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Objective. This study presents a universal phantom for positron emission tomography (PET) that allows arbitrary static and dynamic activity distributions of various complexities to be generated using a single PET acquisition.Approach. We collected a high-statistics dataset (with a total of 22.4 × 109prompt coincidences and an event density of 2.75 × 106events mm-3) by raster-scanning a single plane with a22Na point source mounted on a robotic arm in the field-of-view of the uEXPLORER PET/CT scanner. The source position was determined from the reconstructed dynamic frames. Uniquely, true coincidences were separated from scattered and random events based on the distance between their line-of-response and the known source location. Finally, we randomly sampled the dataset to generate the desired activity distributions modeling several different phantoms.Main results. Overall, the target and the reconstructed phantom images had good agreement. The analysis of a simple geometric distribution showed high quantitative accuracy of the phantom, with mean error of

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10-28) and Estonia (P = 1.25 × 10-5). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.

Prior literature has debated whether syntax is separable from semantics in the brain. Using functional magnetic resonance imaging and multi-voxel pattern analysis, our previous studies investigated brain activity during morpho-syntactic versus semantic processing. These studies only detected semantic specialization in activation patterns and no syntactic specialization in 5- to 6-year-old and 7- to 8-year-old children. To examine if older children who have mastered morpho-syntactic skills would show specialization for syntax, the current study examined 64 9- to 10-year-old children using the same design and analyses. We observed that only the left IFG pars opercularis was sensitive to syntactic but not semantic information, supporting the hypothesis that this region serves as a core region for syntax. In addition, the left STG which has been implicated in the integration of semantics and syntax, as well as the left MTG and IFG pars triangularis which have been implicated in semantics, were sensitive to both semantic and syntactic information with no evidence of specialization. These findings suggest a lexicalized view of syntax, which argues that semantically sensitive regions are also critical regions for syntactic processing during language comprehension.

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32-72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14-40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Patent foramen ovale (PFO) may be an underlying factor in the pathogenesis of migraine, vasospastic angina, and Takotsubo cardiomyopathy. This article reviews the role that PFO may play in each of these clinical entities and discusses potential interventions. It also proposes a novel clinical syndrome wherein PFO may be the unifying link among migraine, coronary vasospasm, and Takotsubo cardiomyopathy in predisposed individuals.

Acute mountain sickness (AMS) commonly plagues people who travel to high altitude and can be life threatening. Clinically, AMS is defined by a constellation of symptoms as outlined in the Lake Louise Criteria. The underlying etiology is thought to be related to a decrease in partial pressure of oxygen leading to tissue hypoxia. Patent foramen ovale (PFO) has been postulated to play a role in AMS through right-to-left shunt, which can worsen hypoxemia. Recent data demonstrate a higher prevalence of PFO in hikers with AMS. Future studies are needed to further elucidate the relationship between PFO and AMS.

BackgroundChronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.MethodsParticipants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.ResultsChronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status.ConclusionsChronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

Persons with end-stage kidney disease treated with dialysis experience distressing reductions in quality of life and increased mortality. Few large, randomized trials in nephrology have reported on health-related quality of life. Rose et al. report beneficial effects of high-volume hemodiafiltration versus high-flux hemodialysis on secondary end points of health-related quality of life in the CONVINCE trial (Comparison of High Dose Hemodiafiltration with High Flux Hemodialysis Trial). These results raise questions regarding hemodiafiltration as a potential modality to preserve health-related quality of life in end-stage kidney disease.

The use of dietary supplements by patients with chronic liver disease is prevalent and rising. Despite the known risks of dietary supplements, including hepatotoxicity, adulteration, and contamination, patients with chronic liver disease often turn to dietary supplements to support their liver and/or overall health but are not necessarily empowered with the information or guidance from their liver practitioner to do so. This article provides practitioners with a framework for balancing the risks and benefits of dietary supplements in patients with chronic liver disease, offering examples of independent resources and certifications to use this framework in clinical practice. We offer 3 common clinical scenarios to highlight how the use of this framework can improve communication and decision-making in clinical practice. By adapting principles from Integrative Medicine, this article advocates for a patient-centered approach to dietary supplements in patients with chronic liver disease, encouraging open dialogue between clinicians and their patients to facilitate informed decision-making and personalized care.

BACKGROUND: Platelets are well known for their roles in hemostasis, but they also play a key role in thromboinflammatory pathways by regulating endothelial health, stimulating angiogenesis, and mediating host defense through both contact dependent and independent signaling. When activated, platelets degranulate releasing multiple active substances. We hypothesized that the soluble environment formed by trauma platelet releasates (TPR) attenuates thromboinflammation via mitigation of trauma induced endothelial permeability and metabolomic reprogramming. METHODS: Blood was collected from injured and healthy patients to generate platelet releasates and plasma in parallel. Permeability of endothelial cells when exposed to TPR and plasma (TP) was assessed via resistance measurement by electric cell-substrate impedance sensing (ECIS). Endothelial cells treated with TPR and TP were subjected to mass spectrometry-based metabolomics. RESULTS: TP increased endothelial permeability, whereas TPR decreased endothelial permeability when compared with untreated cells. When TP and TPR were mixed ex vivo, TPR mitigated TP-induced permeability, with significant increase in AUC compared with TP alone. Metabolomics of TPR and TP demonstrated disrupted redox reactions and anti-inflammatory mechanisms. CONCLUSION: Trauma platelet releasates provide endothelial barrier protection against TP-induced endothelial permeability. Our findings highlight a potential beneficial action of activated platelets on the endothelium in injured patients through disrupted redox reactions and increased antioxidants. Our findings support that soluble signaling from platelet degranulation may mitigate the endotheliopathy of trauma. The clinical implications of this are that activated platelets may prove a promising therapeutic target in the complex integration of thrombosis, endotheliopathy, and inflammation in trauma.

