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Sustainable manufacturing that prioritizes energy efficiency, minimal water use, scalability and the ability to generate diverse materials is essential to advance inorganic materials production while maintaining environmental consciousness. However, current manufacturing practices are not yet equipped to fully meet these requirements. Here we describe a flash-within-flash Joule heating (FWF) technique—a non-equilibrium, ultrafast heat conduction method—to prepare ten transition metal dichalcogenides, three group XIV dichalcogenides and nine non-transition metal dichalcogenide materials, each in under 5 s while in ambient conditions. FWF achieves enormous advantages in facile gram scalability and in sustainable manufacturing criteria when compared with other synthesis methods. Also, FWF allows the production of phase-selective and single-crystalline bulk powders, a phenomenon rarely observed by any other synthesis method. Furthermore, FWF MoSe2outperformed commercially available MoSe2in tribology, showcasing the quality of FWF materials. The capability for atom substitution and doping further highlights the versatility of FWF as a general bulk inorganic materials synthesis protocol.

ABSTRACTAccurate radiocarbon (14C) analysis depends on a successful carbon separation relevant to the studied object. The process of 14C dating involves the following steps: characterization and sample choice, sample treatment, measurements, and evaluation of the results. Here, we provide an overview of conventional approaches to macromolecular samples and address specific issues such as detecting and removing contamination with roots, dolomite, and conservation products. We discuss the application of elemental analysis (%N, %C) in the preparation of bones and the infrared analysis in monitoring the contamination of samples. Our observations provide the basis for the discussions of the existing results and for planning the future sampling.

ABSTRACTThis paper compares various wood pretreatment methods for highly degraded, and problematic fossil wood extracted from the opencast Szczerców site of the Bełchatów Lignite Mine in Central Poland. The study evaluates the pretreatment methods using both large samples (55–255 g, referred to as series A) and small samples (36–150 mg, referred to as series B). Additionally, all preparation methods were applied to medium-sized samples (approximately 3 g, referred to as series C) with solvent washes in the Soxhlet apparatus. Radiocarbon dating was conducted using the LSC technique (subseries A1) and the AMS technique (subseries A2, series B, and C). The effectiveness and utility of each pretreatment protocol were compared based on 14C measurements and FTIR analysis. Through the conducted research and a multi-criteria analysis, the most effective method for preparing old fossil wood was identified. Our experience indicates that an extended, multistage preparation of highly degraded fossil wood samples, with a 14C concentration near the detection limit of the radiocarbon method, may result in a significant increase in 14C content.

A rapidly changing world also requires constant change in the content and provision of teaching materials. In summer 2023, Westermann published a geography textbook for secondary schools in German -speaking Switzerland. Even in the digital age, the careful, systematically structured teaching of content is one of the strengths of the classic textbook and it is the reason for the decision to use this form, even though at first glance it seems to have fallen out of time. But only at first glance: The book is designed as a print version as well as an e-book and it is supplemented by a rich online platform. Structured like a classic textbook, it is nonetheless on the threshold of becoming a purely digital teaching aid. The diverse forms of geography teaching in the heterogeneous Swiss educational landscape are served with a rich palette of classic but also new topics that attempt to meet the demands of both the current state of academic knowledge and world affairs. Particular emphasis is placed on the understanding of interrelationships and on scientific thinking, and attempts are made to convey geographical thinking in the sense of the subject’s “bridging function”. The teaching material should also be a sustainable flagship for the geosciences in society and politics beyond the classroom.

Vestibular Stimulation (VS) has been shown to positively affect various autonomic body functions, including sleep. In the past, VS was often investigated using large and complex rocking beds that would only allow for short intervention periods in constrained lab settings. In this work, we present an overview of the mechanics, kinematics, dynamics, and tuning of our latest rocking bed, the Somnomat Casa. Its compact dimensions, comparable to a standard single bed, its connectivity, and easy usability, allow for prolonged studies in home settings investigating the effects of VS during sleep. In a first six-month study with a 12-year-old boy suffering from primary mitochondrial disease with an associated severe sleep disorder, we observed significant improvements in sleep duration (+25 %) and quality of life, as well as a 75 % reduction in caregiving interactions and a 40 % reduction in overall caregiving time. Based on these promising findings, we are currently testing the Somnomat Casa with various patient groups for multiple months each, including elderly with insomnia, children with sleep disorders, Parkinson’s disease patients, and individuals with post-stroke insomnia.

