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Abstract The Aso-4 explosive eruption on Kyushu, Japan, 89,500 years ago was one of the biggest eruptions in the last one hundred millennia, with a magnitude of approximately M8. Modern society requires the likelihood of natural events with potentially disastrous consequences to be evaluated, even if probabilities of occurrence are diminishingly small. For some situations, it is not satisfactory to assert an event scenario probability is “negligible” or can be “ignored”. Judicial hearings or litigation may require risk levels to be quantified, in which case, statements of scientific confidence could be decisive. Internationally, e.g., for nuclear site safety evaluations, event likelihoods on order of 10–7/year are often considered for quantitative assessment. At such hazard levels, this might include evaluating the proposition that a particular volcano can deliver a future super-eruption, a supposition that could be attached to Aso volcano. But, simplistically taking the average recurrence interval between past caldera-forming eruptions at a given volcano is an unreliable guide to the likelihood of a future repeat: each past event represented a unique set of tectonic and magmatic conditions within a continually evolving volcanic system. Such processes are not temporally stationary nor statistically uniform. To evaluate the probability of a new M8 event at Aso, within the next 100 years, we performed a comprehensive stochastic probability uncertainty analysis using a model implemented with advanced computational Bayes Net (BN) software. Our eruption process model is informed by multiple strands of evidence from volcanology, petrology, geochemistry and geophysics, together with estimates of epistemic (knowledge) uncertainty, adduced from reviews of published data, modelling and from expert judgement elicitation. Several lines of evidence characterise the likely structure, magmatic composition and eruptive state of the present-day Aso volcano, which has had numerous smaller eruptions since Aso-4. To calculate the probability of another M8 eruption of Aso, we implemented probabilistic ‘Importance Sampling’ in our model. With this approach, we find the chance of an Aso-4 scale eruption (characterised by mean volume 500 km3 DRE and approximate 90% credible interval [210 ‥ 1200] km3 DRE) is less than 1–in–1 billion in the next 100 years (i.e.,

An orthogonal system of tube-bearing joints constitutes the oldest fractures in the Tiva Canyon Tuff at Yucca Mountain, Nevada. The joints formed within a month of ignimbrite deposition, prior to major degassing. The system consists of (1) narrow, persistent, northeast-striking joint swarms with trace lengths typically greater than 5 m and between-joint spacings of less than 20 cm and (2) northwest-striking swarms that have a more en echelon geometry and greater between-joint spacings compared to the northeast-striking swarms. Between-swarm spacing for both trends is ~50 m. Questions concerning the joints include the following: (1) What was the origin of driving stress(es) for formation of the joints, particularly as their orientations were not consistent with the regional stress geometry at the time of their formation? (2) What mechanism caused the horizontal principal stresses to be reoriented so as to yield an orthogonal geometry? (3) What insights can be developed for predicting joint geometry in unexposed rock volumes by understanding joint origin? These questions are important because the joints and other fractures may affect the performance of a proposed high-level nuclear waste repository within Yucca Mountain. To address these questions, we use new and existing field data about joint geometry and the relationships of joints to degassing structures, numerical modeling of fault behavior, and work by previous authors. Our interpretation begins with the initial ignimbrite eruption and deposition during caldera collapse. The ignimbrites were deposited over a preexisting topography that possibly included a shallow northwest-trending basin in the Yucca Mountain area. During initial ignimbrite cooling, joint swarms formed as elements of orthogonal fumarolic ridge systems where degassing was associated with vertical dilation. Both joint sets have unusual tubes that are interpreted to have formed during dilation and segmentation of joint faces resulting from lithophysae inflation in the cooling ignimbrite deposit. Modeling supports the interpretation that a combination of regional stresses and stress related to slip on local normal faults controlled the orientation of the joint swarms and favored the formation of the northeast-striking joints first. The faults might have moved in a stress field already perturbed by caldera collapse. Formation of the northwest-striking joints occurred after a local 90 [degrees] switch of horizontal principal stress directions due to the presence of the northeast-striking swarms, possibly aided by differential compaction across the northwest-trending basin. Tube-bearing joints occur in all lithophysae-bearing lithostratigraphic units of the Topopah Spring Tuff, which is the stratigraphic interval for the proposed nuclear waste repository within Yucca Mountain. We conclude that the tube-bearing joints formed in the same manner and share similar geometric characteristics, adding a persistent joint population to the overall fracture system that influences hydrological and mechanical properties. Keywords: orthogonal joints, welded tuffs, cooling joints, degassing tubes, perturbed stress fields, normal faults.