BACKGROUND: Although attempts have been made in the past to establish consensus regarding the definitions and grading of the severity of colorectal anastomotic leakage, widespread adoption has remained limited. OBJECTIVE: A systematic review of the literature was conducted to examine the various elements used to report and define anastomotic leakage in colorectal cancer resections. DATA SOURCES: A systematic review was conducted using the PubMed, Embase, and Cochrane Library Database. STUDY SELECTION: All published randomized controlled trials, systematic reviews, and meta-analyses containing data related to adult patients undergoing colorectal cancer surgery and reporting anastomotic leakage as a primary or secondary outcome, with a definition of anastomotic leakage were included. MAIN OUTCOME MEASURES: Definitions of anastomotic leakage, clinical symptoms, radiological modalities and findings, findings at reoperation, and grading terminology or classifications for anastomotic leakage. RESULTS: Of the 471 articles reporting anastomotic leakage as a primary or secondary outcome, a definition was reported in 95 studies (45 randomized controlled trials, 13 systematic reviews, and 37 meta-analyses) involving a total of 346,140 patients. Of these 95 articles, 68% reported clinical signs and symptoms of anastomotic leakage, 26% biochemical criteria, 63% radiological modalities, 62% radiological findings, and 13% findings at reintervention. Only 45% (n = 43) of included studies reported grading of anastomotic leakage severity or leak classification, and 41% (n = 39) included a time frame for reporting. LIMITATIONS: There was a high level of heterogeneity between the included studies. CONCLUSIONS: This evidence synthesis confirmed incomplete and inconsistent reporting of anastomotic leakage across the published colorectal cancer literature. There is a great need to develop and implement a consensus framework for defining, grading, and reporting anastomotic leakage. REGISTRATION: Prospectively registered at PROSPERO (ID 454660).

INTRODUCTION: Government agencies have identified evidence-based practice (EBP) dissemination as a pathway to high-quality behavioral health care for youth. However, gaps remain about how to best sustain EBPs in treatment organizations in the U.S., especially in resource-constrained settings like publicly-funded youth substance use services. One important, but understudied, determinant of EBP sustainment is alignment: the extent to which multi-level factors that influence sustainment processes and outcomes are congruent, consistent, and/or coordinated. This study examined the role of alignment in U.S. states efforts to sustain the Adolescent Community Reinforcement Approach (A-CRA), an EBP for youth substance use disorders, during the COVID-19 pandemic. METHODS: In this mixed methods study, the qualitative investigation preceded and informed the quantitative investigation. We interviewed state administrators and providers (i.e., supervisors and clinicians) from 15 states that had completed a federal A-CRA implementation grant; providers also completed surveys. The sample included 50 providers from 35 treatment organizations that reported sustaining A-CRA when the COVID-19 pandemic began, and 20 state administrators. In qualitative thematic analyses, we applied the EPIS (Exploration, Preparation, Implementation, Sustainment) framework to characterize alignment processes that interviewees described as influential on sustainment. We then used survey items to quantitatively explore the associations described in qualitative themes, using bivariate linear regressions. RESULTS: At the time of interview, staff from 80 % of the treatment organizations (n = 28), reported sustaining A-CRA. Providers from both sustainer and non-sustainer organizations, as well as state administrators, described major sources of misalignment when state agencies ceased technical assistance post-grant, and because limited staff capacity conflicted with A-CRAs training model, which was perceived as time-intensive. Participants described the pandemic as exacerbating preexisting challenges, including capacity issues. Sustainer organizations reported seeking new funding to help sustain A-CRA. Quantitative associations between self-rated extent of sustainment and other survey items mostly followed the pattern predicted from the qualitative findings. CONCLUSIONS: The COVID-19 pandemic amplified longstanding A-CRA sustainment challenges, but treatment organizations already successfully sustaining A-CRA pre-pandemic largely continued. There are missed opportunities for state-level actors to coordinate with providers on the shared goal of EBP sustainment. A greater focus on alignment processes in research and practice could help states and providers strengthen sustainability planning.

Ethnic-racial identity (ERI) development is consequential for youth adjustment and includes exploration, resolution, and affect about the meaning of ones ethnic-racial group membership. Little is known about how identity-relevant experiences, such as ethnic-racial socialization and discrimination in peer relationships and school contexts, catalyze adolescent ERI development. The present study examines how identity-relevant experiences in friend and school contexts (i.e., proportion of same-ethnoracial friends, cultural socialization among friends, friends ERI dimensions, friends experiences of ethnoracial discrimination, and school promotion of cultural competence and critical consciousness) are associated with ERI development. A multivariate path model with a sample from four southwestern U.S. schools (N = 717; 50.5% girls; Mage = 13.76; 32% Latinx, 31.5% Multiethnic, 25.7% White, 11% other) was used to test these associations. Findings showed that friend and school predictors of ERI did not differ between early and middle adolescents, but significant differences and similarities emerged in some of these associations between ethnoracially minoritized and White youth. Specifically, friend cultural socialization was positively associated with ERI exploration for ethnoracially minoritized youth only, whereas school critical consciousness socialization was positively linked with ERI exploration only for White youth. Friend cultural socialization and friend networks levels of ERI resolution were positively associated with ERI resolution across both ethnoracial groups. These friend and school socialization associations were documented above and beyond significant contributions of personal ethnoracial discrimination to ERI exploration and negative affect for both ethnoracially minoritized and White youth. These findings expand our understanding of how friend and school socialization mechanisms are associated with adolescent ERI development, which is vital to advancing developmental theory and fostering developmental competences for youth to navigate their multicultural yet socially stratified and inequitable world.

