The ester-containing prodrug NT-0796 enhances delivery of the NLRP3 inflammasome inhibitor NDT-19795 to monocytic cells expressing carboxylesterase-1.

NT-0796 is an ester prodrug which is metabolized by carboxylesterase-1 (CES1) to yield the carboxylic acid NDT-19795, an inhibitor of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome. When applied to human monocytes/macrophages which express CES1, however, NT-0796 is much more potent at inhibiting NLRP3 inflammasome activation than is NDT-19795. Comparison of the binding of NDT-19795 and NT-0796 in a cell-based NLRP3 target engagement assay confirms that NDT-19795 is the active species. Moreover, microsomes expressing CES1 efficiently convert NT-0796 to NDT-19795, confirming CES1-dependent activation. To understand the basis for the enhanced potency of the ester prodrug species in human monocytes, we analyzed the accumulation and de-esterification of NT-0796 in cultured cells. Our studies reveal NT-0796 rapidly accumulates in cells, achieving estimated cellular concentrations above those applied to the medium, with concomitant metabolism to NDT-19795 in CES1-expressing cells. Using cells lacking CES1 or a poorly hydrolysable NT-0796 analog demonstrated that de-esterification is not required for NT-0796 to achieve high cellular levels. As a result of a dynamic equilibrium whereby NDT-19795 formed intracellularly is subsequently released to the medium, concentrations of NT-0796 sufficient to inhibit NLRP3 can be completely metabolized to NDT-19795 resulting in a transient pharmacodynamic response. In contrast, when NDT-19795 is applied directly to cells observed cell-associated levels are below those present in the medium and remain stable over time. Dynamics observed within the context of a closed tissue culture system highlight the utility of NT-0796 as a vehicle for delivering the NDT-19795 acid payload to CES1 expressing cells.

Left ventricular apical pacing-induced heart failure in a child after congenital heart surgery: a case report.

Background: Left ventricular apical pacing (LVAP) is considered to preserve left ventricular (LV) systolic function in both patients with and without congenital heart disease. However, sporadic LVAP-associated cardiac dysfunction in children with complex structural heart disease was recently reported. We present the case of a 2.5-year-old child with complex congenital heart disease and LVAP-induced cardiomyopathy. Case summary: Corrective surgery for double outlet right ventricle, subpulmonary ventricular septal defect, and transposition of the great arteries was done at the age of 1.5 months. Late complete atrioventricular block occurred, necessitating VVI pacemaker insertion with LV apical epicardial leads. He presented with heart failure and dilated cardiomyopathy 1.5 years after pacemaker insertion and required persistent circulatory support with intravenous inotropes. Speckle tracking echocardiography identified an important LV apical to basal dyssynchrony. After excluding any coronary artery involvement, cardiac resynchronization therapy was performed. Speckle tracking echocardiography guided lead placement resulted in improved LV contraction synchrony. Cardiac function recovered progressively in combination with oral heart failure medication and is almost normal at 10-month follow-up. Discussion: Right ventricular pacing is a well-known cause of pacing-induced cardiomyopathy. The LV apex and LV free wall are thought to be most optimal locations for ventricular pacing in children. However, LVAP can also be the cause of a pacing-induced cardiomyopathy and decreased systolic LV function in children with complex congenital heart disease due to lack of LV contraction synchrony. Cardiac resynchronization therapy can reverse this LV dysfunction and remodelling.

Can capillary microsampling facilitate a clinical pharmacokinetics study of cefazolin in critically ill children?

Aim: Pharmacokinetic studies in children are limited, in part due to challenges in blood sampling. We compare the use of capillary microsampling and conventional sampling techniques in pediatric patients to show results that can be used in the pharmacokinetic analysis of Cefazolin. Patients & Methods: Paired blood samples (n = 48) were collected from 12 patients (median age/weight 49 months/18 kg). Results: The United States Federal Drug Administration incurred sample reanalysis acceptance criteria was used and identified 79% of paired samples achieved a difference of less than 20% in magnitude with a capillary microsampling bias of -10% (SD 20%). With exclusion of PK outliers, this rose to 88%. Conclusion: Capillary microsampling is reliable, meets acceptance criteria and can be used in pharmacokinetic studies.ACTRN: 12618001469202.

