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The Genomes OnLine Database (GOLD; https://gold.jgi.doe.gov/) at the Department of Energy Joint Genome Institute is a comprehensive online metadata repository designed to catalog and manage information related to (meta)genomic sequence projects. GOLD provides a centralized platform where researchers can access a wide array of metadata from its four organization levels namely Study, Organism/Biosample, Sequencing Project and Analysis Project. GOLD continues to serve as a valuable resource and has seen significant growth and expansion since its inception in 1997. With its expanded role as a collaborative platform, it not only actively imports data from other primary repositories like National Center for Biotechnology Information but also supports contributions from researchers worldwide. This collaborative approach has enriched the database with diverse datasets, creating a more integrated resource to enhance scientific insights. As genomic research becomes increasingly integral to various scientific disciplines, more researchers and institutions are turning to GOLD for their metadata needs. To meet this growing demand, GOLD has expanded by adding diverse metadata fields, intuitive features, advanced search capabilities and enhanced data visualization tools, making it easier for users to find and interpret relevant information. This manuscript provides an update and highlights the new features introduced over the last 2 years.

Human-made chemicals are ubiquitous, leading to chronic exposure to complex mixtures of potentially harmful substances. We investigated chemical exposures in pregnant women in New York City by applying a non-targeted analysis (NTA) workflow to 95 paired prenatal urine and serum samples (35 pairs of preterm birth) collected as part of the New York University Children's Health and Environment Study. We analyzed all samples using liquid chromatography coupled with Orbitrap high-resolution mass spectrometry in both positive and negative electrospray ionization modes, employing full scan and data-dependent MS/MS fragmentation scans. We detected a total of 1524 chemical features for annotation, with 12 chemicals confirmed by authentic standards. Two confirmed chemicals dodecyltrimethylammonium and N,N-dimethyldecylamine N-oxide appear to not have been previously reported in human blood samples. We observed a statistically significant differential enrichment between urine and serum samples, as well as between preterm and term birth (p < 0.0001) in serum samples. When comparing between preterm and term births, an exogenous contaminant, 1,4-cyclohexanedicarboxylic acid (tentative), showed a statistical significance difference (p = 0.003) with more abundance in preterm birth in serum. An example of chemical associations (12 associations in total) observed was between surfactants (tertiary amines) and endogenous metabolites (fatty acid amides).

BACKGROUND: Depressive symptoms are highly prevalent, present in heterogeneous symptom patterns, and share diverse neurobiological underpinnings. Understanding the links between psychopathological symptoms and biological factors is critical in elucidating its etiology and persistence. We aimed to evaluate the utility of using symptom-brain network models to parse the heterogeneity of depressive complaints in a large adolescent sample. METHODS: We used data from the third wave of the IMAGEN study, a multi-center panel cohort study involving 1317 adolescents (52.49 % female, mean ± SD age = 18.5 ± 0.7). Two network models were estimated: one including an overall depressive symptom severity sum score based on the Adolescent Depression Rating Scale (ADRS), and one incorporating individual ADRS item scores. Both networks included measures of cortical thickness in several regions (insula, cingulate, mOFC, fusiform gyrus) and hippocampal volume derived from neuroimaging. RESULTS: The network based on individual item scores revealed associations between cortical thickness measures and specific depressive complaints, obscured when using an aggregate depression severity score. Notably, the insulas cortical thickness showed negative associations with cognitive dysfunction (partial cor. = -0.15); the cingulates cortical thickness showed negative associations with feelings of worthlessness (partial cor. = -0.10), and mOFC was negatively associated with anhedonia (partial cor. = -0.05). LIMITATIONS: This cross-sectional study relied on the self-reported assessment of depression complaints and used a non-clinical sample with predominantly healthy participants (19 % with depression or sub-threshold depression). CONCLUSIONS: This study showcases the utility of network models in parsing heterogeneity in depressive complaints, linking individual complaints to specific neural substrates. We outline the next steps to integrate neurobiological and cognitive markers to unravel MDDs phenotypic heterogeneity.

BACKGROUND: Patient participation in treatment decision making is a pillar of recovery-oriented care and is associated with improvements in empowerment and well-being. Although demand for increased involvement in treatment decision-making is high among veterans with serious mental illness, rates of involvement are low. Collaborative decision skills training (CDST) is a recovery-oriented, skills-based intervention designed to support meaningful patient participation in treatment decision making. An open trial among veterans with psychosis supported CDSTs feasibility and demonstrated preliminary indications of effectiveness. A randomized control trial (RCT) is needed to test CDSTs effectiveness in comparison with an active control and further evaluate implementation feasibility. METHODS: The planned RCT is a hybrid type 1 trial, which will use mixed methods to systematically evaluate the effectiveness and implementation feasibility of CDST among veterans participating in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) in Southern California. The first aim is to assess the effectiveness of CDST in comparison with the active control via the primary outcome, collaborative decision-making behavior during usual care appointments between veterans and their VA mental health clinicians, and secondary outcomes (i.e., treatment engagement, satisfaction, and outcome). The second aim is to characterize the implementation feasibility of CDST within the VA PRRC using the Practical Robust Implementation and Sustainability Model framework, including barriers and facilitators within the PRRC context to support future implementation. DISCUSSION: If CDST is found to be effective and feasible, implementation determinants gathered throughout the study can be used to ensure sustained and successful implementation at this PRRC and other PRRCs and similar settings nationally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04324944. Registered on March 27, 2020. Trial registration data can be found in Appendix 1.

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint.

Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.