BACKGROUND: Rates of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer have improved, especially among human epidermal growth factor 2-positive (HER2+) and triple-negative subtypes. The frequency and significance of biomarker profile change in residual disease are unclear. This study aimed to determine the rate of biomarker profile changes after NAC and the impact on clinical outcomes in a contemporary cohort. METHODS: Upon institutional review board approval, the study identified 634 consecutive patients treated with NAC between 2010 and 2022 at two academic institutions. The study cohort was focused on patients with residual disease who underwent biomarker profile retesting. Biomarker profile change for each subtype was compared across groups using Fisher-Irwin tests. Cox Proportional Hazards Model and Kaplan-Meier plots were performed to evaluate the association of changed versus unchanged biomarker profile with event-free survival. RESULTS: Biomarker retesting was performed for 259 (61.4 %) of 422 patients with residual disease. Biomarker profile change occurred in 18.1 % overall and was significantly higher among those with pre-NAC HER2+ disease (32.7 %, 17/52) than among those with HER2-disease (14.5 %, 30/207) (p = 0.004). Conversion of pre-NAC biomarker profiles of HR+HER2- and HR+HER2+ to triple-negative breast cancer (TNBC) post-NAC may be associated with worse event-free survival, hazard ratios of 2.23 (95 % confidence interval [CI], 0.90-5.53; p = 0.08), trending toward significance, and 36.7 (95 % CI, 2.2-610.8; p = 0.01), respectively. CONCLUSIONS: The results from one of the largest contemporary cohorts demonstrated that biomarker profile change in patients with residual disease after NAC was common. Furthermore, specific biomarker profile change in residual disease may have prognostic value. These findings strengthen the rationale for routine re-testing of biomarkers in residual disease after NAC.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p

BACKGROUND: Community health workers (CHWs) can support patient engagement in care for a variety of health conditions, including HIV. This paper reports on the experiences of HIV clinics and health departments that integrated CHWs into their health systems as part of a capacity-building initiative to address HIV-related disparities in the United States. METHODS: Semi-structured interviews were conducted with key informants (n = 14) in two Ryan White HIV/AIDS program jurisdictions: Mississippi (jurisdiction covers the entire state) and the city of New Orleans, Louisiana. This work was part of a larger evaluation of an initiative that used a Learning Collaborative model to facilitate the implementation of evidence-informed interventions to address HIV care continuum gaps in four jurisdictions. The two jurisdictions that focused on integrating CHWs into HIV care clinics and support service agencies were selected for this sub-analysis. Interview participants included HIV clinic leaders and staff, health department leaders, and other Learning Collaborative leaders. Interview transcripts were coded and analyzed for themes related to the acceptability, feasibility, and perceived impact of CHW integration. RESULTS: Overall, participants expressed interest in having support from CHWs at HIV clinics and service agencies to assist with patient retention and engagement efforts. However, there were challenges integrating CHWs into existing systems (e.g., gaining access to electronic health records, changing policies to conduct home visits, and clarifying roles and scope of work). Negotiating contracts and accessing funding for CHW positions presented major challenges that often contributed to turnover and conflicts around scope of practice. When health departments leveraged existing funding streams to support CHW positions, the clinics and agencies where the CHWs worked had limited flexibility over the hiring process. CONCLUSIONS: Our findings reinforce the value and acceptability of CHWs as part of the workforce in HIV clinical and support service settings; however, integrating CHWs into clinics and service agencies required effort. Training the CHWs was not sufficient; other staff and clinicians had to understand the role of CHWs to facilitate their integration into health systems. Resources are needed to support organizations in incorporating CHWs effectively, and long-term, flexible sources of funding are necessary for these positions.

OBJECTIVES: Up to a quarter of pregnant individuals with SLE have small for gestational age (SGA) infants. We aimed to characterize placental pathology associated with SGA infants in SLE. METHODS: We retrospectively analysed SLE deliveries with placental analysis at UCSD from November 2018 to October 2023, comparing SLE pregnancies resulting in SGA to those that did not, and additionally, to matched pregnancies with SGA but without SLE. RESULTS: Placental analysis was available only for 28/70 (40%) SLE deliveries, which had high rates of adverse outcomes (75%). All exhibited at least one histopathologic abnormality. Key findings distinguishing 12 SLE placentas resulting in SGA infants (vs.16 without) included small placental disc for gestational age (100% vs 56%, P = 0.01), placental disc infarct (50% vs 6%, P = 0.02) and increased perivillous fibrin deposition (PVFD, 58% vs 0%, P = 0.001). All seven SLE placentas with increased PVFD resulted in SGA infants. Compared with matched non-SLE pregnancies with SGA (n = 36), the only distinguishing placental lesion was a higher prevalence of increased PVFD in SLE-associated SGA (58% vs 22%, P = 0.03). CONCLUSION: The higher prevalence of increased PVFD in placentas of SLE-associated SGA may indicate a specific mechanism of placental injury leading to SGA in this context. Thus, its presence, particularly in context of SGA, should prompt providers to screen for an underlying autoimmune disease, including SLE. Systematic placental examination in context of SLE and associated autoimmune diseases could help evaluate responses to existing therapies, comparative studies of novel therapies and correlation to adverse outcomes.