What is this article about? This study assesses a novel method of blood sample collection (capillary microsampling) for the analysis of a common antibiotic, cefazolin. In this study, we compare the results from samples collected using this method to blood tests taken in the traditional way.Capillary microsampling collects a very small volume of blood (about a drop of blood or 0.05 ml) taken from a skin prick and collected in a capillary tube. Traditional blood sampling collects a larger volume of blood (typically from 1 to 3 ml) taken from an artery or a vein. In this study, the patients (10 male and 2 female) had a mean age of 49 months and a mean weight of 18 kg. The amount of cefazolin in the blood samples were analyzed using the same methodology and results compared with assess the variability and reliability of the capillary microsampling method.What were the results? The results showed that difference of the two sample types is within the accepted criteria of the United States Federal Drug Administration and the European Medicines Agency, meaning the results are reliable.What do the results of the study mean? Blood samples for cefazolin can be small and easily obtained from a skin prick as a capillary microsample and can give reliable results. This greatly aids the ability to study the metabolism of cefazolin in children, particularly those that are not able to give a large amount of blood.

Comparison of Force, Neuromuscular, and Metabolic Responses During Sustained, Isometric Handgrip Holds to Failure Anchored to Low and High Perceptual Intensities in Men: An Exploratory Study.

ABSTRACT: Kwak, M, Succi, PJ, Benitez, B, Mitchinson, C, Samaan, MA, Abel, MG, and Bergstrom, HC. Comparison of force, neuromuscular, and metabolic responses during sustained, isometric handgrip holds to failure anchored to low and high perceptual intensities in men: An exploratory study. J Strength Cond Res 38(8): e405-e416, 2024-This study examined the responses of force alterations, relative to critical force (CF), neuromuscular parameters, and muscle oxygenation (SmO2) for isometric handgrip holds to failure (HTF) anchored to ratings of perceived exertion (RPE) of 3 and 7. Twelve men completed pre-maximal voluntary isometric contractions (pre-MVIC), submaximal HTF at 4 percentages of pre-MVIC, HTF at RPE = 3 and 7, and post-MVIC. Mechanomyograpic (MMG) signals and SmO2 were recorded during the RPE HTF. Analyses included paired-samples t-tests and repeated-measures ANOVAs at an alpha level of p ≤ 0.05. Time to task failure was not different between RPE 3 (478.7 ± 196.6 s) and RPE 7 (495.8 ± 173.8 s). Performance fatigability (PF) and MMG amplitude (AMP) were greater for RPE 7 (PF: 37.9 ± 12.9%; MMG AMP: 15.7 ± 7.4% MVIC) than RPE 3 (PF: 30.0 ± 14.5%; MMG AMP: 10.2 ± 6.5% MVIC), but MMG mean power frequency (MPF) was greater for RPE 3 (146.2 ± 31.1% MVIC) than RPE 7 (128.8 ± 23.0% MVIC). There were RPE-dependent decreases in force (p ≤ 0.01) across 3 discernable phases during the HTF. There were decreases in MMG AMP across time for both RPEs, but there were no significant changes in MMG MPF or SmO2. There were overall similar motor unit control strategies and local metabolic demand between RPEs. The majority of the HTF performed below CF at RPE 3 and 7 indicated CF did not reflect the highest sustainable force. When prescribing isometric exercise anchored to RPE, practitioners should be aware of the magnitude of force loss and relative intensity of the task to be sure desired training loads are met.

Sarcoidosis versus Granulomatous and Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency: A Comparative Review.

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

Arenavirus-Based Vectors Generate Robust SIV Immunity in Non-Human Primates.

Arenavirus-based vectors are being investigated as therapeutic vaccine candidates with the potential to elicit robust CD8 T-cell responses. We compared the immunogenicity of replicating (artPICV and artLCMV) and non-replicating (rPICV and rLCMV) arenavirus-based vectors expressing simian immunodeficiency virus (SIV) Gag and Envelope (Env) immunogens in treatment-naïve non-human primates. Heterologous regimens with non-replicating and replicating vectors elicited more robust SIV IFN-γ responses than a homologous regimen, and replicating vectors elicited significantly higher cellular immunogenicity than non-replicating vectors. The heterologous regimen elicited high anti-Env antibody titers when administered intravenously, with replicating vectors inducing significantly higher titers than non-replicating vectors. Intramuscular immunization resulted in more durable antibody responses than intravenous immunization for both vector platforms, with no difference between the replicating and non-replicating vectors. Overall, both replicating and non-replicating arenavirus vectors generated robust T- and B-cell-mediated immunity to SIV antigens in treatment-naïve non-human primates, supporting further evaluation of these vectors in a clinical setting for HIV therapy.