IMPORTANCE: Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear. OBJECTIVE: To determine the prevalence of pretreatment testing that is recommended for patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis). DESIGN, SETTING, AND PARTICIPANTS: This descriptive analysis of US commercial insurance claims databases from December 31, 2002, to December 31, 2020, included adult patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis) who started an immunomodulatory agent, including methotrexate, tumor necrosis factor α inhibitors, interleukin (IL)–17Ai, ustekinumab, IL-23i, dupilumab, or apremilast. MAIN OUTCOMES AND MEASURES: The proportion of patients who underwent the screening tests as suggested by professional societies—including for tuberculosis, hepatitis, and liver function; complete blood cell counts; and lipid panels—were determined within 6 months before and during 2 years after treatment start. RESULTS: A total of 122 308 patients with CISDs (median [IQR] age, 49 [38-58] years; 63 663 [52.1%] male) starting systemic immunomodulatory treatment in the US were included. Treatment for patients with CISDs comprised methotrexate (28 684), tumor necrosis factor α inhibitors (40 965), ustekinumab (12 841), IL-23i (6116), IL-17Ai (9799), dupilumab (7787), or apremilast (16 116). Complete blood cell count was the most common test, performed in 41% (3161/7787) to 69% (19 659/28 684) of individuals before initiation across treatments. Between 11% (889/7787) and 59% (3613/6116) of patients had tuberculosis screening within 6 months before treatment, and 3% (149/4577) to 26% (1559/6097) had updated tests 1 year later. Between 13% (1006/7787) and 41% (16 728/40 965) had hepatitis panels before treatment. Low pretreatment testing levels before apremilast (15% [2331/16 116] to 45% [7253/16 116]) persisted a year into treatment (9% [816/8496] to 36% [2999/8496]) and were similar to dupilumab (11% [850/7787] to 41% [3161/7787] vs 3% [149/4577] to 25% [1160/4577]). CONCLUSIONS AND RELEVANCE: In this descriptive analysis of patients with CISDs starting systemic immunomodulatory treatment in the US, less than 60% received the recommended pretreatment testing. Additional research is required to understand whether variations in testing affect patient outcomes.

Detecting proteins in ultralow concentrations in complex media is important for many applications but often relies on complicated techniques. Herein, a single-molecule protein analyzer with the potential for high-throughput applications is reported. Gold-coated magnetic nanoparticles with DNA-labeled antibodies were used for target recognition and separation. The immunocomplex was loaded into microdroplets generated with centrifugation. Immuno-PCR amplification of the DNA enabled the quantification of proteins at the level of single molecules. As an example, ultrasensitive detection of α-synuclein, a biomarker for neurodegenerative diseases, is achieved. The limit of detection was determined to be ∼50 aM in buffer and ∼170 aM in serum. The method exhibited high specificity and could be used to analyze post-translational modifications such as protein phosphorylation. This study will inspire wider studies on single-molecule protein detection, especially in disease diagnostics, biomarker discovery, and drug development.

Jet engines are important contributors to global CO2emissions and release enormous numbers of ultrafine particles into different layers of the atmosphere. As a result, aviation emissions are affecting atmospheric chemistry and promote contrail and cloud formation with impacts on earth’s radiative balance and climate. Furthermore, the corelease of nanoparticles together with carcinogenic polycyclic aromatic hydrocarbons (PAHs) affects air quality at airports. We studied exhausts of a widely used turbofan engine (CFM56–7B26) operated at five static thrust levels (idle, 7, 30, 65, and 85%) with conventional Jet A-1 fuel and a biofuel blend composed of hydro-processed esters and fatty acids (HEFA). The particles released, the chemical composition of condensable material, and the genotoxic potential of these exhausts were studied. At ground operation, particle number emissions of 3.5 and 0.5 × 1014particles/kg fuel were observed with highest genotoxic potentials of 41300 and 8800 ng toxicity equivalents (TEQ)/kg fuel at idle and 7% thrust, respectively. Blending jet fuel with HEFA lowered PAH and particle emissions by 7–34% and 65–67% at idle and 7% thrust, respectively, indicating that the use of paraffin-rich biofuels is an effective measure to reduce the exposure of airport personnel to nanoparticles coated with genotoxic PAHs (Trojan horse effect).