Across four studies (N = 1544), we examined the relationship between individuals gender role mindsets, or beliefs about the malleability versus fixedness of traditional gender roles, and work-family conflict. We found that undergraduate women (but not men) business students holding a fixed, compared to growth, gender role mindset anticipated more work-family conflict. Next, we manipulated gender role mindset and demonstrated a causal link between womens growth mindsets (relative to fixed mindsets and control conditions) and reduced work-family conflict. We showed mechanistically that growth gender role mindsets unburden women from prescriptive gender roles, reducing work-family conflict. Finally, during COVID-19, we demonstrated a similar pattern among working women in high-achieving dual-career couples. We found an indirect effect of womens gender role mindset on job and relationship satisfaction, mediated through work-family conflict. Our preregistered studies suggest that holding the belief that gender roles can change mitigates womens work-family conflict.

Criteria for recognizing and rewarding scientists primarily focus on individual contributions. This creates a conflict between what is best for scientists careers and what is best for science. In this article, we show how the theory of multilevel selection provides conceptual tools for modifying incentives to better align individual and collective interests. A core principle is the need to account for indirect effects by shifting the level at which selection operates from individuals to the groups in which individuals are embedded. This principle is used in several fields to improve collective outcomes, including animal husbandry, team sports, and professional organizations. Shifting the level of selection has the potential to ameliorate several problems in contemporary science, including accounting for scientists diverse contributions to knowledge generation, reducing individual-level competition, and promoting specialization and team science. We discuss the difficulties associated with shifting the level of selection and outline directions for future development in this domain.

Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p

Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies.

PURPOSE: There is variability in clinical outcomes with vertebral body tethering (VBT) partly due to a limited understanding of the growth modulation (GM) response. We used the largest sample of patients with 3D spine reconstructions to characterize the vertebra and disc morphologic changes that accompany growth modulation during the first two years following VBT. METHODS: A multicenter registry was used to identify idiopathic scoliosis patients who underwent VBT with 2 years of follow-up. Calibrated biplanar X-rays obtained at longitudinal timepoints underwent 3D reconstruction to obtain precision morphological measurements. GM was defined as change in instrumented coronal angulation from post-op to 2-years. RESULTS: Fifty patients (mean age: 12.5 ± 1.3yrs) were analyzed over a mean of 27.7 months. GM was positively correlated with concave vertebra height growth (r = 0.57, p  10°) experienced an additional 1.6 mm (229% increase) of mean concave vertebra growth during study period compared to the Poor Modulators (GM

PURPOSE: To describe clinical outcomes among patients with benign prostatic hyperplasia (BPH) 24 months following prostatic artery embolization (PAE). MATERIALS AND METHODS: This was an international, multicenter, prospective trial of males with BPH with lower urinary tract symptoms (LUTS) or acute urinary retention (AUR) treated with PAE. The primary outcome was the 12 month change in the International Prostate Symptom Score (IPSS) for patients referred for bothersome LUTS, or urinary catheter independence for patients treated for AUR. Secondary outcome measures included changes in IPSS at 3 and 24 months, changes in quality of life (QoL), changes in the Sexual Health Inventory for Men (SHIM) questionnaire, technical success rate, and adverse events (AEs). Data were summarized using descriptive statistics. RESULTS: Four hundred seventy-eight consecutive patients underwent PAE (bothersome LUTS: N = 405; AUR: N = 73), mean age was 70 years. For patients treated for bothersome LUTS, mean total IPSS at baseline was 21.8 and decreased to 9.3, 10.6, and 11.2 at 3, 12, and 24 months following PAE, respectively (all p

OBJECTIVE: We compared the effectiveness and safety of polidocanol 1% endovenous microfoam ablation vs endovenous thermal ablation with radiofrequency or laser energy for treatment of venous insufficiency caused by lower extremity truncal vein incompetence via network meta-analysis of published comparative evidence. METHODS: We conducted a systematic literature review following best practices, including a prospective protocol. We screened studies published in English from 2000 to 2023 for randomized and nonrandomized studies reporting direct or indirect comparisons between polidocanol 1% endovenous microfoam and endovenous thermal ablation. Thirteen studies met our eligibility criteria for the network meta-analysis. The co-primary effectiveness outcomes were the closure rate ≥3 months after procedure and the average change in the Venous Clinical Severity Score. For the subgroup of venous ulcer patients, the ulcer healing rate was the primary effectiveness outcome. The secondary outcomes included safety and patient-reported outcomes. Network meta-analyses were conducted on outcomes having sufficient data. Categorical outcomes were summarized using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity tests and estimates of network inconsistency were used to investigate the robustness of our meta-analysis. RESULTS: We found that polidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure (OR, 0.65; 95% CI, 0.36-1.18; P = .16). Although not the primary aim of the study, the network meta-analysis also provided evidence to confirm our supposition that polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds for vein closure (OR, 2.91; 95% CI, 1.58-5.37; P < .01). A sensitivity analysis using the longest available time point for closure in each study, with a minimum of 12 months of follow-up (median, 48 months; range, 12-72 months), showed results similar to those of the main analysis. No association was found between the risk of deep vein thrombosis and the treatment received. The available data were insufficient for a network meta-analysis of Venous Clinical Severity Score improvement and ulcer healing rates. CONCLUSIONS: Polidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure and deep vein thrombosis risk for chronic venous insufficiency treatment, based on a network meta-analysis of published evidence. Polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds of vein closure. A sensitivity analysis found venous closure findings were robust at follow-up intervals of 12 months or greater and for up to 6 years. New evidence meeting the inclusion criteria for this review will be incorporated at regular intervals into a living network meta-analysis.