Amendments promote Douglas-fir survival on Formosa Mine tailings.

While mining provides valuable metals and minerals to meet societal demands, it can cause environmental contamination from the residuals (i.e., tailings) of mining. Tailings are often acidic, laden with heavy metals, and lacking adequate nutrients and physical conditions for plant growth, precluding the establishment of plant cover to reduce the offsite movement of mining wastes. This paper describes a case study at the Formosa Mine in Douglas County, Oregon, where tailings were amended with a mixture of lime, biosolids, biochar, and microbial inoculum to facilitate establishment of Douglas-fir (Pseudotsuga menziesii [Mirbel] Franco) seedlings. Results show that the tailings pH increased, and Douglas-fir seedlings survived and grew with these amendments. After 2 years, pH did, however, decrease in some downslope locations and was associated with an increase in tree mortality. This suggests that tailings conditions should be monitored, and amendments should be reapplied as needed, particularly in areas receiving acidic runoff from unamended upslope tailings, until the seedlings are fully established. This study not only provides a prescription for the addition of biochar and other amendments to enhance plant growth for revegetation purposes in low-pH, metal-contaminated mine tailings, but it also demonstrates a method that can be used to address similar problems at other mine sites.

Association of Preoperative Copeptin Levels with Risk of All-Cause Mortality in a Prospective Cohort of Adult Cardiac Surgery Patients.

We aimed to investigate the association of preoperative copeptin, a new cardiovascular biomarker, with short- and long-term mortality in a cohort of adult patients undergoing cardiac surgery, including its potential as a prognostic marker for clinical outcome. Preoperative blood samples of the Bern Perioperative Biobank, a prospective cohort of adults undergoing cardiac surgery during 2019, were analyzed. The primary and secondary outcome measures were 30-day and 1-year all-cause mortality. Optimal copeptin thresholds were calculated with the Youden Index. Associations of copeptin levels with the two outcomes were examined with multivariable logistic regression models; their discriminatory capacity was assessed with the area under the receiver operating characteristic (AUROC). A total of 519 patients (78.4% male, median age 67 y (IQR: 60-73 y)) were included, with a median preoperative copeptin level of 7.6 pmol/L (IQR: 4.7-13.2 pmol/L). We identified an optimal threshold of 15.9 pmol/l (95%-CI: 7.7 to 46.5 pmol/L) for 30-day mortality and 15.9 pmol/L (95%-CI: 9.0 to 21.3 pmol/L) for 1-year all-cause mortality. Regression models featured an AUROC of 0.79 (95%-CI: 0.56 to 0.95) for adjusted log-transformed preoperative copeptin for 30-day mortality and an AUROC of 0.76 (95%-CI: 0.64 to 0.88) for 1-year mortality. In patients undergoing cardiac surgery, the baseline levels of copeptin emerged as a strong marker for 1-year all-cause death. Preoperative copeptin levels might possibly identify patients at risk for a complicated, long-term postoperative course, and therefore requiring a more rigorous postoperative observation and follow-up.

Prosapia bicincta (Hemiptera: Cercopidae) abundance, plant associations, and impacts on groundcover in Hawai'i Island rangelands.

The twolined spittlebug, Prosapia bicincta (Say), is a major economic pest of forage grass and turfgrass. Prosapia bicincta was first detected in rangelands on Hawai'i Island in 2016 and has since spread to an estimated 72,000 ha in the North and South Kona districts. This study aimed to quantify P. bicincta abundance, plant associations, and impacts on groundcover over time. Monthly surveys of P. bicincta nymphs and adults were conducted from February 2018 to September 2022 along 17 established 100-m transects at 4 ranches located in Kona, Hawai'i Island, spanning an elevation gradient from 519 to 1,874 m above sea level (a.s.l.). Monitoring revealed P. bicincta occurs from 519 to 1,679 m a.s.l., primarily in Kikuyu grass (Cenchrus clandestinus (Hochst. ex Chiov.)) Morrone (Poales: Poaceae) pastures. Peaks in P. bicincta abundance coincided with the wet season, with most activity occurring from April to October and little to no activity between November and March. Mid elevation (1,000-1,300 m) transects had significantly higher mean P. bicincta abundance (126 nymphs/m2) relative to low (500-999 m) (64 nymphs/m2) and high elevations (>1,300 m) (20 nymphs/m2). Sites with the highest abundance of P. bicincta were also associated with the greatest decrease in mean grass cover (30%) and were replaced by forbs, bare ground, and shrubs. Grasses accounted for 72% of the total P. bicincta detections, with the remaining plants comprised of legumes (16%), sedges (6%), and forbs (6%). Twenty new P. bicincta plant associations were found. This information will help improve the effectiveness of management to suppress populations below economic thresholds.