Cerro Negro volcano, Nicaragua, continued a 147-yr-long duration of cinder-cone activity with a major eruption in 1995. Small, phreatically driven eruptions began in May 1995 and continued for 79 days. Following a 95 day repose, the main eruption produced 8 x [10.sup.6] [m.sup.3] of basalt from Cerro Negro over 13 days of activity and deposited 5 mm of ash in the city of Leon. Although the damage from the 1995 eruptions was fortunately minor, previous tephra falls from Cerro Negro have produced significant crop damage and multiple deaths through building collapse. In spite of its apparent longevity for a historically active cinder cone, Cerro Negro has mass-flow rates typical of arc-related basaltic cinder cone volcanoes. Volcanic hazards beyond 3 km from Cerro Negro consist of tephra falls. Few models are available to calculate tephra-fall risks from basaltic volcanoes such as Cerro Negro, and none have been applied to dispersive cinder cone eruptions. A convective-dispersive model of Suzuki is modified and evaluated using detailed data from the 1995 Cerro Negro eruption and is found to reasonably calculate tephra-fall thickness between 8 and 30 km from the vent. This model is used with detailed data from previous Cerro Negro eruptions in a tephra-fall hazard assessment. Cerro Negro also appears to have had a steady-state eruption rate since about A.D. 1900, which is used to estimate the timing of the next eruption as before A.D. 2006. The potential tephra fall from Cerro Negro in Leon, Nicaragua, is calculated as 2.2 mm/yr until 2006, with 95% confidence that deposits will be

Across lower eukaryotes, the transcription factor Crz1 is dephosphorylated by calcineurin, which facilitates Crz1 translocation to the nucleus to regulate gene expression. In the fungal pathogen Cryptococcus neoformans, calcineurin–Crz1 signaling maintains calcium homeostasis, thermotolerance, cell wall integrity, and morphogenesis. How Crz1 distinguishes different stressors and differentially regulates cellular responses is poorly understood. Through monitoring Crz1 subcellular localization over time, we found that Crz1 transiently localizes to granules after exposure to high temperature or calcium. These granules also host the phosphatase calcineurin and Pub1, a ribonucleoprotein stress granule marker, suggesting a role of stress granules in modulating calcineurin–Crz1 signaling. Additionally, we constructed and analyzed an array of Crz1 truncation mutants. We identified the intrinsically disordered regions in Crz1 contribute to proper stress granule localization, nuclear localization, and function. Our results provide the groundwork for further determination of the mechanisms behind the complex regulation of Crz1.

Major depressive disorder (MDD) is a serious and prevalent mental health issue. As the majority of MDD cases are identified and treated by one's primary care physician, it is imperative that care providers utilize accurate and efficient methods for diagnosing MDD in primary care settings. The present study is the first to investigate the accuracy of the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) as a screen for MDD. A heterogeneous sample of 155 primary care patients completed the QIDS-SR16 6 prior to attending a primary care appointment. Participants were then assessed for psychopathology using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) by clinicians who were blind to QIDS-SR16 scores. Scores on the QIDS-SR16 were compared to clinician-assessed current and lifetime diagnoses derived from the SCID, which represented the gold-standard criterion measure. Receiver operator characteristic analysis was utilized to determine the optimal QIDS-SR16 cut score to correctly classify participants based on their MDD status as assessed by the SOD. The test revealed a robust area under the curve (.82, p<0.00001) and suggested that a cut score of 13 or 14 provided the best balance of sensitivity (76.5 %) and specificity (81.8%) in this primary care sample. Over 80% of participants were correctly classified. Separate analyses by race were conducted to address the possibility that different cut scores may be more accurate for African American and Caucasians. Findings from the present study provide support for the use of the QIDS-SR16 as a screening measure for identifying primary care patients who will meet diagnostic criteria for MDD based on clinician assessment. [ABSTRACT FROM AUTHOR]