Pre-exposure prophylaxis (PrEP) is highly effective at reducing HIV acquisition. We aimed to estimate usage of oral-PrEP, and factors associated with adherence among female sex workers (FSWs) in Nairobi, Kenya, using a novel point-of-care urine tenofovir lateral flow assay (LFA). The Maisha Fiti study randomly selected FSWs from Sex Worker Outreach Program clinics in Nairobi. Data were collected from 1003 FSWs from June-October 2019, including surveys on self-reported oral-PrEP adherence. Adherence was also measured using the LFA for HIV-negative FSWs currently taking oral-PrEP. Informed by a social-ecological theoretical framework, we used hierarchical multivariable logistic regression models to estimate associations between individual, interpersonal/community, and structural/institutional-level factors and either self-reported or LFA-assessed adherence. Overall, 746 HIV-negative FSWs aged 18-40 participated in the study, of whom 180 (24.1%) self-reported currently taking oral-PrEP. Of these, 56 (31.1%) were adherent to oral-PrEP as measured by LFA. In the multivariable analyses, associations with currently taking oral-PrEP included having completed secondary education, high alcohol/substance use, feeling empowered to use PrEP, current intimate partner, no recent intimate partner violence, having support from sex worker organisations, experiencing sex work-related stigma, and seeking healthcare services despite stigma. Associations with oral-PrEP LFA-measured adherence measured included having only primary education, experience of childhood emotional violence, belonging to a higher wealth tertile, and being nulliparous. Oral-PrEP adherence, measured by self-report or objectively, is low among FSWs in Nairobi. Programs to improve oral-PrEP usage among FSWs should work to mitigate social and structural barriers and involve collaboration between FSWs, healthcare providers and policymakers.

The demand for glucose monitoring devices has witnessed continuous growth from the rising diabetic population. The traditional approach of blood glucose (BG) sensor strip testing generates only intermittent glucose readings. Interstitial fluid-based devices measure glucose dynamically, but their sensing approaches remain either minimally invasive or prone to skin irritation. Here, a sweat glucose monitoring system is presented, which completely operates under rest with no sweat stimulation and can generate real-time BG dynamics. Osmotically driven hydrogels, capillary action with paper microfluidics, and self-powered enzymatic biochemical sensor are used for simultaneous sweat extraction, transport, and glucose monitoring, respectively. The osmotic forces facilitate greater flux inflow and minimize sweat rate fluctuations compared to natural perspiration-based sampling. The epidermal platform is tested on fingertip and forearm under varying physiological conditions. Personalized calibration models are developed and validated to obtain real-time BG information from sweat. The estimated BG concentration showed a good correlation with measured BG concentration, with all values lying in the A+B region of consensus error grid (MARD = 10.56% (fingertip) and 13.17% (forearm)). Overall, the successful execution of such osmotically driven continuous BG monitoring system from passive sweat can be a useful addition to the next-generation continuous sweat glucose monitors.

INTRODUCTION: Decisions to prescribe opioids to patients depend on many factors, including illness severity, pain assessment, and patient age, race, ethnicity, and gender. Gender and sex disparities have been documented in many healthcare settings, but are understudied in inpatient general medicine hospital settings. OBJECTIVE: We assessed for differences in opioid administration and prescription patterns by legal sex in adult patient hospitalizations from the general medicine service at a large urban academic center. DESIGNS, SETTING, AND PARTICIPANTS: This study included all adult patient hospitalizations discharged from the acute care inpatient general medicine services at the University of California, San Francisco (UCSF) Helen Diller Medical Center at Parnassus Heights from 1/1/2013 to 9/30/2021. MAIN OUTCOME AND MEASURES: The primary outcomes were (1) average daily inpatient opioids received and (2) days of opioids prescribed on discharge. For both outcomes, we first performed logistic regression to assess differences in whether or not any opioids were administered or prescribed. Then, we performed negative binomial regression to assess differences in the amount of opioids given. We also performed all analyses on a subgroup of hospitalizations with pain-related diagnoses. RESULTS: Our study cohort included 48,745 hospitalizations involving 27,777 patients. Of these, 24,398 (50.1%) hospitalizations were female patients and 24,347 (49.9%) were male. Controlling for demographic, clinical, and hospitalization-level variables, female patients were less likely to receive inpatient opioids compared to male patents (adjusted OR 0.87; 95% CI 0.82, 0.92) and received 27.5 fewer morphine milligram equivalents per day on average (95% CI - 39.0, - 16.0). When considering discharge opioids, no significant differences were found between sexes. In the subgroup analysis of pain-related diagnoses, female patients received fewer inpatient opioids. CONCLUSIONS: Female patients were less likely to receive inpatient opioids and received fewer opioids when prescribed. Future work to promote equity should identify strategies to ensure all patients receive adequate pain management.

BACKGROUND AND OBJECTIVES: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This studys objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD. METHODS: Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5. RESULTS: Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease. DISCUSSION: Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings. TRIAL REGISTRATION INFORMATION: NCT03623672.

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant.

BackgroundThere are no clinical practice guidelines addressing the treatment of tobacco-cannabis co-use and a dearth of studies to inform treatment for co-use. This narrative review aims to (1) summarize promising intervention components used in published co-use treatment studies, (2) describe key gaps and emerging issues in co-use, and (3) provide recommendations and considerations in the development and evaluation of co-use interventions.MethodsWe conducted a literature search in June 2024 across several databases to update previous reviews on tobacco-cannabis co-use treatment. We found 9 published intervention studies that specifically addressed treatment for both substances. Data from these studies were manually extracted and summarized.ResultsMost of the 9 included studies (1) focused on acceptability and/or feasibility, (2) provided both psychosocial/behavioral and pharmacotherapy intervention components, (3) were conducted in adults, and (4) were delivered in-person, with some having digital asynchronous components, for a 5-to-12-week duration. The most common psychosocial/behavioral strategies used were Cognitive Behavioral Therapy, Motivational Interviewing, and Contingency Management; while the most common pharmacotherapy was Nicotine Replacement Therapy. There was no evidence of compensatory use of tobacco or cannabis when providing simultaneous treatment for both substances.ConclusionsThe literature to date provides support for well-integrated multi-component interventions of psychosocial/behavioral and pharmacotherapy strategies for co-use treatment. This review reinforces an urgent need for treatments targeting tobacco and cannabis co-use. Future interventions should address key gaps, including co-use of vaporized products among youth and young adults, tailored interventions for priority populations, and digital applications to increase reach and advance health equity.