Velocity dependence of sensory reweighting in human balance control.

The relative contributions of proprioceptive, vestibular, and visual sensory cues to balance control change depending on their availability and reliability. This sensory reweighting is classically supported by non-linear sway responses to increasing visual surround and/or surface tilt amplitudes. However, recent evidence indicates that visual cues are reweighted based on visual tilt velocity rather than tilt amplitude. Therefore, we designed a study to specifically test the hypothesized velocity dependence of reweighting while expanding on earlier findings for visual reweighting by testing proprioceptive reweighting for standing balance on a tilting surface. Twenty healthy young adults stood with their eyes closed on a toes-up/-down tilting platform. We designed four pseudo-random tilt sequences with either a slow (S) or a fast (F) tilt velocity and different peak-to-peak amplitudes. We used model-based interpretations of measured sway characteristics to estimate the proprioceptive sensory weight (Wprop) within each trial. Additionally, root-mean-square values of measured body centre of mass sway amplitude (RMS) and velocity (RMSv) were calculated for each tilt sequence. Wprop, RMS, and RMSv values varied depending on the stimulus velocity, exhibiting large effects (all Cohen's d's > 1.10). In contrast, we observed no significant differences across stimulus amplitudes for Wprop (Cohen's d's: 0.02-0.16) and, compared to the differences in velocity, there were much smaller changes in RMS and RMSv values (Cohen's d's: 0.05 - 0.91). These results confirmed the hypothesized velocity, rather than amplitude, dependence of sensory reweighting.

Identification of ATP-Competitive Human CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome Function.

The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anti-cancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and a requirement for CMG activity during recovery from replicative stresses such as chemotherapy. Here, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP binding sites and channels within MCM subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi are therefore also MCM complex inhibitors (MCMi). Biological testing shows that CMGi/MCMi inhibit cell growth and DNA replication using multiple molecular mechanisms distinct from other chemotherapy agents. CMGi/MCMi block helicase assembly steps that require ATP binding/hydrolysis by the MCM complex, specifically MCM ring assembly on DNA and GINS recruitment to DNA-loaded MCM hexamers. During S-phase, inhibition of MCM ATP binding/hydrolysis by CMGi/MCMi causes a 'reverse allosteric' dissociation of Cdc45/GINS from the CMG that destabilizes replisome components Ctf4, Mcm10, and DNA polymerase-a, -d, -e, resulting in DNA damage. CMGi/MCMi display selective toxicity toward multiple solid tumor cell types with K-Ras mutations, targeting the CMG and inducing DNA damage, Parp cleavage, and loss of viability. This new class of CMGi/MCMi provides a basis for small chemical development of CMG helicase-targeted anti-cancer compounds with distinct mechanisms of action.

Spesolimab Reduces Inflammation in Generalized Pustular Psoriasis: Molecular Characterisation of Flare Treatment in EFFISAYIL® 1.

EFFISAYIL® 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis (GPP) flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus placebo in approximately half of the patients. Here we present histologic, transcriptomic, and proteomic analyses of lesional and non-lesional skin, and whole-blood samples collected from EFFISAYIL® 1. Treatment with spesolimab led to a transition toward a non-lesional profile, with a downregulation of gene expression in the skin of IL-36 transcripts (IL-36α, IL-36ß, IL-36γ) and those associated with neutrophil recruitment (CXCL1, CXCL6, CXCL8), proinflammatory cytokines (IL-6, IL-19, IL-20), and skin inflammation (DEFB4A, S100A7, S100A8). Changes were manifest at Week 1 and sustained to Week 8. At the systemic level, reductions in serum biomarkers of inflammation (IL-17, IL-8, IL-6) were sustained until 12 weeks post-spesolimab treatment. Considerable overlap was observed in the spesolimab-induced changes in gene and protein expression from skin and blood samples, demonstrating the molecular basis of the effects of spesolimab on controlling local and systemic inflammation. Data are consistent with the mode of action of spesolimab, whereby inhibition of the IL-36 pathway leads to subsequent reductions in the key local and systemic pathologic events associated with acute GPP flares.