In 2011, the UK medical research charity Cure Parkinsons set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinsons disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Global scientific exchange has been profoundly perturbed by the COVID-19 pandemic, altering user travel behaviours and accelerating the use of remote access. Combined with the advent of artificial intelligence (AI), these trends together can change how large-scale user scientific facilities are used by the community and managed by operators.

PURPOSE: VitreoDx is an experimental device enabling push-button collection of a neat vitreous liquid biopsy incidental to an intravitreal injection. We explored the ability of the device to collect a sample usable for proteomic biomarker discovery and testing. DESIGN: Pilot study using ex vivo human eyes. METHODS: Non-vitrectomized, human eyes from nine donors 75-91 years of age were refrigerated in BSS and used within 5 days of death. Four VitreoDx devices fitted with 25G needles, and four staked needle insulin syringes with 30G needles, were inserted at equal intervals through the pars plana of each eye and held in place by a fixture. The sampling mode of each VitreoDx device was triggered to attempt to acquire a liquid biopsy up to 70 μL. The plunger of each insulin syringe was retracted to attempt to obtain a liquid biopsy with a maximum volume of 50 μL. Samples acquired with the VitreoDx were extracted to polypropylene cryovials, refrigerated to -80 ºC, and sent for offsite proteomic analysis by proximity extension assay with a focus on panels containing approved and pipelined drug targets for neovascular disease and inflammatory factors. RESULTS: Of the attempted liquid biopsies with the novel 25G VitreoDx, 92% (66 of 72) resulted in successful acquisition (>25 μL) while 89% (64 of 72) attempted by a traditional 30G needle resulted in a successful acquisition. Sample volume sufficient for proteomics array analysis was acquired by the VitreoDx for every eye. Detectable protein was found for 151 of 166 unique proteins assayed in at least 25% of eyes sampled by VitreoDx. CONCLUSIONS: The high acquisition rate achieved by the prototype was similar to that achieved in previous clinical studies where a standard syringe was used with a 25G needle to biopsy vitreous fluid directly prior to standard intravitreal injection. Successful aspiration rates were likewise high for 30G needles. Together, these suggest that it is possible to routinely acquire liquid vitreous biopsies from patients who typically receive intravitreal injections with an injection device using a standard size needle without a vitreous cutter. Protein analysis shows that proteins of interest survive the sampling mechanism and may have potential to direct care in the future.

Poly- and perfluroroalkylated substances (PFAS) are a major class of surfactants used in industry applications and consumer products. Despite efforts to reduce the usage of PFAS due to their environmental persistence, compounds such as perfluorooctanoic acid (PFOA) are widely detected in human blood and tissue. Although growing evidence supports that prenatal exposures to PFOA and other PFAS are linked to adverse pregnancy outcomes, the target organs and pathways remain unclear. Recent investigations in mouse and human cell lines suggest that PFAS may impact the placenta and impair trophoblast function. In this study, we investigated the effects of PFOA on cytotoxicity and the transcriptome in cultured second trimester human cytotrophoblasts (CTBs). We show that PFOA significantly reduces viability and induces cell death at 24 h, in a concentration-dependent manner. At subcytotoxic concentrations, PFOA impacted expression of hundreds of genes, including several molecules (CRH, IFIT1, and TNFSF10) linked with lipid metabolism and innate immune response pathways. Furthermore, in silico analyses suggested that regulatory factors such as peroxisome proliferator-activated receptor-mediated pathways may be especially important in response to PFOA. In summary, this study provides evidence that PFOA alters primary human CTB viability and gene pathways that could contribute to placental dysfunction and disease.

INTRODUCTION: Enfortumab vedotin is an antibody drug conjugate approved for management of pretreated locally advanced or metastatic urothelial carcinoma, which is associated with a rare risk of drug extravasation and soft tissue reactions. CASE REPORT: We report two cases of EV extravasation with subsequent development of bullae and cellulitis. MANAGEMENT AND OUTCOME: They were both treated for cellulitis and had conservative management without surgical intervention and were able to resume treatment with Enfortumab vedotin without subsequent adverse events. DISCUSSION: We propose that EV acts as a vesicant upon extravasation, highlight measures to prevent extravasation events, and encourage appropriate measures when dealing such as attempt of aspiration, removal of catheter, application of compresses, and thorough documentation with photographic evidence.

BackgroundNontargeted analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications.ObjectivesWe characterized levels of nine exogenous and endogenous chemicals in maternal and cord blood identified, selected, and confirmed in prior NTA steps, including linear and branched isomers perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), monoethylhexyl phthalate, 4-nitrophenol, tetraethylene glycol, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid. We evaluated relationships between maternal and cord levels and between gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy in a diverse pregnancy cohort in San Francisco.MethodsWe collected matched maternal and cord serum samples at delivery from 302 pregnant study participants from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculated distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. We used adjusted logistic regression to calculate the odds of GDM and hypertensive disorders of pregnancy associated with an interquartile range increase in maternal chemical exposures.ResultsWe detected linear PFOS, PFHxS, octadecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. Correlations ranged between -0.1 and 0.9. We observed strong correlations between cord and maternal levels of PFHxS, linear PFOS, and branched PFOS (coefficient=0.9, 0.8, and 0.8, respectively). An interquartile range increase in linear and branched PFOS, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid was associated with increased odds ratio (OR) of GDM [OR=1.33 (95% CI: 0.89, 2.01), 1.24 (95% CI: 0.86, 1.80), 1.26 (95% CI: 0.93, 1.73), 1.24 (95% CI: 0.86, 1.80), and 1.23 (95% CI: 0.87, 1.75), respectively]. Tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [OR=1.28 (95% CI: 0.90, 1.86)].DiscussionWe identified both exogenous and endogenous chemicals seldom quantified in pregnant study participants that were also related to pregnancy complications and demonstrated the utility of NTA to identify chemical exposures of concern. https://doi.org/10.1289/EHP11546.