The goal of probabilistic volcanic hazard assessment is to translate complex volcanological data and numerical models into practical hazard estimates for communities potentially affected by volcanic eruptions. Probabilistic volcanic hazard assessment quantifies volcanic hazards and illustrates uncertainties about the magnitude and consequences of volcanic activity. Planning based on probabilistic volcanic hazard assessment has the potential of mitigating the effects of volcanic eruptions when they occur. This paper presents an approach developed to estimate volcanic hazards related to tephra fallout and illustrates this approach with a tephra fallout hazard assessment for the city of Leo´n, Nicaragua, and the surrounding area. Tephra fallout from eruptions of Cerro Negro volcano has caused damage to property and adverse health effects and has disrupted life in this area. By summarizing the geologic and historical records of past eruptions of Cerro Negro on a probability tree, it is shown that the inhabitants of Leo´n can expect >1 cm of tephra accumulation from approximately 30% of eruptions, and >4 cm of tephra accumulation from approximately 9% of eruptions of Cerro Negro volcano. This historical record is augmented with simulations of tephra dispersion that estimate the likelihood of tephra accumulation given a range of eruption magnitudes and that map the expected distribution of tephra over a broader region. An upper limit value of 0.5 m is calculated using the tephra dispersion model. Without a fundamental change in the eruptive behavior of Cerro Negro, tephra accumulation in Leo´n is not expected to exceed this value. [ABSTRACT FROM AUTHOR]

The relationship between obesity and hypertension has been investigated in a large number of cross-sectional population studies and a smaller number of prospective, observational studies. The results indicate that in most populations, blood pressure increases linearly with increasing relative body weight or body mass index. The relationship is present across all subgroups, although the magnitude of the association appears greater in whites than blacks and greater in younger than older persons. It is estimated that as much as one-third of all hypertension may be attributable to obesity in populations where hypertension and obesity are widely prevalent. Evidence from prospective studies and clinical trials suggests that hypertension in obese patients increases the risk of cardiovascular disease and that drug treatment of hypertension reduces the risk. However, it is uncertain whether the risks associated with hypertension and the benefits of treatment are as great in obese hypertensives as they are in lean hypertensives. The effects of weight reduction on blood pressure have been investigated in a small number of randomized, controlled trials involving a total of about 600 participants. Overall, the results of the trials indicate that weight reduction lowers blood pressure over intervals of up to one year. The magnitude of the blood pressure response appears to be directly proportional to the amount of weight loss achieved. However, the latter is inversely related to the length of follow-up. Adequate maintenance of weight loss remains a major problem for the much-needed, long-term trials of the effects of weight reduction on blood pressure and the cardiovascular complications of hypertension. [ABSTRACT FROM PUBLISHER]

When a leaf is excised from a plant by cutting the petiole in air, the stomata sometimes exhibit an “Iwanoff effect” or temporary increase of aperture before entering the phase of hydroactive closure. Simultaneous and separate measurements of transpiration from upper and lower leaf surfaces, derived from thermocouple psychrometers, photosynthesis measurements from either or both surfaces obtained with an Infrared Gas Analyser and measurements with a nitrous oxide diffusion porometer have been made on leaves of Gossypium hirsutum (cotton) before and after severing the petiole. The effect of previous illumination of the plant on the occurrence of the Iwanoff effect has been studied. The results obtained are consistent with the suggestion that an Iwanoff effect is observed when there is little or no water stress, but fails to appear if water stress has developed, even though it may not yet have reached the level at which hydroactive stomatal closure would occur. Furthermore the Iwanoff effect appears to be limited to the stomata of the upper surface in cotton leaves. This seems to be due to the greater accessibility of the upper than the lower epidermal cells, to the water demand of the internal tissues which follows excision. Evidence is also presented to show that the adaxial stomates do not necessarily close completely in the dark. [ABSTRACT FROM AUTHOR]

The mass spectra of a series of aliphatic acyclic α,β-unsturated aldehydes, ketones and ester have been examined. The spectra do not show evidence for McLafferty rearrangements, alkoxyl migration or for fragmentations which are dependent upon the s- trans or s- cis conformations of the compounds. There is some evidence for cis- trans isomerism about the double bond. [ABSTRACT FROM AUTHOR]

The formation of the styryl ion \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm PhCH = }\mathop {\rm C}\limits^{\rm + } {\rm H} $\end{document} in the mass spectra of some cinnamic compounds is shown to occur via the intermediate formation of the cinnamoyl ion \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm Ph} - {\rm CH} = {\rm CH} - {\rm C} \equiv \mathop {\rm O}\limits^{\rm + } $\end{document} rather than by direct cleavage of the bond α to the double bond. [ABSTRACT FROM AUTHOR]

The mass spectra of B substituted 2,5-dimethyl cyclotetrazenoboranes have been studied. The compounds Me2N4BD, Me2N4BEt, Me2N4BVi, Me2N4BCl and Me2N4BBr give confirmatory evidence that loss of N2+H. from the system occurs by loss of H from the side chain and that the BR bond is very stable under electron impact conditions. Fragmentation proceeds in a similar fashion to that of the 2,5-dimethyl substituted compounds with H bonded to the boron atom. [ABSTRACT FROM AUTHOR]

