Intratumoral Heterogeneity Assessment of the Extracellular Bone Matrix and Immune Microenvironment in Osteosarcoma Using Digital Imaging to Predict Therapeutic Response.

The assessment of chemotherapy response in osteosarcoma (OS) based on the average percentage of viable cells is limited, as it overlooks the spatial heterogeneity of tumor cell response (foci of resistant cells), immune microenvironment, and bone microarchitecture. Despite the resulting positive classification for response to chemotherapy, some patients experience early metastatic recurrence, demonstrating that our conventional tools for evaluating treatment response are insufficient. We studied the interactions between tumor cells, immune cells (lymphocytes, histiocytes, and osteoclasts), and bone extracellular matrix (ECM) in 18 surgical resection samples of OS using multiplex and conventional immunohistochemistry (IHC: CD8, CD163, CD68, and SATB2), combined with multiscale characterization approaches in territories of good and poor response (GRT/PRT) to treatment. GRT and PRT were defined as subregions with <10% and ≥10% of viable tumor cells, respectively. Local correlations between bone ECM porosity and density of immune cells were assessed in these territories. Immune cell density was then correlated to overall patient survival. Two patterns were identified for histiocytes and osteoclasts. In poor responder patients, CD68 osteoclast density exceeded that of CD163 histiocytes but was not related to bone ECM load. Conversely, in good responder patients, CD163 histiocytes were more numerous than CD68 osteoclasts. For both of them, a significant negative local correlation with bone ECM porosity was found (P < .01). Moreover, in PRT, multinucleated osteoclasts were rounded and intermingled with tumor cells, whereas in GRT, they were elongated and found in close contact with bone trabeculae. CD8 levels were always low in metastatic patients, and those initially considered good responders rapidly died from their disease. The specific recruitment of histiocytes and osteoclasts within the bone ECM, and the level of CD8 represent new features of OS response to treatment. The associated prognostic signatures should be integrated into the therapeutic stratification algorithm of patients after surgery.

Trajectories of depressive symptoms and subjective well-being before and after the onset of the COVID-19 pandemic: Two six-year longitudinal studies.

Previous research investigated the trajectories of mental health and well-being during and after the onset of the COVID-19 pandemic. However, less is known about the trajectories of mental health and well-being before, during, and two years after the onset of the pandemic. The aim of the current study was to investigate the trajectory of depression symptoms and subjective well-being (i.e., life satisfaction and positive and negative affect) trajectories over six time points (2017-2022), three before the pandemic and three after the onset of the pandemic. To increase the robustness of our overall conclusions and avoid reliance on data from only one country, we used data from two nationwide representative longitudinal surveys conducted in Germany (GESIS Panel study; N = 5184) and Switzerland (Swiss Household Panel study; N = 17,074). Using covariance pattern mixture models, the results revealed that a four-class model best fit the data. The Stable/resilient trajectory was the most common across outcomes (74.2%-90.1% of participants). Three additional trajectories of Chronic/Low, Upright U-shaped, and Inverted U-shaped emerged in the analysis of negative affect and depression symptoms, while distinct trajectory classes of Worsening, Improving/Stable, and Upright U-shaped also emerged for analyses of positive affect and life satisfaction shaped. In conclusion, there was no evidence of a long-term impact of the pandemic for the vast majority of participants (about 90%). For the remaining participants, the COVID-19 pandemic (along with its exceptional circumstances) was a turning point or a catalyst that reversed, accelerated, or flattened a pre-pandemic trend. These changes in trends were not only negative (e.g., greater depression symptoms), but also positive (e.g., less depression symptoms).

Adaptive and maladaptive pathways of COVID-19 worry on well-being: A cross-national study.

OBJECTIVE: In a preregistered study, we examined whether worries about COVID-19 are simultaneously linked with enhanced well-being through social interaction and with reduced well-being through depression symptoms. METHOD: In August 2020, census-matched participants from high- and low-prevalence regions in the United States and Italy (N = 857) completed assessments of COVID-19 worry, social interaction, depression symptoms, and well-being. RESULTS: Worries about COVID-19 predicted both more social interaction and more depression (ps < 0.001). In multiple mediational analyses, an adaptive pathway of COVID-19 worry through social interaction was associated with higher well-being, whereas a maladaptive pathway through depression symptoms was associated with lower well-being. Further, a comparison of high and low COVID-19 prevalence regions replicated the mediational findings for social interaction, providing evidence against reverse causation and common method variance. CONCLUSION: Findings suggest that normative worries about acute stressors may both benefit and undermine well-being, depending on their impact on social behavior or depression symptoms.