BackgroundDifferential risks for adverse pregnancy outcomes may be influenced by prenatal chemical exposures, but current exposure methods may not fully capture data to identify harms and differences.MethodsWe collected maternal and cord sera from pregnant people in Fresno and San Francisco, and screened for over 2420 chemicals using LC-QTOF/MS. We matched San Francisco participants to Fresno participants (N = 150) and compared detection frequencies. Twenty-six Fresno participants wore silicone wristbands evaluated for over 1500 chemicals using quantitative chemical analysis. We assessed whether living in tracts with higher levels of pollution according to CalEnviroScreen correlated with higher numbers of chemicals detected in sera.ResultsWe detected 2167 suspect chemical features across maternal and cord sera. The number of suspect chemical features was not different by city, but a higher number of suspect chemicals in cosmetics or fragrances was detected in the Fresno versus San Francisco participants' sera. We also found high levels of chemicals used in fragrances measured in the silicone wristbands. Fresno participants living in tracts with higher pesticide scores had higher numbers of suspect pesticides in their sera.ConclusionsMultiple exposure-assessment approaches can identify exposure to many chemicals during pregnancy that have not been well-studied for health effects.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation.SignificanceEarly management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

ObjectiveMutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.MethodsFollowing clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp.ResultsWe identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits.SignificanceThis is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Synopsis: Fossil fuels contribute to climate change and petrochemicals, both of which increase maternal and child disease. Reducing fossil fuels can reap a double benefit for climate change and improved health.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p

ImportanceThe US faces a pivotal moment of opportunity and risk regarding issues affecting children (aged 0-17 years). Although the US remains the only United Nations member state to not have ratified the Convention on the Rights of the Child (CRC), a child rights framework is essential for child health professionals seeking to advance many issues affecting children in the US. The Reimagining Children's Rights project (2020-2021) conducted an in-depth environmental scan of relevant literature and policy analysis using the Three Horizons design process to assess strategies that could advance the rights and well-being of children in the US. The project was overseen by a steering committee and informed by an advisory committee composed of youth leaders and experts in children's rights, advocacy, health, law, and a range of child-specific issues (eg, youth justice, early childhood development), who provided expert input on strategic considerations for advancing children's rights.ObservationsSeven findings about advancing children's rights in the US are notable, all reflecting current gaps and opportunities for using a whole-child rights framework in the US, even without formal adoption of the CRC. Actionable strategies, tactics, and tools to leverage sustainable change in the multitude of issue areas can advance the current state of children's rights. High-potential strategies for catalyzing advancement of children's rights include youth activism, innovations in governance and accountability, legislative action, impact litigation, place-based initiatives, education and public awareness, alignment with other children's movements, and research. The child rights framework is unifying and adaptive to future unforeseen challenges.Conclusions and relevanceChildren's rights provide a powerful, synergistic framework for child health professionals-in partnership with youth and other leaders-to increase equity and protect the rights and well-being of all children in the US.

This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p

BackgroundExposure to environmental chemicals during pregnancy adversely affects maternal and infant health, and identifying socio-demographic differences in exposures can inform contributions to health inequities.MethodsWe recruited 294 demographically diverse pregnant participants in San Francisco from the Mission Bay/Moffit Long (MB/ML) hospitals, which serve a primarily higher income population, and Zuckerberg San Francisco General Hospital (ZSFGH), which serves a lower income population. We collected maternal and cord sera, which we screened for 2420 unique formulas and their isomers using high-resolution mass spectrometry using LC-QTOF/MS. We assessed differences in chemical abundances across socioeconomic and demographic groups using linear regression adjusting for false discovery rate.ResultsOur participants were racially diverse (31% Latinx, 16% Asian/Pacific Islander, 5% Black, 5% other or multi-race, and 43% white). A substantial portion experienced financial strain (28%) and food insecurity (20%) during pregnancy. We observed significant abundance differences in maternal (9 chemicals) and cord sera (39 chemicals) between participants who delivered at the MB/ML hospitals versus ZSFGH. Of the 39 chemical features differentially detected in cord blood, 18 were present in pesticides, one per- or poly-fluoroalkyl substance (PFAS), 21 in plasticizers, 24 in cosmetics, and 17 in pharmaceuticals; 4 chemical features had unknown sources. A chemical feature annotated as 2,4-dichlorophenol had higher abundances among Latinx compared to white participants, those delivering at ZSFGH compared to MB/ML, those with food insecurity, and those with financial strain. Post-hoc QTOF analyses indicated the chemical feature was either 2,4-dichlorophenol or 2,5-dichlorophenol, both of which have potential endocrine-disrupting effects.ConclusionsChemical exposures differed between delivery hospitals, likely due to underlying social conditions faced by populations served. Differential exposures to 2,4-dichlorophenol or 2,5-dichlorophenol may contribute to disparities in adverse outcomes.