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTNand chr19q13.32 near APOEthat were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

Abstract.The high phytic acid (PA) concentration in the diet based on teff injera is a likely contributing cause of iron deficiency in Ethiopia. We monitored PA during teff injera fermentation in 30 households in Debre Zeyit, Ethiopia and evaluated its influence on iron bioavailability, considering contaminant soil iron in teff flour. After fermentation (48h), mean PA concentration in injera batter decreased from 0.87 to 0.58 g/100 g dm (P < 0.001). Low phytase activity in teff flour (0.44 μmol phosphate/min/g) and a rapid drop in pH, indicated that PA degradation was driven by microbial phytases. The iron concentration in injera batter among the households ranged widely from 14.5–160.4 mg/100 g dm (mean: 34.7 mg/100 g dm) principally due to contamination with soil. Estimated intrinsic iron concentration of teff based on the strong correlation between total iron and aluminium concentrations (P < 0.001; aluminium concentrations in injera batter: 28.7–184.9 mg/100 g dm) was 4.4 mg/100 g dm, indicating that 86–97 % is extrinsic iron from soil. The median daily iron intakes from 3-day weighed food records in 10 young children were 18.9 mg/day including soil iron vs. 4.9 mg/day without soil iron (P < 0.01). The PA:iron molar ratios indicated low iron bioavailability from teff injera, particularly when soil iron was excluded. Traditional fermentation thus has a modest influence on PA levels and more complete degradation is needed to improve iron bioavailability. There is an urgent need to better understand the bioavailability of contamination iron from soil before considering national fortification or biofortification strategies in Ethiopia.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing–remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector T cells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

New discoveries in catalysis by earth-abundant materials can be guided by leveraging knowledge across two sub-disciplines of heterogeneous catalysis: electrocatalysis and thermocatalysis. Cobalt sulfide has been reported to be a highly active electrocatalyst for the oxygen evolution reaction (OER). Under these oxidative conditions, cobalt sulfide forms oxidized surfaces that outperform directly prepared cobalt oxide in OER catalysis. We postulated that the catalytic activity of oxidized cobalt sulfide for OER could reflect a more general ability to catalyze O-transfer reactions. Herein, we show that cobalt sulfide (CoSx) indeed catalyzes the epoxidation of cyclooctene, a thermal O-transfer reaction. Similarly to OER, the surface-oxidized CoSxformed under reaction conditions outperformed the directly prepared cobalt oxide, hydroxide, and oxyhydroxide for epoxidation catalysis. Another notable phenomenological parallel to OER was revealed by the electron paramagnetic resonance (EPR) analysis of all spent Co-based catalysts that showed significant structural changes and the formation of paramagnetic Co(ii) and Co(iv) species. Mechanistic investigations suggest that a higher density of Co(ii) and/or an easier formation of high-valent Co species in the case of surface-oxidized cobalt sulfide is responsible for its high activity as an epoxidation catalyst. Our results provide important insight into the surface chemistry of Co-based catalysts and show the potential of oxidized CoSxas an earth-abundant catalyst for O-transfer reactivity beyond OER. This work highlights the utility of bridging electrocatalysis and thermocatalysis for the development of more sustainable chemical processes.

Medical applications in which patient movements are tracked with 3-D surface imaging systems are becoming increasingly popular. The 3-D imaging systems used for such applications must be able to cope with controlled and uncontrolled motions of the human body. The key factors for producing a high-quality 3-D representation of the moving human body are the spatial resolution, accuracy, and precision of the 3-D imaging system. To our knowledge, no international standard yet exists to assess these parameters. In this article, we propose a phantom model, a method, and parameters for the assessment of spatial resolution, accuracy, and precision to evaluate systems for the 3-D imaging of moving objects. The proposed phantom model is an extension of the standard 1951 USAF resolution test chart to 3-D and consists of two parallel staircases with varying step heights. The phantom model is actuated with an industrial robot. The application of our method to the Photoneo MotionCam-3-D showed that their multishot structured-light mode has a higher accuracy for static and slowly moving objects (accuracy of 0.1 mm) than their single-shot structured-light mode (accuracy of 0.5 mm). However, the single-shot mode can capture fast-moving objects without much loss of accuracy and precision. This provides practical quantifications for the Photoneo MotionCam-3-D. Furthermore, this confirms that the proposed phantom model, method, and parameters can be used as part of a standard to assess the spatial resolution, accuracy, and precision of systems for the 3-D imaging of moving objects.