Midfacial toddler excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders: midfacial toddler excoriation syndrome (MiTES; itch with normal pain sensation associated with 18 homozygous alanines (18A); and congenital insensitivity to pain (CIP) with normal itch associated with 19 homozygous alanines (19A). Knowledge of the phenotype, genotype and disease mechanism of MiTES is incomplete. Why 18A vs. 19A PRDM12 can cause almost opposite phenotypes is unknown; no other polyalanine or polyglutamine tract expansion disease causes two such disparate phenotypes. OBJECTIVES: To assess the genotype and phenotype of nine new, nine atypical and six previously reported patients diagnosed with MiTES. METHODS: Using cell lines with homozygous PR domain zinc finger protein 12 (PRDM12) containing 12 alanines (12A; normal), 18A (MiTES) and 19A (CIP), we examined PRDM12 aggregation and subcellular localization by image-separation confocal microscopy and subcellular fractionation Western blotting. RESULTS: MiTES presents in the first year of life; in all cases the condition regresses over the first decade, leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12 CIP are rarely found. The genotype-phenotype study of the PRDM12 polyalanine tract shows that having 7-15 alanines is normal; 16-18 alanines is associated with MiTES; 19 alanines leads to CIP; and no clinically atypical cases of MiTES had a polyalanine tract expansion. PRDM12 aggregation and subcellular localization differed significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein-aggregation disease. CONCLUSIONS: We provide diagnostic criteria for MiTES and improved longitudinal data. MiTES and CIP are distinct phenotypes, despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells. We hypothesize that the developmental environment of the trigeminal ganglion is unique and critically sensitive to pre- and postnatal levels of PRDM12.

Midfacial toddler excoriation syndrome (MiTES) causes facial itching and scratching in babies during their first year of life. MiTES tends to improve over the time period of approximately 10 years, but it can leave scars. Congenital insensitivity to pain (CIP) is a condition where a person cannot feel pain and is present from birth. This study looked at two conditions: MiTES and CIP. We specifically investigated changes in a gene called PRDM12, focusing on a part of the gene called the polyalanine tract ­ a sequence of many alanines (alanine is a type of amino acid). We discovered that the normal range for this sequence is between 7 and 15 alanines. If there are 16 to 18 alanines, it is associated with MiTES and causes the PRDM12 protein to clump together inside the cell. However, if there are 19 alanines, it leads to CIP, and the PRDM12 protein clumps together and moves to the cytoplasm, where it should not be. We found new evidence to suggest that MiTES is a disease where proteins clump together. Overall, our study findings show that despite there only being a small change in the same gene, MiTES and CIP are very different conditions.

Atopic Dermatitis in Children.

Atopic dermatitis (AD) is extremely common in the pediatric population, and most children with AD will first present to their primary care provider (PCP). The PCP can recognize AD by its clinical features, including itch, a chronic relapsing course, and the characteristic eruption. The cornerstone of AD therapy is dry skin care, typically a short daily bath/shower followed by an emollient applied to all skin. Most children with AD will also require topical medications, such as topical corticosteroids and/or topical nonsteroidal therapies. For children with more severe disease, systemic agents, including several novel therapies, may be required. In managing AD, the clinician must monitor for side effects of medications as well as complications of the AD itself, the most common of which is secondary infection. An understanding of the pathogenesis, treatments, and complications of AD is essential for the PCP, as untreated (or undertreated) AD has a significant impact on the quality of life of affected children and their caregivers. [Pediatr Ann. 2024;53(4):e121-e128.].

Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Media exposure related to COVID-19 is associated with worse mental health consequences in the United States compared to Italy.