Background: Greater left ventricular (LV) wall stress is associated with adverse outcomes among patients with prevalent heart failure (HF). Less is known about the association between LV wall stress and incident HF., Objectives: The purpose of the study was to identify clinical factors associated with wall stress and test the association between wall stress and incident HF., Methods: We studied 4,601 ARIC (Atherosclerosis Risk In Communities) study participants without prevalent HF who underwent echocardiography between 2011 and 2013. LV end systolic and diastolic wall stress (LVESWS, LVEDWS) were calculated from chamber and wall thickness, systemic blood pressure, and transmitral Doppler E/e' as a surrogate for LV end diastolic pressure. Incident HF was ascertained by International Classification of Diseases (ICD)-9/10 claims for hospitalized HF through December 31, 2016. We used Cox regression to test the association between wall stress and incident HF, adjusted for demographics, traditional cardiovascular risk factors, prevalent coronary artery disease and atrial fibrillation, creatinine, N-terminal pro-B-type natriuretic peptide, troponin, triglycerides, C-reactive protein, LV ejection fraction, and LV mass., Results: The cohort had a median age of 75 years and 58% women, with 18% identifying as Black. Median LVESWS and LVEDWS were 48.8 (25th-75th percentile: 39.3-60.1) and 18.9 (25th-75th percentile: 15.8-22.5) kdynes/cm 2 , respectively. LVESWS and LVEDWS were modestly related (rho = 0.30, P  < 0.001). Over 4.6 years of median follow-up (156 HF events), each 1 kdyne/cm 2 greater LVEDWS was significantly associated with higher risk of incident HF (HR: 1.03; 95% CI: 1.01-1.06), while LVESWS was not (HR: 1.00; 95% CI: 0.99-1.01)., Conclusions: Among community-dwelling elderly individuals, greater LVEDWS is associated with a higher risk for incident HF., Competing Interests: This study was funded by the 10.13039/100000002National Institutes of Health (Drs White, Brittain, Lindman, Mosley, Shah, Wells, Kuipers, Gupta [R01HL153607, R01HL148661, R01HL154153, R38HL167237]); 10.13039/100005485American College of Cardiology/Association of Black Cardiologists Bristol Myers Squibb (Dr Dixon), Department of Veteran’s Affairs (VA), 10.13039/100000968American Heart Association (Drs Perry and Shah), 10.13039/100006520Edwards Lifesciences (Dr Lindman), and Cytokinetics (Dr Shah). Dr Shah is a co-inventor on a patent for ex-RNAs’ signatures of cardiac remodeling and in the past 12 months has served as a consultant for Cytokinetics. Dr Lindman has in the past 12 months served as a consultant for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated., Research Question: Are risk scores originally developed for PAH predictive in PH groups 1 through 4?, Study Design and Methods: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including the Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, European Society of Cardiology/European Respiratory Society 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata., Results: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH)., Interpretation: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups., Trial Registry: ClinicalTrials.gov; No.: NCT05329714; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. Y. has received personal fees from MSD. H. G. has received personal fees from Actelion, AstraZeneca, Bayer, BMS, GossamerBio, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. M. R. W. reports personal fees from MorphogenIX, Janssen, Chiesi, and Aerami; grants from British Heart Foundation and NIHR; and personal fees from MSD, Benevolent AI, and Tiakis Biotech, outside the submitted work. L. H. reports personal fees and nonfinancial support from Janssen and personal fees from MSD, Gossamer, and Altavant. D. G. K. reports support for the present manuscript from the Sheffield Biomedical Research Centre and consulting fees and other payments from Jansen Pharmaceuticals, Ferrer, Altavant, MSD, and United therapeutics. P. M. H. reports personal fees from Merck Co. S. Y. C. reports personal fees from Janssen, Bayer, Pfizer, United Therapeutics, and Acceleron Pharma and is a director, officer, and shareholder of Synhale Therapeutics. S. O. reports personal fees from MSD, Janssen, and Gallenica-Ferrer. H. A. G. has received fees from Actelion, AstraZeneca, Bayer, GSK, Janssen-Cilag, Lilly, Novartis, OMT, Pfizer, and United Therapeutics. M. J. R. has received support from Janssen Pharmaceutica and Bayer Pharma AG and speaker fees from Janssen Pharmaceutica and OMT. S. S. reports personal fees from Gossamer Bio, Merck, Keros, Janssen, United Therapeutics, and Liquidia. K. T. has received personal fees from Bayer, AstraZeneca, and Gossamer. W. S. has received consultancy fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticals, Abivax, Pfitzer, and Medspray BV. None declared (M. Fünderich, A.L., Y. S., O. T., A. J. S., R. T. Z., P. G. W., M. Frauendorf, A. Arvanitaki, G. G., K. S., H. R. C., R. F., I. A. G., E. B., J. S. A., A. P., S. G., A. Anthi, R. W. M., J. W., F. G.), (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with COPD frequently develop pulmonary hypertension (PH-COPD). Severe PH-COPD, identified by a pulmonary vascular resistance (PVR) >5 Wood Units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear., Research Question: Is PH-targeted therapy associated with improved transplant-free survival in PH-COPD?, Study Design and Methods: This study included PVRI GoDeep meta-registry patients with PH-COPD and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function tests. Immortal time bias was addressed through a landmark approach., Results: As of December 2023, the GoDeep meta-registry included 26981 patients (28% PH-Group 1, 13% PH-Group 2, 12% PH-Group 3, 10% PH-Group 4, 2% PH-Group 5, 26% undefined and 9% control). Out of these, 836 patients were diagnosed as PH-COPD and included in this analysis, with median age 66 [59,73]years, FEV1 51 [34,69]%predicted, mPAP 35 [28,44]mmHg, PVR 5 [4,8]WU, cardiac index 2.5 [2.0,2.9]L/min.m2, and mostly WHO functional class III were included. 5-year transplant-free survival was 42%, significantly worse than group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1 as a major predictor of outcome. 418 patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio 0.65 [0.57,0.75] for the entire PH-COPD cohort and 0.83 [0.74,0.94] when performing landmark analysis. This PDE5i effect was robustly reproduced when performing subgroup analyses for patients with moderate/severe PH, various comorbidities, and supplemental oxygen requirement, and when assessing the impact of unobserved confounders., Interpretation: PH-COPD patients exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models., (Copyright © 2024. Published by Elsevier Inc.)