We investigate the electrical properties of electron-selective passivating contacts based on thin tunnel oxide capped by a phosphorus-doped poly-Si layer. The poly-Si formation relies on the sputtering of the amorphous-Si layer subsequently annealed. We study the impact of the doping method, the phosphorus content of the Si target, sputtering parameters as well as annealing temperature on surface passivation and carrier extraction. The possibility to deposit in the same sputtering tool both the tunnel oxide and the poly-Si layer is also investigated. It is found that similar levels of implied VOC and contact resistivity are attained when the tunnel oxide is grown chemically or deposited by sputtering. In-situ doping of the silicon layer with doped Si targets leads to the same level of passivation and carrier extraction than when the doping is performed in a second step, ex-situ, by POCl3 or plasma-assisted process, with values of implied VOC above 730 mV and contact resistivity down to 2 mΩ.cm2. The implementation of such sputtered poly-Si at the rear side of n-passivated emitter rear totally diffused (n-PERT) solar cells enabled to reach certified cell efficiency of 22.8% with VOC of 697 mV and fill factor (FF) of 80.5%.

Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

Animal studies show aging varies between individuals as well as between organs within an individual1–4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h.

Transition metal phosphides have shown promise as catalysts for water splitting and hydrotreating, especially when a small amount of sulfur is incorporated into the phosphides. However, the effect of sulfur on catalysis is not well understood. In part, this is because conventional preparation methods of sulfur-doped transition metal phosphides lead to sulfur both inside and at the surface of the material. Here, we present an alternative method of modifying cobalt phosphide (CoP) with sulfur using molecular S-transfer reagents, namely, phosphine sulfides (SPR3). SPR3added sulfur to the surface of CoPand using a series of SPR3reagents having different P═S bond strengths enabled control over the amount and type of sulfur transferred. Our results show that there is a distribution of different sulfur sites possible on the CoPsurface with S-binding strengths in the range of 69 to 84 kcal/mol. This provides fundamental information on how sulfur binds to an amorphous CoPsurface and provides a basis to assess how number and type of sulfur on CoPinfluences catalysis. For the catalytic hydrogenation of cinnamaldehyde, intermediate amounts of sulfur with intermediate binding strengths at the surface of CoPwere optimal. With some but not too much sulfur, CoPexhibited a higher hydrogenation productivity and a decreased formation of secondary reaction products. Our work provides important insight into the S-effect on the catalysis by transition metal phosphides and opens new avenues for catalyst design.

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+T cell exhaustion. Overexpression of NFAT5 in CD8+T cells reduced tumor control, while deletion of NFAT5 improved tumor control by promoting the accumulation of tumor-specific CD8+T cells that had reduced expression of the exhaustion-associated proteins TOX and PD-1 and produced more cytokines, such as IFNɣ and TNF, than cells with wild-type levels of NFAT5, specifically in the precursor exhausted PD–1+TCF1+TIM–3–CD8+T cell population. NFAT5 did not promote T cell exhaustion during chronic infection with clone 13 of lymphocytic choriomeningitis virus. Expression of NFAT5 was induced by TCR triggering, but its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. Thus, NFAT5 promoted the exhaustion of CD8+T cells in a tumor-selective fashion.

Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1–3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.