BACKGROUND: Prolonged media exposure after collective crises is widely shown to have adverse effects on people's mental health. Do these effects show variation across different countries? In the present study, we compared the link between media exposure related to COVID-19 and mental health-related outcomes in the United States and Italy, two countries with high levels of early COVID-19 prevalence. METHOD: Participants matched on age and gender in the United States (n = 415) and Italy (n = 442) completed assessments of media exposure, stress, anxiety, COVID-19 worry, and other variables shortly after the first wave of infections in 2020. RESULTS: COVID-19 related media exposure predicted higher levels of stress, anxiety, and COVID-19 worry, net of the effects of neuroticism, political identification, and demographics. Moreover, COVID-19 related media exposure interacted with country to predict more stress and COVID-19 worry in the United States than in Italy. CONCLUSIONS: Findings are among the first to document cross-national differences in the association of media exposure with mental health outcomes.

Disruptions in self-regulatory processes predict depression and sleep disturbance in bereaved young adults.

Losing a loved one is both common and profoundly stressful for young adults. Little research has examined the longitudinal course of post-loss cognitive processing, depression, and sleep difficulties. Further, little is known about the context of other stressors or the role of individual regulatory resources, such as attentional regulation, that might determine whether loss-related cognitive processing reduces distress. This prospective study examined changes in depression and sleep disturbance over 9 weeks as a function of within- and between-person variation in stress exposure, loss-related cognitive processing, and attention regulation. Participants were 108 recently bereaved college students completing a lab-based assessment of attention regulation and four self-report surveys, spaced three weeks apart. Results revealed that most participants gradually reduced loss-related processing over the study period, with corresponding improvements in depression and sleep. Stress exposure was associated with increased processing, depression, and sleep disturbance. In exploratory analyses, high attentional alertness and slow re-orienting strengthened the association of within-person loss processing with sleep disturbance. Both within- and between-person variation in stress appear to engender risk for a prolonged course of bereavement. Future research should integrate objective attention measures with self-reported adjustment to stress to illuminate reciprocal links between depression, sleep, and loss-related cognitive processing.

Bullous Aplasia Cutis as a Presenting Sign of Encephalocele.

This case report describes a congenital cystic scalp nodule on a 2-week-old infant.

Happiness before and during the COVID-19 pandemic in Italy: A population-based longitudinal study.

The aims of the present study were to investigate (1) whether the COVID-19 pandemic and the restrictive measures to control its spread were associated with changes in happiness before and after the pandemic and (2) whether household size, living with a partner/spouse, living with at least one son/daughter, financial support, income loss, and job loss following the pandemic were associated with happiness after controlling for previous levels of happiness. We use data from the Italian Survey on Household Income and Wealth (SHIW). Specifically, we used longitudinal data from 2283 respondents who participated in the SHIW 2016 and SHIW 2020. Results revealed a small but significant increase in happiness from 2016 to 2021. In addition, living with a partner/spouse predicted higher happiness with a medium effect size, and total income loss predicted lower happiness with a small to medium effect size. Household size, living with at least one son/daughter, financial support, partial income loss, and job loss following the pandemic were unrelated to happiness.

Social and behavioral consequences of the COVID-19 pandemic: Validation of a Pandemic Disengagement Syndrome Scale (PDSS) in four national contexts.

The aim of the present study was to develop and validate a self-report measure that investigates people's general disengagement after the acute phases of the pandemic. Across three studies, we examined the psychometric features of the Pandemic Disengagement Syndrome Scale (PDSS) in four national contexts. In Study 1, we developed the instrument and investigated the factorial structure, internal consistency, measurement invariance across gender and countries (the United States and Italy), and discriminant validity. A bifactor model with two specific factors (Social Avoidance and Alienation) provided a better fit than the competing models. In Study 2, we tested the stability of the PDSS as well as its predictive validity. In Study 3, we conducted a quasi-experimental comparison between Norway and Sweden, to investigate whether scores on the PDSS are related to a markedly distinct approach to the pandemic in terms of mandatory lockdown. Overall, results from the three studies demonstrated that the PDSS is a valid and reliable measure of a syndrome of disengagement from others following a pandemic. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Contribution of risk and resilience factors to anxiety trajectories during the early stages of the COVID-19 pandemic: A longitudinal study.