ABSTRACTJustice-impacted persons may inconsistently access HIV testing. This cross-sectional secondary analysis investigates lifetime HIV testing prevalence among adults with prior histories of incarceration in Southern California, United States, participating in health-focused programming (n = 3 studies). Self-reported demographic and lifetime HIV testing data were collected between 2017-2023; descriptive analyses were conducted. Across the three samples, at least 74% of participants were male; Latino and African American individuals accounted for nearly two-thirds of participants. Lifetime HIV testing ranged from 72.8% to 84.2%. Males were significantly more likely than females to report never being tested in two samples and accounted for >95% of those never tested. No statistically significant differences in testing were observed by race/ethnicity. Single young adults (ages 18-26) were less likely than their partnered peers to report testing. HIV testing is critical for ensuring that individuals access prevention and treatment. HIV testing among justice-impacted adults in this study was higher than in the general population, potentially due to opt-out testing in correctional settings. Nevertheless, these findings underscore the importance of implementing targeted interventions to reduce structural (e.g., health insurance, access to self-testing kits) and social barriers (e.g., HIV stigma) to increase HIV testing among justice-impacted males and single young adults.

In this study, we employed a pre-interview survey and conducted interviews with nursing home staff members and residents/family members to understand their perceptions of whether the COVID-19 restrictions fulfilled obligations to nursing home residents under various principles, including autonomy, beneficence, nonmaleficence, justice, and privacy. We conducted 20 semi-structured interviews with staff members from 14 facilities, and 20 with residents and/or family members from 13 facilities. We used a qualitative descriptive study design and thematic analysis methodology to analyze the interviews. Findings from the pre-interview survey indicated that, compared to nursing home staff, residents and their families perceived lower adherence to bioethics principles during the pandemic. Qualitative analysis themes included specific restrictions, challenges, facility notifications, consequences, communication, and relationships between staff and residents/family members. Our study exposes the struggle to balance infection control with respecting bioethical principles in nursing homes, suggesting avenues for improving processes and policies during public health emergencies.

PURPOSE: To assess the effect of various pelvic fixation techniques and number of rods on biomechanics of the proximal junction of long thoracolumbar posterior instrumented fusions. METHODS: A validated spinopelvic finite-element (FE) model was instrumented with L5-S1 ALIF and one of the following 9 posterior instrumentation configurations: (A) one traditional iliac screw bilaterally (2 Iliac/2 Rods); (B) T10 to S1 (Sacral Only); (C) unilateral traditional iliac screw (1 Iliac/2 Rods); (D) one traditional iliac screw bilaterally with one midline accessory rod (2 Iliac/3 rods); (E) S2AI screws connected directly to the midline rods (2 S2AI/2 Rods); and two traditional iliac screws bilaterally with two lateral accessory rods connected to the main rods at varying locations (F1: T10-11, F2: T11-12, F3: T12-L1, F4: L1-2) (4 Iliac/4 Rods). Range of motions (ROM) at T10-S1 and T9-T10 were recorded and compared between models. The T9-T10 intradiscal pressures and stresses of the T9-10 discs annulus in addition to the von Mises stresses of the T9 and T10 vertebral bodies were recorded and compared. RESULTS: For T10-S1 ROM, 4 iliac/4 rods had lowest ROM in flexion and extension, while 2 S2AI/2 rods showed lowest ROM in rotation. Constructs with 3 or 4 rods had lower stresses on the primary rods compared to 2-rod constructs. At the proximal adjacent disc (T9-10), 4 iliac/4 rods showed lowest ROM, lowest intradiscal pressures, and lowest annular stress in all directions (most pronounced in flexion-extension). Under flexion and extension, 4 iliac/4 rods also showed the lowest von Mises stresses on the T10 vertebral body but the highest stresses on the T9 vertebral body. CONCLUSIONS: Dual iliac screws with 4 rods across the lumbosacral junction and extending to the thoracolumbar junction demonstrated the lowest T10-S1 ROM, the lowest adjacent segment disc (T9-T10) ROM, intradiscal pressures, and annular stresses, and the lowest UIV stresses, albeit with the highest UIV + 1 stresses. Additional studies are needed to confirm whether these biomechanical findings dictate clinical outcomes and effect rates of proximal junctional kyphosis and failure.

BACKGROUND: While bedside assistants play a critical role in many robotic operations, substantial heterogeneity remains in bedside assistant training pathways. As such, this study aimed to develop consensus guidelines for bedside assistant skills required for team members in robotic operations. METHODS: We designed a study using the Delphi process to develop consensus guidelines around bedside assistant skills. We generated an initial list of bedside assistant skills from the literature, training materials, and expert input. We selected experts for the Delphi process based on prior scholarship in the area of robotic bedside assistant education and experience facilitating robotic bedside assistant training. For each item, respondents specified which robotic team members should have the skill from a list of basic bedside assistants, advanced bedside assistants, surgeons, surgical technologists, and circulating nurses. We conducted two rounds of the Delphi process and defined 80% agreement as sufficient for consensus. RESULTS: Fourteen experts participated in two rounds of the Delphi process. By the end of the second round, the group had reached consensus on 253 of 305 items (83%). The group determined that basic bedside assistants should have 52 skills and that advanced bedside assistants should have 60 skills. The group also determined that surgeons should have 54 skills, surgical technologists should have 25 skills, and circulating nurses should have 17 skills. Experts agreed that all participants should have certain communication skills and basic knowledge of aspects of the robotic system. CONCLUSIONS: We developed consensus guidelines on the skills required during robotic surgery by bedside assistants and other team members using the Delphi process. These findings can be used to design training around bedside assistant skills and assess team members to ensure that each team member has the appropriate skills. Hospitals can also use these guidelines to standardize expectations for robotic team members.

