and mediators explaining racial/ethnic group differences., Objective: The present study prospectively examines potential mediators for racial/ethnic group differences in parenting attitudes in a diverse sample of emerging adults (EA)., Participants & Setting: Participants are EA and their caregivers (N = 891) who participated in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN)., Methods: Adverse childhood experiences (ACEs), parenting attitudes, and caregiver-child relationship quality and involvement were assessed. Mediators of racial/ethnic group differences were tested using Structural Equation Modeling with bias-corrected confidence intervals based on 1000 bootstrapped samples., Results: Black EA had less appropriate developmental expectations and perceptions of family roles, empathy toward children, and rejection of physical punishment, compared to White EA. Latinx EA also had less empathy toward children compared to White EA. Caregivers' parenting attitudes mediated group differences, beyond ACEs and relationship quality and involvement. Significant mediation effects include: appropriate developmental expectations, R 2 = 0.08, p < .05; rejection of physical punishment, R 2 = 0.06, p < .05; appropriate family roles, R 2 = 0.16, p < .05; and empathy toward children, R 2 = 0.15, p < .05, for Black relative to White EA, as well as, empathy toward children, R 2 = 0.12, p < .05, for Latinx relative to White EA., Conclusion: Findings highlight the mediating role of intergenerational transmission of parenting attitudes for explaining racial-ethnic differences and supporting positive parenting practices in diverse communities., (Copyright © 2020. Published by Elsevier Ltd.)

Resident vascular adventitial SCA1+ progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage-tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA-sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling were significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM-specific expression of GLI-Kruppel family member GLI1 (Gli1), we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell-specific Kruppel-like factor 4 (Klf4) depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a profibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable antifibrotic approach.

The tumor suppressor protein TP53 (p53) plays a multifaceted role in all cells of the human body. Mutations in the TP53 gene are often involved in cancer induction and disease progression. Despite its important role in health and development, structural information for p53 remains incomplete. Here, we present a microchip-based technology to facilitate structural studies of p53 assemblies derived from human cancer cells. These devices do not introduce foreign sequences to the p53 gene and maintain naturally occurring post-translational modifications. Using cryo-electron microscopy, structures for the p53 monomer (∼50 kDa) and tetramer (∼200 kDa) were resolved to ∼4.8 and ∼7 Å, respectively. These structures revealed new insights for flexible regions of p53 along with biologically relevant ubiquitination sites. Collectively, the convergence of nanotechnology tools and structural imaging builds a strong framework to understand the oncogenic impact of p53 in human tissues.

Background: It is known that depression remains largely untreated in underserved communities. Hence, it is desirable to gain more knowledge on the prevalence and correlates of untreated depression among African-American (AA) older adults in economically disadvantaged areas. This knowledge may have the public health benefit of improving detection of AA older adults with depression who are at high risk of not receiving treatment, thereby reducing this health disparity., Objective: To study health and social correlates of untreated depression among AA older adults in economically disadvantaged areas., Methods: Between 2015 and 2018, this cross-sectional survey was conducted in South Los Angeles. Overall, 740 AA older adults who were 55+ years old entered this study. Independent variables were age, gender, living arrangement, insurance type, educational attainment, financial strain, chronic medical conditions, and pain intensity. Untreated depression was the dependent variable. Logistic and polynomial regression models were used to analyze these data., Results: According to the polynomial regression model, factors such as number of chronic medical conditions and pain intensity were higher in individuals with depression, regardless of treatment status. As our binary logistic regression showed, age, education, and number of providers were predictive of receiving treatment for depression., Conclusion: Age, educational attainment, number of providers (as a proxy of access to and use of care) may be useful to detect AA older adults with depression who are at high risk of not receiving treatment. Future research may focus on decomposition of the role of individual-level characteristics and health system-level characteristics that operate as barriers and facilitators to AA older adults receiving treatment for depression.