BackgroundDespite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus.ObjectiveThe aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood.MethodsWe collected experimental values of the concentration ratio between cord and maternal blood (RCM) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred. We used the compiled database to, train and test an artificial neural network (ANN). And then applied the best performing model to predict RCM for a large dataset of PFAS chemicals (n = 7982). We, finally, examined the calculated physicochemical descriptors of the chemicals to identify which properties correlated significantly with RCM.ResultsWe determined that 7855 compounds were within the applicability domain and 127 compounds are outside the applicability domain of our model. Our predictions of RCM for PFAS suggested that 3623 compounds had a log RCM > 0 indicating preferable partitioning to cord blood. Some examples of these compounds were bisphenol AF, 2,2-bis(4-aminophenyl)hexafluoropropane, and nonafluoro-tert-butyl 3-methylbutyrate.SignificanceThese observations have important public health implications as many PFAS have been shown to interfere with fetal development. In addition, as these compounds are highly persistent and many of them can readily cross the placenta, they are expected to remain in the population for a long time as they are being passed from parent to offspring.ImpactUnderstanding the behavior of chemicals in the human body during pregnancy is critical in preventing harmful exposures during critical periods of development. Many chemicals can cross the placenta and expose the fetus, however, the mechanism by which this transport occurs is not well understood. In our study, we developed a machine learning model that describes the transplacental transfer of chemicals as a function of their physicochemical properties. The model was then used to make predictions for a set of 7982 per- and polyfluorinated alkyl substances that are listed on EPA's CompTox Chemicals Dashboard. The model can be applied to make predictions for other chemical categories of interest, such as plasticizers and pesticides. Accurate predictions of RCM can help scientists and regulators to prioritize chemicals that have the potential to cause harm by exposing the fetus.

This study explored the generality versus specificity of two trait-liability factors for externalizing problems-disinhibition and callousness-in the concurrent and prospective prediction of symptoms of conduct disorder, attention-deficit/hyperactivity disorder (ADHD), and substance use (i.e., alcohol use disorder and history of illicit substance use). Disinhibition involves an impulsive, unrestrained cognitive-behavioral style; callousness entails a dispositional lack of social-emotional sensitivity. Participants were European adolescents from the multisite IMAGEN project who completed questionnaires and clinical interviews at ages 14 (N = 1,504, Mage = 14.41, 51.13% female) and 16 (N = 1,407, Mage = 16.46, 51.88% female). Disinhibition was related concurrently and prospectively to greater symptoms of conduct disorder, ADHD, and alcohol use disorder; higher scores on a general externalizing factor; and greater likelihood of having tried an illicit substance. Callousness was selectively related to greater conduct disorder symptoms. These findings indicate disinhibition confers broad liability for externalizing spectrum disorders, perhaps due to its affiliated deficits in executive function. In contrast, callousness appears to represent more specific liability for antagonistic (aggressive/exploitative) forms of externalizing, as exemplified by antisocial behavior. Results support the utility of developmental-ontogenetic and hierarchical-dimensional models of psychopathology and have important implications for early assessment of risk for externalizing problems. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BackgroundIn the era of enhanced recovery after surgery, there is significant discussion regarding the impact of intraoperative anesthetic management on short-term outcomes following liver transplantation (LT), with no clear consensus in the literature.ObjectivesTo identify whether or not intraoperative anesthetic management affects short-term outcomes after liver transplantation.Data sourcesOvid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central.MethodsA systematic review following PRISMA guidelines was undertaken. The systematic review was registered on PROSPERO (CRD42021239758). An international expert panel made recommendations for clinical practice using the GRADE approach.ResultsAfter screening, 14 studies were eligible for inclusion in this systematic review. Six were prospective randomized clinical trials, three were prospective nonrandomized clinical trials, and five were retrospective studies. These manuscripts were reviewed to look at five questions regarding anesthetic care and its impact on short term outcomes following liver transplant. After review of the literature, the quality of evidence according to the following outcomes was as follows: intraoperative and postoperative morbidity and mortality (low), early allograft dysfunction (low), and hospital and ICU length of stay (moderate).ConclusionsFor optimal short term outcomes after liver transplantation, the panel recommends the use of volatile anesthetics in preference to total intravenous anesthesia (TIVA) (Level of Evidence: Very low; Strength of Recommendation: Weak) and minimum alveolar concentration (MAC) versus bispectral index (BIS) for depth of anesthesia monitoring (Level of Evidence: Very low; Strength of Recommendation: Weak). Regarding ventilation and oxygenation, the panel recommends a restrictive oxygenation strategy targeting a PaO2 of 70-120 mmHg (10-14 kPa), a tidal volume of 6-8 ml/kg ideal body weight (IBW), administration of positive end expiratory pressure (PEEP) tailored to patient intraoperative physiology, and recruitment maneuvers. (Level of evidence: Very low; Strength of Recommendation: Strong). Finally, the panel recommends the routine use of antiemetic prophylaxis. (Level of evidence: low; Strength of Recommendation: Strong).

AimsStatin intolerance (SI) represents a significant public health problem for which precise estimates of prevalence are needed. Statin intolerance remains an important clinical challenge, and it is associated with an increased risk of cardiovascular events. This meta-analysis estimates the overall prevalence of SI, the prevalence according to different diagnostic criteria and in different disease settings, and identifies possible risk factors/conditions that might increase the risk of SI.Methods and resultsWe searched several databases up to 31 May 2021, for studies that reported the prevalence of SI. The primary endpoint was overall prevalence and prevalence according to a range of diagnostic criteria [National Lipid Association (NLA), International Lipid Expert Panel (ILEP), and European Atherosclerosis Society (EAS)] and in different disease settings. The secondary endpoint was to identify possible risk factors for SI. A random-effects model was applied to estimate the overall pooled prevalence. A total of 176 studies [112 randomized controlled trials (RCTs); 64 cohort studies] with 4 143 517 patients were ultimately included in the analysis. The overall prevalence of SI was 9.1% (95% confidence interval 8.0-10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria [7.0% (6.0-8.0%), 6.7% (5.0-8.0%), 5.9% (4.0-7.0%), respectively]. The prevalence of SI in RCTs was significantly lower compared with cohort studies [4.9% (4.0-6.0%) vs. 17% (14-19%)]. The prevalence of SI in studies including both primary and secondary prevention patients was much higher than when primary or secondary prevention patients were analysed separately [18% (14-21%), 8.2% (6.0-10%), 9.1% (6.0-11%), respectively]. Statin lipid solubility did not affect the prevalence of SI [4.0% (2.0-5.0%) vs. 5.0% (4.0-6.0%)]. Age [odds ratio (OR) 1.33, P = 0.04], female gender (OR 1.47, P = 0.007), Asian and Black race (P 4 million patients, the prevalence of SI is low when diagnosed according to international definitions. These results support the concept that the prevalence of complete SI might often be overestimated and highlight the need for the careful assessment of patients with potential symptoms related to SI.