The COVID-19 pandemic, and the response of governments to mitigate the pandemic's spread, resulted in exceptional circumstances that comprised a major global stressor, with broad implications for mental health. We aimed to delineate anxiety trajectories over three time-points in the first 6 months of the pandemic and identify baseline risk and resilience factors that predicted anxiety trajectories. Within weeks of the pandemic onset, we established a website (covid19resilience.org), and enrolled 1362 participants (n = 1064 from US; n = 222 from Israel) who provided longitudinal data between April-September 2020. We used latent growth mixture modelling to identify anxiety trajectories and ran multivariate regression models to compare characteristics between trajectory classes. A four-class model best fit the data, including a resilient trajectory (stable low anxiety) the most common (n = 961, 75.08%), and chronic anxiety (n = 149, 11.64%), recovery (n = 96, 7.50%) and delayed anxiety (n = 74, 5.78%) trajectories. Resilient participants were older, not living alone, with higher income, more education, and reported fewer COVID-19 worries and better sleep quality. Higher resilience factors' scores, specifically greater emotion regulation and lower conflict relationships, also uniquely distinguished the resilient trajectory. Results are consistent with the pre-pandemic resilience literature suggesting that most individuals show stable mental health in the face of stressful events. Findings can inform preventative interventions for improved mental health.

Multicenter retrospective review of pulsed dye laser in nonulcerated infantile hemangioma.

BACKGROUND/OBJECTIVES: We sought to describe the experience among members of the Hemangioma Investigator Group with pulsed dye laser (PDL) in the treatment of nonulcerated infantile hemangioma (IH) in pediatric patients in the pre- and post-beta-blocker era. METHODS: A multicenter retrospective cohort study was conducted in patients with nonulcerated IH treated with laser therapy. Patient demographics, IH characteristics, indications for/timing of laser therapy, as well as laser parameters were collected. Responses to laser therapy were evaluated using a visual analog scale (VAS). RESULTS: One hundred and seventeen patients with IH were treated with PDL. 18/117 (15.4%) had early intervention (defined as <12 months of life), and 99/117 (84.6%) had late intervention (≥12 months of life). In the late intervention group, 73.7% (73/99) had additional medical management of their IH. The mean age at PDL initiation for the late intervention group was 46.7 ± 35.3 months of life (range 12-172 months) with total number of treatments to maximal clearing of 4.2 ± 2.8 (range 1-17). Those who received propranolol prior to PDL received fewer sessions (1.1 fewer sessions, approaching significance [p = .056]).     On the VAS, there was a mean 85% overall improvement compared to baseline (range 18%-100%), with most improvement noted in erythema and/or telangiectasias. The incidence of adverse effects was 6/99 (6.1%). CONCLUSIONS: PDL is a useful tool in the treatment of IH, with notable improvement of telangiectasia and erythema and low risk of complications.   PDL is often introduced after the maximal proliferative phase.

Subcutaneous fat necrosis of the newborn: A retrospective study of 32 infants and care algorithm.

OBJECTIVE: To describe the clinical and laboratory outcomes of infants with subcutaneous fat necrosis of the newborn (SCFN) and propose a care algorithm. METHODS: This single-center, retrospective study of infants diagnosed with SCFN at Ann & Robert H. Lurie Children's Hospital of Chicago from 2009 to 2019. RESULTS: Of 32 infants who met inclusion criteria, most were born full-term (84%), born via cesarean section (58%), had normal weight for gestational age (69%), and experienced delivery complications (53%). Twenty-nine infants (91%) had calcium drawn, and all had hypercalcemia. Three infants developed clinical symptoms of hypercalcemia, two required hospital admission, two developed nephrocalcinosis, and one developed acute kidney injury. The majority of infants (62%) had a peak ionized calcium between 1.5 and 1.6 mmol/L. No infants with peak ionized calcium less than 1.5 mmol/L developed complications of hypercalcemia. Most patients were diagnosed with hypercalcemia (86%) and demonstrated peak ionized calcium levels (59%) within the first 28 days of life. No patients developed hypercalcemia after 3 months of age. CONCLUSION: Hypercalcemia occurred in 100% of infants who had laboratory monitoring. We recommend obtaining an initial ionized calcium level when SCFN is suspected, and monitoring for the first 3 months of life if hypercalcemia has not been detected. In patients with asymptomatic hypercalcemia less than 1.5 mmol/L, there appears to be low likelihood of related complications. For symptomatic, markedly elevated (>1.6 mmol/L), or persistently elevated levels (>6 months) we suggest coordinated care with endocrinology or nephrology, consider hospitalization, and urinary system ultrasound.