Background: While food allergy (FA) can be fatal, the greatest public health impact of FA arguably lies in its detrimental effect on quality of life (FAQOL). Understanding the factors that contribute to FAQOL at different ages is essential to develop personalized interventions that will improve FAQOL., Objective: To determine the most influential factors that impact FAQOL across ages in well-phenotyped participants with confirmed FA., Methods: One hundred and twenty-five individuals aged 2-28 years with IgE-mediated FA completed validated age-specific FAQOL questionnaires. The relationship between demographic/clinical variables and scores were analyzed to identify key predictors of FAQOL., Results: Poor FAQOL was associated with increasing age, strict avoidance practices, reactions to trace exposures, and more severe reactions as assessed by epinephrine use, anaphylaxis, and/or treatment in the emergency department; FAQOL improved with time from the event. FAQOL was worse in subjects avoiding >2 versus ≤2 foods and in those avoiding milk, egg, soy, sesame, or wheat. Number of foods avoided had greatest impact on children ages 2-7 years, while total number of allergic reactions strongly impacted FAQOL in teens and adults; FAQOL of subjects ages 8-12 years appeared less affected by these variables compared to other age groups. A decision tree analysis identified key predictors of overall FAQOL (age, number of food avoidances, and time since epinephrine use) that can be used to guide intervention strategies to improve FAQOL., Conclusion: We directly compared FAQOL in extensively phenotyped children, teenagers, and adults with confirmed IgE-mediated FA. Age; timing, number, and severity of reactions; type and number of FA; and food avoidance practices influence FAQOL and should guide intervention strategies., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

The definition of pulmonary hypertension (PH) has been revised recently, with the mean pulmonary artery pressure (mPAP) threshold (assessed by right heart catheterization) reduced from ⩾25 mm Hg to >20 mm Hg. This change reflects the mPAP upper limit of normal and a lower limit that is independently associated with adverse outcomes. To improve the specificity of diagnosing pathogenic increases in mPAP, however, a diagnosis of precapillary PH now also includes pulmonary vascular resistance >2.0 Wood units (WU) (lowered from >3.0 WU). These changes are positioned to capture approximately 55% more patients with PH. Because all clinical trials showing a benefit of pulmonary vasodilator therapy in precapillary PH used the classical hemodynamic definition, the approach to the diagnosis and management of patients with mild PH (i.e., mPAP 21-24 mm Hg and pulmonary vascular resistance 2-3 WU) requires particular consideration. Here, we use a question/answer format to discuss key areas in the management of mild PH, including practical information tailored to clinicians without training in PH.

Background: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines., Objective: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions., Methods: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements., Results: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes., Conclusions: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)