Comparative pharmacokinetics of a single oral dose of meloxicam in the California sea lion (Zalophus californianus) and Pacific harbor seal (Phoca vitulina richardii).

Pharmacokinetics studies have investigated meloxicam, a non-steroidal anti-inflammatory drug, dosing strategies in a wide variety of non-domestic animals; however, there is no prior study examining well-founded dosing for pinnipeds. To develop dosing protocols, pharmacokinetic information is needed, with an examination of differences between pinniped species. Apparently, healthy California sea lions (Zalophus californianus: CSL; n = 13) and Pacific harbor seals (Phoca vitulina richardii: PHS; n = 17) that had completed rehabilitation were enrolled into a population-based pharmacokinetic study. Each animal was administered a single oral dose of meloxicam at 0.1 mg/kg, and two blood samples were collected from each animal at varying intervals during a 96-h study period. Plasma concentrations of meloxicam were determined by high-pressure liquid chromatography. Data were analyzed with nonlinear mixed effects modeling (Phoenix® NLME™, Certara, St. Louis, MO 63105, USA). The results indicated that in PHS, peak plasma concentration (Cmax) was 0.33 µg/mL with an elimination half-life (Ke t½) of 31.53 h. In CSL, Cmax was 0.17 µg/mL with Ke t½ of 32.71 h. All animals enrolled completed the study without outward adverse clinical signs. The elimination half-life was longer than previously recommended dosing intervals for pinnipeds; however, we cannot speculate in the optimum clinical dose from these results.

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder.

Opioid use disorder (OUD) is a neuropsychological disease that has a devastating impact on public health. Substantial individual differences in vulnerability exist, the neurobiological substrates of which remain unclear. To address this question, we investigated genome-wide gene transcription (RNA-seq) and chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats exhibiting differential vulnerability in behavioral paradigms modeling different phases of OUD: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD across its trajectory. Analyses of gene networks and upstream regulators implicated processes involved in oligodendrocyte maturation and myelination in WIA, neuroinflammation in Demand, and metabolism in Reinstatement. Motif analysis of ATAC-seq showed changes in chromatin accessibility to a small set of transcription factor (TF) binding sites as a function either of opioid exposure (i.e., morphine versus saline) generally or of individual vulnerability specifically. Some of these were shared across the 3 paradigms and others were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and OUD vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder.

High Prevalence and Broad Distribution of Trichomonas gypaetinii in Bald Eagles (Haliaceetus leucocephalus) in the USA.

Trichomonas gypaetinii was detected in 117 (88%) of 133 Bald Eagles (Haliaceetus leucocephalus) and in 0 of 7 Golden Eagles (Aquila chrysaetos) in the USA, with no sex or age prevalence difference. All eagles lacked associated lesions. This study indicated that T. gypaetinii is common and widespread in Bald Eagles, but rarely associated with disease.

PROGnostic RolE of strain measurements in stress cardiac MRI in predicting major adverse cardiac events.