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.

BACKGROUND: The Get With The Guidelines-Stroke program is a quality improvement initiative designed to enhance adherence to evidence-based stroke care. Since its inception in 2003, over 2800 hospitals in the United States have participated in the program. METHODS: We examined patient characteristics, adherence to performance measures, and in-hospital outcomes in patients hospitalized for acute ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack in The Get With The Guidelines-Stroke hospitals from 2003 through 2022. We quantified temporal changes in performance measure adherence and clinical outcomes over time. Performance measure denominators consisted of patients who were eligible, excluding those with contraindications. RESULTS: Over the 20 years of the program, a total of 7837 849 stroke cases (median age 71 years, 51.0% female; 69.2% ischemic strokes, 3.9% SAHs, 11.5% ICHs, and 15.3% TIAs) were entered into the registry. Except for antithrombotics at discharge, in which the baseline performance was >92%, there was sustained improvement in all performance metrics regardless of type of cerebrovascular event (P

Most studies of developing visual attention are conducted using screen-based tasks in which infants move their eyes to select where to look. However, real-world visual exploration entails active movements of both eyes and head to bring relevant areas in view. Thus, relatively little is known about how infants coordinate their eyes and heads to structure their visual experiences. Infants were tested every 3 months from 9 to 24 months while they played with their caregiver and three toys while sitting in a highchair at a table. Infants wore a head-mounted eye tracker that measured eye movement toward each of the visual targets (caregiver's face and toys) and how targets were oriented within the head-centered field of view (FOV). With age, infants increasingly aligned novel toys in the center of their head-centered FOV at the expense of their caregiver's face. Both faces and toys were better centered in view during longer looking events, suggesting that infants of all ages aligned their eyes and head to sustain attention. The bias in infants' head-centered FOV could not be accounted for by manual action: Held toys were more poorly centered compared with non-held toys. We discuss developmental factors-attentional, motoric, cognitive, and social-that may explain why infants increasingly adopted biased viewpoints with age.

AimThe current study investigated the prospective relationships between parental monitoring, family conflict, and screen time across six screen time modalities in early adolescents in the USA.MethodsWe utilised prospective cohort data of children (ages 10-14 years) from the Adolescent Brain Cognitive Development (ABCD) Study (years baseline to Year 2 of follow-up; 2016-2020; N = 10 757). Adjusted coefficients (B) and 95% confidence intervals (CIs) were estimated using mixed-effect models with robust standard errors.ResultsA higher parental monitoring score was associated with less total screen time (B = -0.37, 95% CI -0.58, -0.16), with the strongest associations being with video games and YouTube videos. Conversely, a higher family conflict score was associated with more total screen time (B = 0.08, 95% CI 0.03, 0.12), with the strongest associations being with YouTube videos, video games, and watching television shows/movies in Years 1 and 2.ConclusionThe current study found that greater parental monitoring was associated with less screen time, while greater family conflict was linked to more screen time. These results may inform strategies to reduce screen time in adolescence, such as improving communication between parents and their children to strengthen family relationships.

ObjectiveSexual and gender minority individuals are more likely to use tobacco and cannabis and have lower cigarette cessation. This study examined cannabis use associations with daily cigarettes smoked in sexual and gender minority individuals before and during a quit attempt.MethodParticipants included dual smoking same-sex/gender couples from California that were willing to make a quit attempt (individual n = 205, 68.3% female sex). Participants reported baseline past 30-day cannabis use and number of cigarettes smoked and cannabis use (yes/no) during 35 nightly surveys. Individuals with current cannabis use reported baseline cannabis use and/or nightly survey cannabis use. Multilevel linear models predicted number of cigarettes smoked by cannabis use.ResultsNumber of cigarettes decreased from before to during a quit attempt, but this decrease was smaller in individuals with current cannabis use compared to no current cannabis use (p < .001). In individuals with current cannabis use, number of cigarettes smoked was greater on days with cannabis use (p < .001). Furthermore, cannabis use that day increased overall number of cigarettes in those with relatively high overall cannabis use but only during a quit attempt in those with relatively low cannabis use (Within-Subject Cannabis Use × Between-Subject Cannabis Use × Quit Attempt interaction; p < .001).ConclusionsSexual and gender minority individuals with cannabis and cigarette use may have a harder time quitting smoking than those who do not use cannabis. For those with cannabis use, guidance on not using cannabis during a quit attempt may improve cigarette cessation outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand smoke exposure: persistent pollutant reservoirs, pollutant transport, routes of exposure, the time gap between initial cause and effect, and remediation and disposal. We examine four policy considerations to better protect the public from involuntary exposure to tobacco smoke pollutants from all sources. We call for (a) redefining smokefree as free of tobacco smoke pollutants from secondhand and thirdhand smoke; (b) eliminating exemptions to comprehensive smoking bans; (c) identifying indoor environments with significant thirdhand smoke reservoirs; and (d) remediating thirdhand smoke. We use the case of California as an example of how secondhand smoke-protective laws may be strengthened to encompass thirdhand smoke protections. The health risks and economic costs of thirdhand smoke require that smokefree policies, environmental protections, real estate and rental disclosure policies, tenant protections, and consumer protection laws be strengthened to ensure that the public is fully protected from and informed about the risks of thirdhand smoke exposure.