IMPORTANCE: Studies have linked bullous pemphigoid (BP) with venous thromboembolism (VTE) across several data sources finding 6-fold to 15-fold increased incidence rates. OBJECTIVE: To determine the incidence of VTE in patients with BP compared with similar controls. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used insurance claims data from a nationwide US health care database from January 1, 2004, through January 1, 2020. Patients with dermatologist-recorded BP were identified (≥2 diagnoses of BP [International Classification of Diseases, Ninth Revision (ICD-9) 694.5 and ICD-10 L12.0] recorded by dermatologists within 1 year). Risk-set sampling identified comparator patients without BP and free of other chronic inflammatory skin diseases. Patients were followed-up until the first of the following events occurred: VTE, death, disenrollment, or end of data stream. EXPOSURES: Patients with BP compared with those without BP and free of other chronic inflammatory skin diseases (CISD). MAIN OUTCOME: Venous thromboembolism events were identified and incidence rates were computed before and after propensity-score (PS) matching to account for VTE risk factors. Hazard ratios (HRs) compared the incidence of VTE in BP vs non-CISD. RESULTS: Overall, 2654 patients with BP and 26 814 comparator patients without BP or another CISD were identified. The mean (SD) age in the BP group was 73.0 (12.6) years and 55.0 (18.9) years in the non-CSID group. With a median follow-up time was 2 years, the unadjusted incidence rate (per 1000 person-years) of outpatient or inpatient VTE was 8.5 in the BP group compared with 1.8 in patients without a CISD. Adjusted rates were 6.7 in the BP group compared with 3.0 in the non-CISD group. Age-specific adjusted incidence rates (per 1000 person-years) in patients aged 50 to 74 years was 6.0 (vs 2.9 in the non-CISD group) and in those aged 75 years or older was 7.1 (vs 4.53 in the non-CISD group). After 1:1 propensity-score matching including 60 VTE risk factors and severity markers, BP was associated with a 2-fold increased risk of VTE (2.24 [1.26-3.98]) vs those in the non-CISD group. When restricting to patients aged 50 years or older, the adjusted relative risk of VTE was 1.82 (1.05-3.16) for the BP vs non-CISD groups. CONCLUSIONS: In this nationwide US cohort study, BP was associated with a 2-fold increased incidence of VTE after controlling for VTE risk factors in a dermatology patient population.

AbstractProviding adequate security to civilian nuclear materials and facilities exemplifies the long-standing, dynamic challenge of addressing the potential for facility damage under operational uncertainty. Estimating attack likelihood with enough precision to be useful and actionable for security risk management is philosophically, scientifically, and practically challenging. In response, this paper discusses the conceptual and analytical shortcomings of various approaches to calculating the likelihood of attack as a foundational element of security risk management. From these shortcomings emerge a set of characteristics that can guide the creation of alternative concepts that provide more robust and actionable security risk management approaches better aligned with the Ievolutionary growth in civilian nuclear facilities. Such broader conceptions would support movement from traditional interpretations of probability of attack toward more nuanced and complex depictions to enhance security risk management.

IMPORTANCE: Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled. OBJECTIVE: To estimate the 6-month rate of infections among children with psoriasis who started treatment with ustekinumab, etanercept, or methotrexate. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used insurance claims data from clinical practices across the US on children aged 17 years or younger with psoriasis who were receiving treatment with a topical medication for psoriasis and started new treatment with ustekinumab, etanercept, or methotrexate. The analysis was stratified by the time before pediatric labeling (2009-2015) and after pediatric approval (2016-2021). Patient follow-up started 1 day after initiating treatment and ended at 6 months. EXPOSURES: New treatment with ustekinumab, etanercept, and methotrexate. MAIN OUTCOMES AND MEASURES: During follow-up, the frequency of inpatient serious infections and outpatient infections requiring treatment was compared. Event rates and rate ratios were estimated after propensity score decile stratification. RESULTS: After exclusions, we identified 2338 patients (1368 girls [57.8%]) who initiated new treatment with a targeted immunomodulating agent. In all, 379 patients started treatment with ustekinumab, 779 patients started treatment with etanercept, and 1180 patients started treatment with methotrexate from 2009 through 2021. The propensity score–adjusted incidence rate of serious infection was 18.4 per 1000 person-years (3 events) for ustekinumab users, 25.6 per 1000 person-years (9 events) for etanercept users, and 14.9 per 1000 person-years (8 events) for methotrexate users. The adjusted rate of outpatient infections was 254.9 per 1000 person-years (39 events) for ustekinumab users, 435.7 per 1000 person-years (139 events) for etanercept users, and 433.6 per 1000 person-years (209 events) for methotrexate users. The adjusted rate ratio of outpatient infections was 0.58 (95% CI, 0.41-0.83) for ustekinumab vs etanercept, 0.66 (95% CI, 0.48-0.91) for ustekinumab vs methotrexate, and 0.95 (95% CI, 0.75-1.21) for etanercept vs methotrexate. Rate ratios were similar during the off-label use era and after pediatric labeling. CONCLUSIONS AND RELEVANCE: Among children with psoriasis who started treatment with immunomodulating agents, serious infections were infrequent. This cohort study suggests that there was no increase in the risk of outpatient infections for children who started treatment with ustekinumab compared with etanercept or methotrexate.