OBJECTIVES: We aimed to investigate the role of feature-tracking (FT) strain in long-term risk stratification of patients with known or suspected coronary artery disease (CAD) who underwent stress cardiac MRI with dipyridamole; to determine if contrast-free stress cardiac MRI with strain measurements could provide comparable prognostic value to myocardial perfusion. MATERIALS AND METHODS: This retrospective study included consecutive patients with stable symptoms suggesting possible cardiac ischemia who underwent stress cardiac MRI with dipyridamole. The mean follow-up period was 5.8 years ±1.2 [SD]. FT cardiac MRI analysis was performed for each patient to obtain 2D global peak circumferential strain (GCS). The primary outcome measure was major adverse cardiac events (MACE), defined as nonfatal myocardial infarction and cardiac death. RESULTS: A total of 729 patients (mean age, 63 years ±10 [SD]; 616 males) were included. MACE occurred in 70 (9.6%) patients. The presence of late gadolinium enhancement (LGE) ([HR] 2.74, [95% CI: 1.53, 4.88]; P < .001) and stress GCS (HR, 1.06 [95% CI: 1.01, 1.12]; P = .016) were independently associated with MACE. A model based on contrast-free assessment of LVEF and stress GCS showed similar performance for predicting MACE than LVEF and perfusion (P = .056). CONCLUSIONS: In patients with known or suspected CAD undergoing stress cardiac MRI with dipyridamole, GCS and LGE presence were independent predictors of MACE. Contrast-free stress cardiac MRI with stress GCS measurement offered prognostic value akin to myocardial perfusion assessment. CLINICAL RELEVANCE STATEMENT: Stress global circumferential strain represented an additional method to predict major adverse cardiac events in patients undergoing stress cardiac MRI, even without the use of contrast agents. This would be of particular significance in patients with severe renal impairment.

Preventive Service Usage and New Chronic Disease Diagnoses: Using PCORnet Data to Identify Emerging Trends, United States, 2018-2022.

Background: Data modernization efforts to strengthen surveillance capacity could help assess trends in use of preventive services and diagnoses of new chronic disease during the COVID-19 pandemic, which broadly disrupted health care access. Methods: This cross-sectional study examined electronic health record data from US adults aged 21 to 79 years in a large national research network (PCORnet), to describe use of 8 preventive health services (N = 30,783,825 patients) and new diagnoses of 9 chronic diseases (N = 31,588,222 patients) during 2018 through 2022. Joinpoint regression assessed significant trends, and health debt was calculated comparing 2020 through 2022 volume to prepandemic (2018 and 2019) levels. Results: From 2018 to 2022, use of some preventive services increased (hemoglobin A1c and lung computed tomography, both P < .05), others remained consistent (lipid testing, wellness visits, mammograms, Papanicolaou tests or human papillomavirus tests, stool-based screening), and colonoscopies or sigmoidoscopies declined (P < .01). Annual new chronic disease diagnoses were mostly stable (6% hypertension; 4% to 5% cholesterol; 4% diabetes; 1% colonic adenoma; 0.1% colorectal cancer; among women, 0.5% breast cancer), although some declined (lung cancer, cervical intraepithelial neoplasia or carcinoma in situ, cervical cancer, all P < .05). The pandemic resulted in health debt, because use of most preventive services and new diagnoses of chronic disease were less than expected during 2020; these partially rebounded in subsequent years. Colorectal screening and colonic adenoma detection by age group aligned with screening recommendation age changes during this period. Conclusion: Among over 30 million patients receiving care during 2018 through 2022, use of preventive services and new diagnoses of chronic disease declined in 2020 and then rebounded, with some remaining health debt. These data highlight opportunities to augment traditional surveillance with EHR-based data.

Combining treat-to-target principles and shared decision-making: International expert consensus-based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis.

BACKGROUND: Current treat-to-target recommendations for atopic dermatitis (AD) may not include high enough treatment targets and do not fully consider patient needs. OBJECTIVE: To develop recommendations for optimized AD management, including disease severity assessments, treatment goals and targets, and guidance for treatment escalation/modification. METHODS: An international group of expert dermatologists drafted a series of recommendations for AD management using insights from a global patient study and 87 expert dermatologists from 44 countries. Experts voted on recommendations using a modified eDelphi voting process. RESULTS: The Aiming High in Eczema/Atopic Dermatitis (AHEAD) recommendations establish a novel approach to AD management, incorporating shared decision-making and a concept for minimal disease activity (MDA). Consensus (≥70% agreement) was reached for all recommendations in 1 round of voting; strong consensus (≥90% agreement) was reached for 30/34 recommendations. In the AHEAD approach, patients select their most troublesome AD feature(s); the clinician chooses a corresponding patient-reported severity measure and objective severity measure. Treatment targets are chosen from a list of 'moderate' and 'optimal' targets, with achievement of 'optimal' targets defined as MDA. CONCLUSIONS: Patient and expert insights led to the development of AHEAD recommendations, which establish a novel approach to AD management. Patients were not involved in the eDelphi voting process used to generate consensus on each recommendation. However, patient perspectives were captured in a global, qualitative patient research study that was considered by the experts in their initial drafting of the recommendations.