PET imaging of programmed cell death ligand 1 (PD-L1) may help to noninvasively predict and monitor responses to anti-programmed cell death 1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of 3 radioligands derived from the anti-PD-L1 IgG1 complement 4 (C4). In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, as well as a double-mutant IgG C4 (H310A/H435Q) with minimal affinity for the murine neonatal Fc receptor. Methods: The pharmacokinetics, biodistribution, and dosimetry of the 3 89Zr-labeled C4 ligands were compared by longitudinal PET/CT imaging in nude mice bearing subcutaneous human non-small cell lung cancer xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The C4 radioligands substantially accumulated in PD-L1-positive tumors but not in PD-L1-negative tumors or in blocked PD-L1-positive tumors, confirming their PD-L1-specific tumor targeting. 89Zr-Fab C4 and 89Zr-IgG C4 (H310A/H435Q) were rapidly eliminated compared with 89Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios were obtained earlier, at 4 h after injection for 89Zr-Fab C4 (ratio, ∼6) and 24 h after injection for 89Zr-IgG C4 (H310A/H435Q) (ratio, ∼9), versus 48 h after injection for 89Zr-IgG C4 (ratio, ∼8). Background activity in nontumor tissues was low, except for high kidney retention of 89Zr-Fab C4 and persistent liver accumulation of 89Zr-IgG C4 (H310A/H435Q) compared with 89Zr-IgG C4. Dosimetry estimates suggested that the C4 radioligands would yield organ-absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter pharmacokinetics for PD-L1 immuno-PET imaging in a preclinical model and encourages further clinical translation of such radioligands.

While important advances have been made in high-resolution mass spectrometry (HRMS) and its applications in non-targeted analysis (NTA), the number of identified compounds in biological and environmental samples often does not exceed 5% of the detected chemical features. Our aim was to develop a computational pipeline that leverages data from HRMS but also incorporates physicochemical properties (equilibrium partition ratios between organic solvents and water; Ksolvent-water) and can propose molecular structures for detected chemical features. As these physicochemical properties are often sufficiently different across isomers, when put together, they can form a unique profile for each isomer, which we describe as the "physicochemical fingerprint". In our study, we used a comprehensive database of compounds that have been previously reported in human blood and collected their Ksolvent-water values for 129 partitioning systems. We used RDKit to calculate the number of RDKit fragments and the number of RDKit bits per molecule. We then developed and trained an artificial neural network, which used as an input the physicochemical fingerprint of a chemical feature and predicted the number and types of RDKit fragments and RDKit bits present in that structure. These were then used to search the database and propose chemical structures. The average success rate of predicting the right chemical structure ranged from 60 to 86% for the training set and from 48 to 81% for the testing set. These observations suggest that physicochemical fingerprints can assist in the identification of compounds with NTA and substantially improve the number of identified compounds.

BackgroundCranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage.MethodsPatients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference.ResultsOf 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2-14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3-5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7-12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4-37.7; P, 0.026).ConclusionsThe risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

BackgroundThe molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status.MethodsAnonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated.ResultsA total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively).ConclusionPatients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy.

OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Stills disease with atypical lung disease. We sought to characterise features of patients with Stills disease with DRESS compared with drug-tolerant Stills controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort. METHODS: In a case/control study, we collected a multicentre series of patients with Stills disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Stills controls (n=65). We retrospectively analysed clinical data from all Stills subjects and typed 94/131 for HLA. European Stills-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Stills cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Stills-DRESS cases (n=64) compared with drug-tolerant Stills controls (n=30). KD subjects (n=19) were similarly studied. RESULTS: Stills-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Stills-DRESS (64%) versus drug-tolerant Stills (3%; p=1.2×10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Stills-DRESS cases versus INCHARGE Stills controls (p=7.5×10-13) and versus self-identified, ancestry-matched Stills controls (p=6.3×10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

ObjectiveNegative symptoms and cognitive impairment in schizophrenia (SZ) remain unmet treatment needs as they are highly prevalent, associated with poor functional outcomes, and resistant to pharmacologic treatment. The current pilot randomized controlled trial examined the efficacy of an integrated Cognitive-Behavioral Social Skills Training and Compensatory Cognitive Training (CBSST-CCT) intervention compared to Goal-focused Supportive Contact (SC) on negative symptoms and cognitive performance.MethodsFifty-five adults with SZ or schizoaffective disorder with moderate-to-severe negative symptoms were randomized to receive 25 twice-weekly, 1-h manualized group sessions (12.5 weeks total duration) of either CBSST-CCT or SC delivered by master's level clinicians in five community settings. Assessments of negative symptom severity (primary outcomes) and neuropsychological performance, functional capacity, social skills performance, and self-reported functional ability/everyday functioning, psychiatric symptom severity, and motivation (secondary outcomes) were administered at baseline, mid-treatment, post-treatment, and 6-month follow-up.ResultsMixed-effects models using baseline, mid-treatment, and post-treatment data demonstrated significant CBSST-CCT-associated effects on negative symptom severity, as assessed by the Scale for the Assessment of Negative Symptoms (p = .049, r = 0.22), with improvements in diminished motivation driving this effect (p = .037, r = 0.24). The CBSST-CCT group also demonstrated improved verbal learning compared to SC participants (p = .026, r = 0.36). The effects of CBSST-CCT appeared to be durable at 6-month follow-up.ConclusionsCBSST-CCT improved negative symptom severity and verbal learning in high-negative-symptom individuals relative to SC. CBSST-CCT warrants larger investigations to examine its efficacy in treating negative symptoms, along with other symptoms, cognition, and, ultimately, real-world functional outcomes. Clinical Trial registration number NCT02170051.