Cancer stem cells, characterized by high tumorigenicity and drug-resistance, are often responsible for tumor progression and metastasis. Aldehyde dehydrogenases, often overexpressed in cancer stem cells enriched tumors, present a potential target for specific anti-cancer stem cells treatment. In this study, we report a self-assembled nano-prodrug composed of aldehyde dehydrogenases activatable photosensitizer and disulfide-linked all-trans retinoic acid for diagnosis and targeted treatment of cancer stem cells enriched tumors. The disulfide-linked all-trans retinoic acid can load with photosensitizer and self-assemble into a stable nano-prodrug, which can be disassembled into all-trans retinoic acid and photosensitizer in cancer stem cells by high level of glutathione. As for the released photosensitizer, overexpressed aldehyde dehydrogenase catalyzes the oxidation of aldehydes to carboxyl under cancer stem cells enriched microenvironment, activating the generation of reactive oxygen species and fluorescence emission. This generation of reactive oxygen species leads to direct killing of cancer stem cells and is accompanied by a noticeable fluorescence enhancement for real-time monitoring of the cancer stem cells enriched microenvironment. Moreover, the released all-trans retinoic acid, as a differentiation agent, reduce the cancer stem cells stemness and improve the cancer stem cells enriched microenvironment, offering a synergistic effect for enhanced anti-cancer stem cells treatment of photosensitizer in inhibition of in vivo tumor growth and metastasis.

This paper proposes a smartphone-based method for measuring Blood Pressure (BP) using the oscillometric method. For oscillometry, it is necessary to measure (1) the pressure applied to the artery and (2) the local blood volume change. This is accomplished by performing an oscillometric measurement at the fingers digital artery, whereby a user presses down on the phones camera with steadily increasing force. The camera is used to capture the blood volume change using photoplethysmography. We devised a novel method for measuring the force applied of the finger without the use of specialized smartphone hardware with a technique called Vibrometric Force Estimation (VFE). The fundamental concept of VFE relies on a phenomenon where a vibrating object is dampened when an external force is applied on to it. This phenomenon can be recreated using the phones own vibration motor and measured using the phones Inertial Measurement Unit (IMU). A cross device reliability study with three smartphones of different manufacturers, shape, and prices results in similar force estimation performance across all smartphone models. In an N = 24 proof of concept study of the BP measurement, the smartphone technique achieves a mean absolute error of 9.21 mmHg and 7.77 mmHg of systolic and diastolic BP, respectively, compared to an FDA approved BP cuff. The vision for this technology is not necessarily to replace existing BP monitoring solutions, but rather to introduce a downloadable smartphone software application that could serve as a low-barrier hypertension screening measurement fit for widespread adoption.

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, we identified several compounds with potent (low-nM IC50) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.

Fast, nondestructive three-dimensional (3D) imaging of live suspension cells remains challenging without substrate treatment or fixation, precluding scalable single-cell morphometry with minimal alterations. While optical sectioning techniques achieve 3D live cell imaging, lateral versus depth resolution differences further complicate analysis. We present a scalable microfluidic method capable of 3D fluorescent isotropic imaging of live, nonadherent cells suspended inside picoliter droplets with high-speed single-cell volumetric readout (800 to 1,200 slices in 5 to 8 s) and near-diffraction limit resolution (~216 nm). The platform features a droplet trap array that leverages flow-induced droplet interfacial shear to generate intradroplet microvortices, which rotate single cells on their axis to enable optical projection tomography (OPT)-based imaging. This allows gentle (~1 mPa shear stress) observation of cells encapsulated inside nontoxic isotonic buffer droplets, facilitating scalable OPT acquisition by simultaneous spinning of hundreds of cells. We demonstrate 3D imaging of live myeloid and lymphoid cells in suspension, including K562 cells, as well as naive and activated T cells-small cells prone to movement in their suspended phenotype. Our fully suspended, orientation-independent cell morphometry, driven by isotropic imaging and spherical harmonic analysis, enabled the study of primary T cells across various immunological activation states. This approach unveiled six distinct nuclear content distributions, contrasting with conventional 2D images that typically portray spheroid and bean-like nuclear shapes associated with lymphocytes. Our arrayed-droplet OPT technology is capable of isotropic, single live-cell 3D imaging, with the potential to perform large-scale morphometry of immune cell effector function states while providing compatibility with microfluidic droplet operations.

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species-random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.

Mass spectrometry-based methods can provide a global expression profile and structural readout of proteins in complex systems. Preserving the in vivo conformation of proteins in their innate state is challenging during proteomic experiments. Here, we introduce a whole animal in vivo protein footprinting method using perfusion of reagents to add dimethyl labels to exposed lysine residues on intact proteins which provides information about protein conformation. When this approach is used to measure dynamic structural changes during Alzheimers disease (AD) progression in a mouse model, we detect 433 proteins that undergo structural changes attributed to AD, independent of aging, across 7 tissues. We identify structural changes of co-expressed proteins and link the communities of these proteins to their biological functions. Our findings show that structural alterations of proteins precede changes in expression, thereby demonstrating the value of in vivo protein conformation measurement. Our method represents a strategy for untangling mechanisms of proteostasis dysfunction caused by protein misfolding. In vivo whole-animal footprinting should have broad applicability for discovering conformational changes in systemic diseases and for the design of therapeutic interventions.