Although great strides have been made to tackle hospital-acquired pressure ulcers (HAPUs), there is a need for greater recognition of device-related pressure ulcers (DRPUs), including their causes, management and prevention. This consensus statement, an updated second edition, aims to continue raising awareness of these largely preventable injuries and, crucially, to stimulate action. DRPUs are relatively common and account for a growing proportion of HAPUs. Updated information on the incidence of DRPUs is described in chapter 1. Although it is recognised that DRPUs increase the financial burden of healthcare, there is little formal analysis of their economic impact. This needs to be addressed; robust evidence on the burden of DRPUs and the value that can be released by adopting prevention strategies is needed to help drive action. Our understanding of the pathophysiology of DRPUs has improved significantly over the past few years; this is described in chapter 2. One crucial difference between PUs and DRPUs is that body-weight forces are less significant in DRPUs, with the force being exerted from a device that is typically strapped or taped onto the body. Devices and their securement may generate high stress concentrations in tissues, leading to cell and tissue-damage pathways associated with sustained deformation. As more evidence is published on DRPUs, recurring themes are emerging, as outlined in chapter 3: The most vulnerable patients are bearing the brunt of DRPUs; paediatric and neonatal patients, and all those needing critical care are particularly susceptible. During the COVID-19 pandemic, a new high-risk population (people with severe COVID-19 infection) emerged. They are at increased risk of DRPUs because of their need for prolonged ventilatory support, especially when 'proning' Devices associated with DRPUs are often used to perform essential, life-saving functions. They include continuous positive airway pressure (CPAP) masks or endotracheal tubes. Minimising their use is clearly not an option, so practice innovation is needed Although the most common locations for DRPUs are the face, ears, lower legs and heels, any location where a device comes into close contact with the skin can be at risk. In the same vein, any device, whether needed for a medical purpose or not, has the capacity to cause injury if its use is not properly managed. Vigilance is needed for all patients. What can be done? The importance of routine risk assessment is covered in chapter 4. Although use of a validated risk assessment tool is the vital first step, this will not be enough on its own. Several steps can be taken to ensure the safe use of devices. These are described in chapter 5 and include device repositioning, cushioning with prophylactic dressings and moisture control (only where possible and clinically appropriate). Of key importance is the development of an institutional protocol and champions to ensure all necessary steps are adopted. For any of these changes to be put into practice, awareness of DRPUs needs to increase. A number of proposals are outlined in chapter 6. A change of focus among health professionals and policy makers, along with more investment in education and training, are needed. All patients being managed with a medical device must be considered as at high risk. The pandemic introduced the world to the problem of DRPUs in health professionals caused by the extended wear of personal protective equipment. Health professionals also have a right to expect institutional protocols and provision of devices that protect them from DRPUs. Cutting-edge ideas and technologies that may be available in the future are described in chapter 7. When designing new products, manufacturers of medical devices have a duty of care to investigate the risks of DRPUs associated with their products and mitigate them, wherever possible. Our developing understanding of how the design, structure and materials used in medical devices contribute to DRPUs will help us develop new solutions for tomorrow. The first step is for everyone involved to ask themselves, 'what can I do to help?' There is work to be done-your journey to reduce DRPUs starts here!.

Cytomegalovirus (CMV) infection is associated with graft rejection in renal transplantation. Memory-like natural killer (NK) cells expressing NKG2C and lacking FcεRIγ are established during CMV infection. Additionally, CD8+ T cells expressing NKG2C have been observed in some CMV-seropositive patients. However, in vivo kinetics detailing the development and differentiation of these lymphocyte subsets during CMV infection remain limited. Here, we interrogated the in vivo kinetics of lymphocytes in CMV-infected renal transplant patients using longitudinal samples compared with those of nonviremic (NV) patients. Recipient CMV-seropositive (R+) patients had preexisting memory-like NK cells (NKG2C+CD57+FcεRIγ-) at baseline, which decreased in the periphery immediately after transplantation in both viremic and NV patients. We identified a subset of prememory-like NK cells (NKG2C+CD57+FcεRIγlow-dim) that increased during viremia in R+ viremic patients. These cells showed a higher cytotoxic profile than preexisting memory-like NK cells with transient up-regulation of FcεRIγ and Ki67 expression at the acute phase, with the subsequent accumulation of new memory-like NK cells at later phases of viremia. Furthermore, cytotoxic NKG2C+CD8+ T cells and γδ T cells significantly increased in viremic patients but not in NV patients. These three different cytotoxic cells combinatorially responded to viremia, showing a relatively early response in R+ viremic patients compared with recipient CMV-seronegative viremic patients. All viremic patients, except one, overcame viremia and did not experience graft rejection. These data provide insights into the in vivo dynamics and interplay of cytotoxic lymphocytes responding to CMV viremia, which are potentially linked with control of CMV viremia to prevent graft rejection.

BackgroundAdaptation of interventions is inevitable during translation to new populations or settings. Systematic approach to adaptation can ensure that fidelity to core functions of the intervention are preserved while optimizing implementation feasibility and effectiveness for the local context. In this study, we used an iterative, mixed methods, and stakeholder-engaged process to systematically adapt Collaborative Decision Skills Training for Veterans with psychosis currently participating in VA Psychosocial Rehabilitation and Recovery Centers.MethodsA modified approach to Intervention Mapping (IM-Adapt) guided the adaptation process. An Adaptation Resource Team of five Veterans, two VA clinicians, and four researchers was formed. The Adaptation Resource Team engaged in an iterative process of identifying and completing adaptations including individual qualitative interviews, group meetings, and post-meeting surveys. Qualitative interviews were analyzed using rapid matrix analysis. We used the modified, RE-AIM enriched expanded Framework for Reporting Adaptations and Modifications to Evidence-based interventions (FRAME) to document adaptations. Additional constructs included adaptation size and scope; implementation of planned adaptation (yes-no); rationale for non-implementation; and tailoring of adaptation for a specific population (e.g., Veterans).ResultsRapid matrix analysis of individual qualitative interviews resulted in 510 qualitative codes. Veterans and clinicians reported that the intervention was a generally good fit for VA Psychosocial Rehabilitation and Recovery Centers and for Veterans. Following group meetings to reach adaptation consensus, 158 adaptations were completed. Most commonly, adaptations added or extended a component; were small in size and scope; intended to improve the effectiveness of the intervention, and based on experience as a patient or working with patients. Few adaptations were targeted towards a specific group, including Veterans. Veteran and clinician stakeholders reported that these adaptations were important and would benefit Veterans, and that they felt heard and understood during the adaptation process.ConclusionsA stakeholder-engaged, iterative, and mixed methods approach was successful for adapting Collaborative Decision Skills Training for immediate clinical application to Veterans in a psychosocial rehabilitation center. The ongoing interactions among multiple stakeholders resulted in high quality, tailored adaptations which are likely to be generalizable to other populations or settings. We recommend the use of this stakeholder-engaged, iterative approach to guide adaptations.

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.SignificanceSingle-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution. See related commentary by Hilton and Scott, p. 2965. This article is highlighted in the In This Issue feature, p. 2945.

BackgroundDysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues.MethodsA subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels.ResultsMultimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%.ConclusionsAdolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

ImportanceThe incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.ObservationsWithin the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and relevanceThe clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Non-targeted analysis (NTA), including both suspect screening analysis (SSA) and unknown compound analysis, has gained increasing popularity in various fields for its capability in identifying new compounds of interests. Current major challenges for NTA SSA are that (1) tremendous effort and resources are needed for large-scale identification and confirmation of suspect chemicals and (2) suspect chemicals generally show low matching rates during identification and confirmation processes. To narrow the gap between these challenges and smooth implementation of NTA SSA methodology in the biomonitoring field, we present a thorough SSA workflow for the large-scale screen, identification, and confirmation of industrial chemicals that may pose adverse health effects in pregnant women and newborns. The workflow was established in a study of 30 paired maternal and umbilical cord serum samples collected at delivery in the San Francisco Bay area. By analyzing LC-HRMS and MS/MS data, together with the assistance of a combination of resources including online MS/MS spectra libraries, online in silico fragmentation tools, and the EPA CompTox Chemicals Dashboard, we confirmed the identities of 17 chemicals, among which monoethylhexyl phthalate, 4-nitrophenol, tridecanedioic acid, and octadecanedioic acid are especially interesting due to possible toxicities and their high-volume use in industrial manufacturing. Similar to other previous studies in the SSA field, the suspect compounds show relatively low MS/MS identification (16%) and standard confirmation (8%) rates. Therefore, we also investigated origins of false positive features and unidentifiable suspected features, as well as technical obstacles encountered during the confirmation process, which would promote a better understanding of the flaw of low confirmation rate and encourage gaining more effective tools for tackling this issue in NTA SSA.

Recent technological advances in mass spectrometry have enabled us to screen biological samples for a very broad spectrum of chemical compounds allowing us to more comprehensively characterize the human exposome in critical periods of development. The goal of this study was three-fold: (1) to analyze 590 matched maternal and cord blood samples (total 295 pairs) using non-targeted analysis (NTA); (2) to examine the differences in chemical abundance between maternal and cord blood samples; and (3) to examine the associations between exogenous chemicals and endogenous metabolites. We analyzed all samples with high-resolution mass spectrometry using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in both positive and negative electrospray ionization modes (ESI+ and ESI-) and in soft ionization (MS) and fragmentation (MS/MS) modes for prioritized features. We confirmed 19 unique compounds with analytical standards, we tentatively identified 73 compounds with MS/MS spectra matching, and we annotated 98 compounds using an annotation algorithm. We observed 103 significant associations in maternal and 128 in cord samples between compounds annotated as endogenous and compounds annotated as exogenous. An example of these relationships was an association between three poly and perfluoroalkyl substances (PFASs) and endogenous fatty acids in both the maternal and cord samples indicating potential interactions between PFASs and fatty acid regulating proteins.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Recent technological advances in mass spectrometry have enabled us to screen biological samples for a very broad spectrum of chemical compounds allowing us to more comprehensively characterize the human exposome in critical periods of development. The goal of this study was three-fold: (1) to analyze 590 matched maternal and cord blood samples (total 295 pairs) using non-targeted analysis (NTA); (2) to examine the differences in chemical abundance between maternal and cord blood samples; and (3) to examine the associations between exogenous chemicals and endogenous metabolites. We analyzed all samples with high-resolution mass spectrometry using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in both positive and negative electrospray ionization modes (ESI+ and ESI-) and in soft ionization (MS) and fragmentation (MS/MS) modes for prioritized features. We confirmed 19 unique compounds with analytical standards, we tentatively identified 73 compounds with MS/MS spectra matching, and we annotated 98 compounds using an annotation algorithm. We observed 103 significant associations in maternal and 128 in cord samples between compounds annotated as endogenous and compounds annotated as exogenous. An example of these relationships was an association between three poly and perfluoroalkyl substances (PFASs) and endogenous fatty acids in both the maternal and cord samples indicating potential interactions between PFASs and fatty acid regulating proteins.

Our proof-of-concept study develops a suspect screening workflow to identify and prioritize potentially ubiquitous chemical exposures in matched maternal/cord blood samples, a critical period of development for future health risks. We applied liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF/MS) to perform suspect screening for ∼3500 industrial chemicals on pilot data from 30 paired maternal and cord serum samples (n = 60). We matched 662 suspect features in positive ionization mode and 788 in negative ionization mode (557 unique formulas overall) to compounds in our database, and selected 208 of these for fragmentation analysis based on detection frequency, correlation in feature intensity between maternal and cord samples, and peak area differences by demographic characteristics. We tentatively identified 73 suspects through fragmentation spectra matching and confirmed 17 chemical features (15 unique compounds) using analytical standards. We tentatively identified 55 compounds not previously reported in the literature, the majority which have limited to no information about their sources or uses. Examples include (i) 1-(1-acetyl-2,2,6,6-tetramethylpiperidin-4-yl)-3-dodecylpyrrolidine-2,5-dione (known high production volume chemical) (ii) methyl perfluoroundecanoate and 2-perfluorooctyl ethanoic acid (two PFAS compounds); and (iii) Sumilizer GA 80 (plasticizer). Thus, our workflow demonstrates an approach to evaluating the chemical exposome to identify and prioritize chemical exposures during a critical period of development.

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

The current study examined the feasibility and acceptability of an integrated Cognitive-Behavioral Social Skills Training and Compensatory Cognitive Training (CBSST-CCT) intervention compared with Goal-Focused Supportive Contact (SC) in a pilot randomized controlled trial for people with schizophrenia with high negative symptom severity. The sample included 55 participants from five community settings; masters-level study clinicians delivered interventions on-site. Participants completed assessments of cognitive, functional, and psychiatric symptoms at baseline, mid-treatment, post-treatment (12.5 weeks), and 6-month follow-up. Enrollment goals were not initially met, necessitating the addition of a fifth site; however, all groups and assessments were completed on-site. Study procedures were acceptable, as evidenced by 100% enrollment and completion of baseline assessments following informed consent; however, over 1/3rd of participants dropped out. No modifications were necessary to the intervention procedures and CBSST-CCT fidelity ratings were acceptable. The intervention was deemed acceptable among participants who attended ≥1 session, as evidenced by similar attendance rates in CBSST-CCT compared to SC. Among CBSST-CCT participants, lower positive symptoms were significantly associated with better attendance. Overall, we found mixed evidence for the feasibility and acceptability of the CBSST-CCT protocol in people with schizophrenia with high negative symptoms. Challenges are highlighted and recommendations for future investigations are provided.

Chemical exposure via dust ingestion is of great interest to researchers and regulators because children are exposed to dust through their daily activities, and as a result, to the many chemicals contained within dust. Our goal was to develop a workflow to identify and rank organic chemicals that could be used as tracers to calculate children's dust ingestion rates. We proposed a set of criteria for a chemical to be considered a promising tracer. The best tracers must be (1) ubiquitous in dust, (2) unique to dust, (3) detectable as biomarkers in accessible biological samples, and (4) have available or obtainable ADME information for biomarker-based exposure reconstruction. To identify compounds meeting these four criteria, we developed a workflow that encompasses non-targeted analysis approaches, literature and database searching, and multimedia modeling. We then implemented an ad hoc grading system and ranked candidate chemicals based on fulfillment of our criteria (using one small, publicly available dataset to show proof of concept). Initially, five chemicals (1,3-diphenylguanidine, leucine, piperine, 6:2/8:2 fluorotelomer phosphate diester, 6:2 fluorotelomer phosphate diester) appeared to satisfy many of our criteria. However, a rigorous manual investigation raised many questions about the applicability of these chemicals as tracers. Based on the results of this initial pilot study, no individual compounds can be unequivocally considered suitable tracers for calculating dust ingestion rates. Future work must therefore consider larger datasets, generated from broader measurement studies and literature searches, as well as refinements to selection criteria, to identify robust and defensible tracer compounds.

BackgroundPrior to implementing an antibiotic stewardship intervention for asymptomatic bacteriuria (ASB), we assessed institutional barriers to change using the Organizational Readiness to Change Assessment.MethodsSurveys were self-administered on paper in inpatient medicine and long-term care units at 4 Veterans Affairs facilities. Participants included providers, nurses, and pharmacists. The survey included 7 subscales: evidence (perceived strength of evidence) and six context subscales (favorability of organizational context). Responses were scored on a 5-point Likert-type scale.ResultsOne hundred four surveys were completed (response rate = 69.3%). Overall, the evidence subscale had the highest score; the resources subscale (mean 2.8) was significantly lower than other subscales (P < .001). Scores for budget and staffing resources were lower than scores for training and facility resources (P < .001 for both). Pharmacists had lower scores than providers for the staff culture subscale (P = .04). The site with the lowest scores for resources (mean 2.4) also had lower scores for leadership and lower pharmacist effort devoted to stewardship.ConclusionsAlthough healthcare professionals endorsed the evidence about nontreatment of ASB, perceived barriers to antibiotic stewardship included inadequate resources and leadership support. These findings provide targets for tailoring the stewardship intervention to maximize success.

Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .