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Background and Objectives: Peripheral neuropathy is a common manifestation of systemic and nonsystemic vasculitides; however, there is limited literature on vasculitic myopathy. We aim to describe the clinical, laboratory, and pathologic characteristics and treatment outcomes of vasculitic myopathy., Methods: A retrospective chart review of patients with a diagnosis of vasculitis and myopathy (1980-2022) was performed. Patients were included with either biopsy-proven vasculitic myopathy or biopsy-proven vasculitis (of nonmuscle tissue) and concomitant active myopathy after excluding alternative causes. All muscle biopsy slides were reviewed, and additional immunohistochemistry studies were performed., Results: Twenty-five patients with vasculitic myopathy were identified, 60% were female, and the median age at diagnosis was 63 (interquartile range 38-81) years. Ten patients (40%) had a primary systemic vasculitis, 12 secondary systemic vasculitis (48%), and 3 had nonsystemic vasculitic myopathy (12%). Myopathy was the initial manifestation of vasculitis in 20 of 25 patients (80%). Weakness was proximal and symmetric in most cases. Nineteen patients (76%) had pain at presentation: 2 with only neuropathic pain, 10 with only myalgia, and 7 had a combination of neuropathic pain distally and myalgia proximally. Creatine kinase (CK) was elevated in 3 of 23 patients (13%) and aldolase elevated in 10 of 16 patients (63%). Electromyography revealed short duration motor unit potentials in proximal and axial muscles in 23 of 24 patients (96%) and superimposed peripheral neuropathy in 15 of 24 (63%). Muscle biopsy showed perivascular inflammation in all biopsies, vessel wall inflammation and destruction in 18 of 21 (86%), and fibrinoid necrosis in 13 of 21 biopsies (62%). Masson trichrome stain facilitated the detection of fibrinoid necrosis. All muscle specimens had increased major histocompatibility complex class I sarcolemmal reactivity in nonnecrotic fibers. In most patients, the inflammatory infiltrates were predominantly CD4 + T cells, with complement deposition on blood vessels in some. Twenty-four patients improved with immunotherapy, and only 3 patients relapsed. Seven patients died during the study period, 1 from vasculitis complications. Probability of survival at 1 and 5 years was 96% and 84%, respectively., Discussion: Myopathy can be the initial manifestation of a primary or secondary systemic vasculitis or may occur as a nonsystemic form. Most patients present with proximal predominant weakness with normal CK and elevated aldolase levels. Patients usually respond well to immunotherapy.

Background and Objectives: Current formulations of primary progressive aphasia (PPA) derive largely from English-speaking patients. We hypothesized that language-specific characteristics influence PPA phenotypes in 2 contrasting languages: Italian and English., Methods: We undertook a retrospective, cross-sectional, observational comparison of 2 patient cohorts representing all major PPA syndromes, in London and Florence. Neuropsychological scores in a range of linguistic and general cognitive domains were normalized to native speaker controls and dichotomized as impaired/unimpaired. Proportions were compared using χ 2 tests and adjusted for symptom duration and severity of cognitive impairment using logistic regression., Results: The cohorts comprised 106 (48.1% female) Italian speakers (14 nonfluent/agrammatic [nfvPPA], 20 semantic [svPPA], 41 logopenic variant [lvPPA], 31 mixed PPA [mPPA]) and 166 (45.2% female) English speakers (70 nfvPPA, 45 svPPA, 42 lvPPA, 9 mPPA). Comparing cohorts, the English cohort was younger (mean 62.7 [SD = 8.4] vs 65.9 [7.8] years; p = 0.003, Cohen d = 0.39), with longer symptom duration (4.6 [4.3] vs 3.1 [2.5] years; p = 0.048, d = 1.08), a higher proportion of nfvPPA cases (42% vs 13%, χ 2 = 25.4, p < 0.001), and lower proportions of lvPPA (25% vs 38%, χ 2 = 5.46, p = 0.019) and mPPA (5% vs 29%, χ 2 = 29.3, p < 0.001). English-speaking nfvPPA patients had less frequent expressive agrammatism (46% vs 93%, p = 0.015, odds ratio [OR] 16.05, 95% CI 1.70-151.13) but more frequently impaired single-word comprehension (60% vs 8%, p = 0.013, OR 0.06, 95% CI 0.00-0.56). English svPPA patients had more frequent surface dyslexia (68% vs 30%, p = 0.046, OR 0.24, 95% CI 0.06-0.97) and dysgraphia (38% vs 10%, p = 0.021, OR 0.09, 95% CI 0.01-0.70) while English lvPPA patients had more frequently impaired single-word comprehension (89% vs 29%, p < 0.001, OR 0.05, 95% CI 0.01-0.28), word repetition (61% vs 26%, p = 0.020, OR 0.24, 95% CI 0.07-0.80), nonword repetition (78% vs 30%, p = 0.010, OR 0.18, 95% CI 0.05-0.06), nonverbal working memory (69% vs 36%, p = 0.005, OR 0.10, 95% CI 0.02-0.51), and visuomotor function (89% vs 25%, p < 0.001, OR 0.02, 95% CI 0.01-0.20)., Discussion: Language-specific characteristics influenced PPA phenotypes, with more frequent expressive agrammatism in Italian (reflecting its morphologic complexity), more frequently impaired word processing in English (reflecting its articulatory, acoustic, and orthographic complexity), and increased prevalence of mPPA in Italian. These findings have implications for PPA diagnosis and management. Limitations of test heterogeneity and cohort size should be addressed in future, prospective, multicenter initiatives using cross-linguistic tools.

Background and Objectives: Acute stroke is associated with a spectrum of functional deficits. The objective of this analysis was to explore whether the importance of individual risk factors differ by stroke severity, which may be of relevance to public health strategies to reduce disability., Methods: INTERSTROKE is an international case-control study of risk factors of first acute stroke (recruitment 2007-August 2015) in 32 countries. Stroke severity was measured using the modified Rankin Scale (mRS) score within 72 hours of admission to hospital. Severe stroke is defined as mRS scores of 4-6 (and non-severe stroke, score of 0-3). We used multinomial logistic regression to estimate comparative odds ratios (ORs; 95% CIs) for severe and non-severe stroke and tested for heterogeneity ( p ). We also conducted a matched case-case analysis (matched for age, sex, country, and primary stroke subtype) to determine whether the prevalence of risk factors differed significantly between severe and non-severe stroke. A significant difference in the association of a risk factor of severe stroke compared with non-severe stroke was defined as heterogeneity ). We also conducted a matched case-case analysis (matched for age, sex, country, and primary stroke subtype) to determine whether the prevalence of risk factors differed significantly between severe and non-severe stroke. A significant difference in the association of a risk factor of severe stroke compared with non-severe stroke was defined as p < 0.05 for both p heterogeneity and p case-case ., Results: Of patients with acute stroke (n = 13,460), 64.0% (n = 8,612) were reported to have mRS scores of 0-3 and 36.0% (n = 4,848) scores of 4-6. The mean age was 61.7 years for patients with non-severe stroke and 62.9 years for patients with severe stroke ( p = 0.72). 38.1% (n = 3,278) of patients with non-severe stroke and 44.6% (n = 2,162) of patients with severe stroke were female. Hypertension (OR 3.21; 95% CI 2.97-3.47 for severe stroke, OR 2.87; 95% CI 2.69-3.05 for non-severe stroke; p heterogeneity = 0.03; p case-case < 0.001), atrial fibrillation (OR 4.70; 95% CI 4.05-5.45 for severe stroke, OR 3.61; 95% CI 3.16-4.13 for non-severe stroke; p heterogeneity = 0.009; p case-case < 0.001), and smoking (OR 1.87; 95% CI 1.72-2.03 for severe stroke, OR 1.65; 95% CI 1.54-1.77 for non-severe stroke; p heterogeneity = 0.02; p case-case < 0.001) had a stronger association with severe stroke, compared with non-severe stroke. The waist-to-hip ratio had a stronger association with non-severe stroke compared with severe stroke ( p heterogeneity < 0.001; p case-case < 0.001)., Discussion: Hypertension, atrial fibrillation, and smoking had a stronger magnitude of association with severe stroke (compared with non-severe stroke) while the increased waist-to-hip ratio had a stronger magnitude of association with non-severe stroke.

Competing Interests: None.

Background: Chronic kidney disease (CKD) is a progressive disease impacting the physical function and mental health of sufferers. Depression is known to negatively impact quality of life, whereas handgrip strength and demoralization are important factors affecting physical and mental health. Lower handgrip strength has been associated with sarcopenia and higher risk of hospitalization in patients and higher workloads for nurse caregivers. Few studies have investigated the complex relations among these factors in patients with CKD., Purpose: This study was designed to investigate the mediating effects of grip strength and demoralization on the relationship between depression and quality of life in patients with CKD., Methods: Two hundred fifty patients with CKD comprised the study sample. The hypotheses were tested using the PROCESS macro., Results: Depression was found to be negatively associated with handgrip strength and quality of life but positively associated with demoralization. The results indicate that both handgrip strength and demoralization mediate the association between depression and quality of life. Moreover, the results of multiple mediation model analysis showed handgrip strength and demoralization both play important roles in the link between depression and quality of life., Conclusions: The results of this study indicate that handgrip strength and demoralization mediate the relationship between depression and quality of life in patients with CKD. Thus, increasing handgrip strength and decreasing demoralization levels may mitigate the impact of depression on quality of life. Therefore, nurses should better appreciate the importance of handgrip strength for patients with CKD and evaluate handgrip strength. Nurses should also develop physical and mental interventions to increase handgrip strength and decrease demoralization., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Countries around the world have large aging adult populations. There is wide public health concern about the health and well-being of aging adults, and a movement to transform healthcare systems to become age-friendly. The concept of "successful aging" recognizes the importance of aging and expands the goal beyond the absence of disease to functioning and well-being. In this perspective, we discuss aging as a part of life that should be considered in whole person health and cite work with the US veteran population as an example of how successful aging and age-friendly practices can be incorporated into whole person health for adult populations. We also review studies of successful aging that may offer important ways to define and measure whole person health and discuss how it might be instructive to assess successful aging with multiple indicators across the adult life span, particularly in underserved populations at-risk of premature aging and poor health. Finally, we conclude with a discussion of the "life course perspective" that may serve as a useful model for the interplay between successful aging and whole person health., Competing Interests: The authors declare no conflict of interest.

Objective: To describe "What Matters" to older adults seeking emergency department (ED) care and to identify patient characteristics associated with meeting desired outcomes., Background: As part of the 4Ms framework, identifying "What Matters" has been captured across healthcare settings, yet limited attention has been directed to older adults in the ED., Methods: We performed a secondary analysis of a multicenter prospective observational study. The study enrolled 1013 patients aged 65 and older during an ED encounter and performed 90-day follow-up interviews. The primary outcome was the quantification of "What Matters" (concerns and desired outcomes) to older adults during emergency care. As secondary outcomes, we assessed concerns at day 90, if desired outcomes were met at follow-up, and patient characteristics associated with outcome achievement by estimating multivariable logistic regression models., Results: Older adults reported specific concerns at the time of the ED visit including: (1) symptom identification and/or persistence (31.4%), (2) ability to take care of oneself (19.4%), and (3) end-of-life (17.8%). Desired outcomes expressed by participants included: (1) getting well and symptom resolution (72.0%), (2) obtaining a diagnosis (25.7%), and (3) functional independence (19.5%). At day 90 follow-up, concerns remained similar to the initial ED visit, and the majority of participants (66.2%) achieved their desired outcome. Frailty (adjusted odds ratio = 0.56, 95% CI: 0.38-0.83, P < 0.01) was associated with older adults not meeting their desired outcomes., Conclusions: Older adults identified a variety of concerns during emergency care, and two-thirds reported that desired outcomes were met at longitudinal day 90 follow-up., Competing Interests: C.J.G. is a Pepper Scholar with support from the Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342), the National Institute on Aging (NIA) of the National Institutes of Health (NIH; R03AG073988, R33AG058926), and the West Health Institute. M.T. receives funding from the John. A. Hartford Foundation. J.T. is supported by awards from the NIA (K76AG074922; 1R01AG080630-01A1) and Robert Wood Johnson Foundation (77872). A.K.V. reports support by the American Board of Emergency Medicine National Academy of Medicine Anniversary fellowship during this work and prior support from the Yale Center for Clinical Investigation grant KL2 TR000140 from the National Center for Advancing Translational Science (NCATS/NIH). L.S. has funding from the National Institute of Health (K23 AG061284). S.M.D. receives funding from the National Institute on Aging (R33AG058926, R33AG069822, U54AG063546), and the Agency for Healthcare Quality and Research (R01HS026489). C.J.G. and A.K.V. receive support for contracted work from the Centers for Medicare and Medicaid Services to develop hospital and healthcare outcome and efficiency quality measures and rating systems. The remaining authors declare no conflict of interest.

Objectives: In 2023, the U.S. Veterans Health Administration convened a State of the Art meeting to evaluate the existing evidence and make recommendations for measuring the well-being of the whole person in clinical care, health research, and population health evaluation. In this article, we describe findings and recommendations concerning each of these health care system functions, as well as key takeaways from the meeting as a whole., Background: There has been a growing call for health care organizations to expand their focus beyond disease-based concepts to consider both positive aspects of health and indicators of well-being that extend beyond the health domain. Yet, knowledge remains limited regarding how best to integrate these types of measurements in clinical care, health research, and population health evaluation efforts., Method: State of the Art activities were organized into 3 workstreams, each focused on a core health care system function (clinical care, health research, and population health evaluation). Drawing from existing literature on the measurement of the well-being of the whole person in the assigned health care function, workgroups evaluated the existing state of knowledge and made recommendations for future work on well-being measurement in the health care setting., Results: Cross-cutting themes included: (1) difficulty evaluating the current state of knowledge due to varied use of terminology in this literature; (2) appreciation for the value of well-being measurement in each health care function; (3) need for additional research on the use and benefits of well-being measures, including their role as predictors and moderators of health and health care outcomes; (4) importance of ensuring that measures are applicable for diverse patient groups and adequately reflect the "patient voice;" and (5) need for additional leadership investment and resource allocation to support use of these measures in the health care setting., Conclusions: Knowledge from this meeting can be applied to enhance the use and application of measurement of well-being to improve patients' health and health care outcomes., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: This review discusses novel concepts of acute kidney injury (AKI), including subphenotyping, which may facilitate the development of target treatment strategies for specific subgroups of patients to achieve precision medicine., Recent Findings: AKI is a multifaceted syndrome with a major impact on morbidity and mortality. As efforts to identify treatment strategies have largely failed, it is becoming increasingly apparent that there are different subphenotypes that require different treatment strategies. Various ways of subphenotyping AKI have been investigated, including the use of novel renal biomarkers, machine learning and artificial intelligence, some of which have already been implemented in the clinical setting. Thus, novel renal biomarkers have been recommended for inclusion in new definition criteria for AKI and for the use of biomarker bundled strategies for the prevention of AKI. Computational models have been explored and require future research., Summary: Subphenotyping of AKI may provide a new understanding of this syndrome and guide targeted treatment strategies in order to improve patient outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Air embolism is a potentially serious complication of central venous catheter (CVC) use. While CVC insertion is usually performed by a trained specialist, extraction is frequently the responsibility of junior staff members. This complication can be easily prevented by following several simple measures described in common guidelines., Aim: We conducted a single-center survey to assess knowledge and practices concerning the prevention of air embolism associated with CVC removal among healthcare workers from nonintensive care units., Methods: The correct answers to the questionnaire were determined according to best-practice recommendations for CVC removal. Based on a comparison of the total sum of correct answers between the categories of groups, factors that predicted the level of knowledge were identified using an independent sample t test., Results: Of the 156 respondents, one-third were unfamiliar with air embolism as a complication of CVC extraction. Almost 80% were unaware of the existence of a CVC removal protocol. Almost half of respondents did not follow guidelines regarding patient position when removing a CVC, 72% did not ask the patient to perform the Valsalva maneuver during the procedure, and 54% did not ask the patient to remain supine after the procedure. Adherence to the protocol was correlated with professional experience, with a lower level among those with experience of less than 1 year and, particularly, among interns., Conclusions: Our survey revealed inappropriately low awareness of CVC removal-associated air embolism risk and low familiarity with CVC removal best-practice recommendations among nonintensive care unit healthcare workers. Staff members with experience of less than 1 year, including interns, were found to have a lower level of knowledge. These findings emphasize the importance of development and distribution an internal hospital protocol and the integration of educational intervention into a preliminary internship program., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Considering the limited data regarding clinical outcomes of patients with non-ST-segment on the ECG elevation myocardial infarction (NSTEMI), this study compared the outcomes of patients undergoing percutaneous coronary intervention with newer-generation drug-eluting stents stratified by the presence/absence of complex lesions and symptom-to-balloon time (SBT; <48 h or ≥48 h)., Methods: We enrolled 4373 patients with NSTEMI from the Korea Acute Myocardial Infarction Registry-National Institute of Health dataset and stratified them into the complex group (2106 patients; SBT < 48 h, n  = 1365; SBT ≥48 h, n  = 741) and the noncomplex group (2267 patients; SBT < 48 h, n  = 1573; SBT ≥48 h, n  = 694). The primary outcome was the 3-year all-cause mortality rate. The secondary outcomes were any major adverse cardiac events (MACE), including cardiac death (CD), recurrent myocardial infarction, and stroke., Results: The incidence of all-cause mortality (adjusted hazard ratio, 0.656; P  = 0.009), CD ( P  = 0.037), and MACE ( P  = 0.047) in the complex group and of stroke in the noncomplex group ( P  = 0.020) were significantly lower in patients with SBT < 48 h than in those with SBT ≥48 h. Among patients with SBT < 48 h, the stroke incidence ( P  = 0.019) was higher in the complex group than in the noncomplex group, while among patients with SBT ≥48 h, the MACE incidence ( P  = 0.011) was higher in the former than in the latter., Conclusion: SBT reduction effectively decreased the 3-year mortality in patients with NSTEMI in the complex group compared with the noncomplex group., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Radiation therapy (RT) is a cornerstone in cancer treatment (used in 50% of cases), yet challenges persist because damage to normal tissue through direct impact of radiation or bystander effects is inevitable. Injury of macrovessels by RT manifests as obstructive disease, which is akin to atherosclerotic disease. Historically observed in coronary arteries of patients treated for breast cancer and lymphoma, it also affects patients receiving contemporary therapy for lung and chest cancers. Moreover, radiation at various sites can lead to peripheral vascular disease. An aspect of radiation-induced injury that has received little attention is microvascular injury, which typically results from damage to the endothelium and is considered the primary driver of RT-induced toxicity in the skin, kidney, and brain. This review delves into the clinical manifestations of RT-induced vascular disease, signaling pathways, cellular targets affected by radiation injury, and preclinical models of RT-induced vascular injury. The goal is to inspire the development of innovative strategies to prevent RT-related cardiovascular disease., Competing Interests: None.

Purpose of Review: The pathogenesis of granulomatous disease in common variable immunodeficiency (CVID) is still largely unknown, which hampers effective treatment. This review describes the current knowledge on the pathogenesis of granuloma formation in CVID and the biological basis of the current treatment options., Recent Findings: Histological analysis shows that T and B cells are abundantly present in the granulomas that are less well organized and are frequently associated with lymphoid hyperplasia. Increased presence of activation markers such as soluble IL-2 receptor (sIL-2R) and IFN-ɣ, suggest increased Th1-cell activity. Moreover, B-cell abnormalities are prominent in CVID, with elevated IgM, BAFF, and CD21low B cells correlating with granulomatous disease progression. Innate immune alterations, as M2 macrophages and neutrophil dysregulation, indicate chronic inflammation. Therapeutic regimens include glucocorticoids, DMARDs, and biologicals like rituximab., Summary: Our review links the biological context of CVID with granulomatous disease or GLILD to currently prescribed therapies and potential targeted treatments., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: Primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) are the leading causes of graft loss in lung transplant recipients. The development of mouse lung transplant models has allowed for the genetic dissection of cellular and molecular pathways that prevent graft survival. This review provides an overview into recent mechanistic insights into PGD and CLAD., Recent Findings: Mouse orthotopic lung transplant models and investigations of human lung transplant recipeints have revealed new molecular and cellular targets that promote PGD and CLAD. Donor and recipient-derived innate immune cells promote PGD and CLAD. PGD is driven by communication between classical monocytes and tissue-resident nonclassical monocytes activating alveolar macrophages to release chemokines that recruit neutrophils. Products of cell damage trigger neutrophil NET release, which together with NK cells, antibodies and complement, that further promote PGD. The development of CLAD involves circuits that activate B cells, CD8 + T cells, classical monocytes, and eosinophils., Summary: Effective targeted management of PGD and CLAD in lung transplant recipient to improve their long-term outcome remains a critical unmet need. Current mechanistic studies and therapeutic studies in mouse models and humans identify new possibilities for prevention and treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays key pathogenic roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutic strategies across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs, and discusses major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology., Competing Interests: N. Potere received training fellowships and travel grants from the International Society on Thrombosis and Società Italiana per lo Studio dell’Emostasi e della Trombosi, and research grants, paid to his institution, from the International Society on Thrombosis and Haemostasis and the International Network of Venous Thromboembolism Clinical Research Networks. A. Abbate received consulting fees from Cardiol Therapeutics, Kiniksa Pharmaceuticals, Monte Rosa Therapeutics, and Novo Nordisk.

Purpose of Review: This review comes at a time where new techniques in immunotherapy administration are being developed, new innovations are being incorporated to standard techniques, and new regulations are being adopted regarding the creation and storage of allergen extracts. Prior to the release of updated practice parameters regarding allergic rhinitis and immunotherapies, this review article provides a synopsis of current recommendations, a comparison of the practices in the United States and those of Europe, and an examination of experimental methods that are being studied., Recent Findings: This article seeks to review and discuss the various methods of administration, build up schedules, efficacy, effect on other atopic symptoms, and safety associated with allergen immunotherapy., Summary: Innovations in standard techniques, such as new allergoids for SCIT, appear to be effective in improving symptoms and increasing IgG levels for grass allergens. Data for newer techniques is less clear. There appears to be increased treatment-related adverse events for ILIT, worse symptom scores compared with placebo for IDIT, and insufficient studies regarding the effectiveness of EPIT for aeroallergens. New regulations seek to standardize the documentation, storage, and creation of allergen extracts., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Since hyperuricemia is a risk factor for cardiovascular disease and chronic kidney disease, it is necessary to pay attention to trends in uric acid levels when treating hypertensive patients with drugs. The present study investigated the effect of switching from angiotensin II receptor blocker (ARB) to sacubitril/valsartan on serum uric acid levels in treated hypertensive patients and further examined what factors could be associated with its effect., Methods: In 75 hypertensive patients under treatment with at least one antihypertensive agent including ARB, clinic blood pressure and biochemical parameters were assessed before and after drug switching to sacubitril/valsartan (200 mg/day)., Results: Clinic SBP and DBP significantly decreased after drug switching to sacubitril/valsartan ( P  < 0.0001, respectively). Serum creatinine, estimated glomerular filtration rate (eGFR), and urinary protein did not change after switching to sacubitril/valsartan, but serum uric acid significantly decreased (5.70 ± 1.44 to 5.40 ± 1.43 mg/dl, P  = 0.0017). The degree of uric acid lowering was greater in patients switching from ARB plus diuretic than in those switching from ARB, but switching to sacubitril/valsartan from ARB only (except losartan) also significantly decreased uric acid levels. In all subjects, the change in serum uric acid after drug switching to sacubitril/valsartan was closely correlated with the change in eGFR ( r  = -0.5264, P  < 0.0001)., Conclusion: Our findings indicate that switching from ARB to sacubitril/valsartan reduces serum uric acid levels in hypertensive patients and suggest that this uric acid-lowering effect may be associated with an increase in eGFR., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Germline and somatic genetic/genomic testing are commonly ordered for gynecologic oncology patients. Genetic tests can inform disease etiology, prognosis, treatment decisions, and risk to the patient's relatives. Variants of uncertain significance (VUSs) are frequently encountered and have a more nuanced interpretation than straightforward pathogenic or benign variant classifications. Clinical care providers should be familiar with why and how VUSs are reported, their clinical significance, variant reclassification practices, and patient perceptions of VUSs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The connection between eosinophilic esophagitis (EoE) and food and airborne allergens is complex. Exposure to allergens (mainly food) is often the trigger for EoE flares. The development of EoE has been described as a side effect of allergen immunotherapy, especially oral immunotherapy (OIT, with food allergens), while isolated cases of EoE have been reported during sublingual immunotherapy (SLIT, with extracts of aeroallergens)., Recent Findings: EoE is currently recognized as a common side effect of OIT, while a solid correlation between SLIT and EoE is missing. Animal models have been developed to study the pathophysiological link between sensitization to aeroallergens and the induction of EoE and will probably provide an interpretation of why there are cases of EoE developed during SLIT. Recent findings in animal models suggest a genetic connection to EoE development after sensitization and re-exposure to airborne allergens. Subcutaneous allergen immunotherapy does not have a causative effect on EoE; on the contrary, a beneficial effect on EoE has been reported. Moreover, epicutaneous immunotherapy with a vector containing milk has also been used to treat children with milk-induced EoE., Summary: Discovering the immune links between allergens and EoE will further guide the proper use of allergen immunotherapy and help define future strategies for the management of EoE., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to explore the epidemiology of cutaneous malignant melanoma (CMM) and the associated risk factors influencing its occurrence and survival among Koreans aged <20 years. In this retrospective cohort investigation, we identified cases of incident melanoma diagnosed in Korean patients aged 0-19 years between 2004 and 2019, utilizing the National Health Insurance database. We assessed annual fluctuations in age-adjusted incidence rates and examined 5-year survival rates based on various factors, including sex, age, income level, sun-exposed sites, and the Charlson Comorbidity Index. Of 1160 patients, 51.4% were male and 48.6% were female. The mean age of the patients was 11 years, mostly belonging to the top 25% high-income group. The head and neck regions were the most frequently affected sites. The overall age-adjusted incidence rate of melanoma was 0.22 per 100,000 persons. This rate witnessed a decline of 4.5% annually from 2004 to 2012, followed by a subsequent increase of 12.6% annually from 2012 to 2019. Notably, patients with CMM in low-sun-exposed sites exhibited poorer survival rates compared with those in high-sun-exposed areas ( P  < 0.05). The incidence of melanomas in children and adolescents in Korea has shown a rising trend since 2012. Further research is needed to investigate the etiology and risk factors in pediatric patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: In myocardial infarction with nonobstructive coronary arteries (MINOCA), there are limited patient-level data on outcomes by sex and race., Objective: The aim of this study was to assess baseline demographics and 3-year outcomes by sex and race for MINOCA patients., Methods: Patients admitted to a single center with acute myocardial infarction (MI) between 1 January 2012 and 31 December 2018, were identified by chart and angiographic review. The primary outcome was nonfatal MI with secondary outcomes including nonfatal cerebrovascular accident (CVA), chest pain readmission, and repeat coronary angiography., Results: During the study period, 304 patients were admitted with MINOCA. The cohort was predominantly female (66.4%), and women were significantly older (64.6 vs. 59.2). One-sixth of the total population were Black patients, and nearly half of Black patients (47.2%) were male. Prior CVA (19.7%) and comorbid anxiety, depression, or post-traumatic stress disorder (41.1%) were common. Rates of nonfatal MI were 6.3% without difference by sex or race. For secondary outcomes, rates of CVA were 1.7%, chest pain readmission was 22.4%, and repeat angiography was 8.9%. Men were significantly more likely to have repeat angiography (13.7 vs. 6.4%), and Black patients were more likely to be readmitted for angina (34.0 vs. 19.1%). Over one-quarter of patients underwent repeat stress testing, with 8.9% ultimately undergoing repeat angiograms and low numbers (0.7%) undergoing revascularization. Men were more likely to be referred for a repeat angiogram (13.7 vs. 6.4%, P  = 0.035). In multivariate analysis, Black race [odds ratio (OR), 2.31; 95% confidence interval (CI), 1.06-5.03] was associated with an increased risk of readmission for angina, while female sex was associated with decreased odds of repeat angiography (OR, 0.36; 95% CI, 0.14-0.90) and current smoking was associated with increased odds of repeat angiography (OR, 4.07; 95% CI, 1.02-16.29)] along with hyperlipidemia (OR, 4.65; 95% CI, 1.22-17.7)., Conclusion: White women presented more frequently with MINOCA than White men, however, Black men are equally as affected as Black women. Rates of nonfatal MI were low without statistical differences by sex or race., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: This review aims to highlight the multifaceted nature of brucellosis, emphasizing the latest advancements in its diagnosis and management. Given the global prevalence and potential complications of brucellosis, understanding recent advancements in diagnostic techniques and treatment strategies is crucial for clinicians., Recent Findings: Recent literature reveals significant progress in diagnostic methods, including the application of fluorescence polarization immunoassay and time-resolved fluorescence resonance energy transfer technologies as well as the invention of artificial Brucella antigens, which offer enhanced sensitivity and specificity. Advances in molecular diagnostics and serological tests have improved early detection rates, however their interpretation remains challenging. Evolving treatment regimens such as the use of hydroxychloroquine as part of triple therapy and the use of nano-delivery systems in therapies have shown promise, in hopes of reducing relapse rates and managing chronic cases., Summary: The findings underscore the necessity for clinicians to adopt a comprehensive approach to diagnosing and managing brucellosis. Integrating advanced diagnostic tools with tailored therapeutic strategies can significantly improve patient outcomes. Future research should focus on optimizing these diagnostic techniques and exploring novel therapeutic agents., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Congenital heart disease (CHD) is a group of complex heart defects associated with hematologic abnormalities, including increased risk of thrombotic and bleeding events. Past studies have observed evidence of platelet hyperreactivity, while other studies showed decreased platelet activation in patients with CHD. The goal of this study was to develop a mass spectrometry approach to characterize single platelets in infants with CHD and identify potential etiology for such discrepant results., Methods: We enrolled 19 infants with CHD along with 21 non-CHD controls at Yale New Haven Children's Heart Center. A single-cell high-dimensional mass cytometry method was developed to quantitatively interrogate platelet surface markers in whole blood. Additionally, plasma cytokine analysis was performed through a multiplexed panel of 52 vascular and inflammatory markers to assess for platelet releasates., Results: We found that infants with CHD had significant differences in platelet activation and functional markers by mass cytometry compared with non-CHD controls. Based on cell surface markers, we classified the platelets into 8 subpopulations (P0 to P7). Distinct subpopulations of platelets (P1, P4, and P5) exhibiting decreased aggregatory phenotype but altered secretory phenotypes were also identified and found to be more abundant in the blood of infants with CHD. Electron microscopy identified increased proportion of hypogranular platelets in CHD. Moreover, cytokine analysis demonstrated an overall increase in plasma cytokines and biomarkers in CHD, including IL (interleukin)-6, IL-8, IL-27, RANTES (regulated upon activation, normal T cell expressed and secreted), and VWF (von Willebrand factor), which are expressed in platelet granules and can be released upon activation., Conclusions: We developed a robust mass cytometry approach to identify platelet phenotypic heterogeneity. Infants with CHD had alterations in distinct subpopulations of platelets with overall reduced aggregatory phenotype and secretory dysfunction. These findings suggest that platelets in infants with CHD may be exhausted due to persistent stimulation and may explain both bleeding and thrombotic vascular complications associated with CHD., Competing Interests: None.

Purpose: To synthesize the current literature regarding patients with inherited bleeding disorders and suggest comprehensive evaluation and preoperative recommendations for these patients before undergoing corneal refractive surgery., Methods: The literature search was conducted through PubMed, Embase, and Google Scholar databases for publications through January 4, 2024 for reports of ocular bleeding manifestations in patients with inherited bleeding disorders and reports of patients without a history of bleeding disorders who had intraoperative or postoperative hemorrhagic complications with corneal refractive surgery. Additional cases from the literature and a retrospective chart review at a corneal practice were obtained describing patients with inherited bleeding disorders who underwent corneal refractive surgery., Results: Four articles were found detailing ocular bleeding manifestations in patients with inherited bleeding disorders who underwent ocular surgery other than corneal refractive surgery. Thirty articles were found detailing intraoperative and postoperative bleeding manifestations in patients without a history of inherited bleeding disorders who underwent corneal refractive surgery. Eight cases (3 patients from the literature search and 5 patients from a retrospective chart review) were found regarding patients with inherited bleeding disorders who underwent corneal refractive surgery., Conclusions: For corneal refractive surgery with topical anesthesia, the perioperative risk and need for any hemostasis intervention in individuals with an inherited bleeding disorder depends on the type of disorder, status of preoperative factor level concentrations, or a prior history of bleeding. If required, clotting factor optimization should be tailored to each candidate on a case-by-case basis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: This review examines the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on lipid profiles in individuals with type 2 diabetes mellitus and/or obesity, crucial for optimizing cardiovascular risk management., Recent Findings: GLP-1RAs affect lipid levels by reducing intestinal apolipoprotein B48 production and mesenteric lymph flow, while increasing catabolism of apolipoprotein B100. It remains unknown whether these effects are direct or indirect, but the improvements in lipid levels are strongly correlated to the drug-induced weight loss. Clinical trials demonstrate improvements in lipid profiles, with different effects per agent and dose. We deem it unlikely that improved lipid levels are sufficient to explain the beneficial effects of GLP-1RA on cardiovascular risk, especially given the improvement of many other risk factors (body weight, glycemic control, inflammation) while using these agents. Posthoc mediation analyses of large cardiovascular outcome trials may shed some light on the relative importance of each risk factor., Summary: GLP-1RAs improve lipid profiles in clinical trials, but their complete cardiovascular benefits likely involve multifactorial mechanisms beyond lipid modulation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: We aim to review the rationale, methods, and experiences with diagnostic stewardship targeted at urinary tract infection (UTI) and related urinary syndromes., Recent Findings: In the last 18 months, several articles have demonstrated the impact of diagnostic stewardship interventions at limiting inappropriate diagnosis of UTIs or inappropriate antibiotic-prescribing, targeting the urinary tract. Antimicrobial stewardship programs may create and implement interventions at the point of urine test ordering, urine test resulting, or at the point of prescribing antibiotics after results have returned. Specific design and implementation of stewardship interventions depends on context. To maximize their impact, interventions should be accompanied by education and garner buy-in from providers., Summary: Diagnostic stewardship can decrease unnecessary antibiotics and inappropriate diagnosis of UTI with multifaceted interventions most likely to be effective. Remaining questions include how to reduce ASB treatment in new populations, such as those with immune compromise, and persistent unknowns regarding UTI diagnosis and diagnostics., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is a stroke and heart complication risk but is often overlooked due to subtle symptoms. The accessibility of sphygmomanometers that can detect AF, may play crucial roles in identifying asymptomatic patients. AViTA BPM63B is an automatic blood pressure (BP) monitor for atrial fibrillation detection. This study validated the performance of BPM63B for AF detection using two novel algorithms of time-domain analysis and frequency-domain analysis which evaluate multiple statistics., Methods: The study included 100 participants, with 47 participants being male (47%) and ages ranging from 24 to 89 years (mean ± SD: 59 ± 17 years). Each participant received three consecutive readings from the subject device and a 12-lead ECG assessment. The pulse wave data from subject device was analyzed using the two algorithms. The atrial fibrillation status thus determined was compared to the ECG results interpreted by a physician., Results: Among the 100 participants, 52 patients had chronic atrial fibrillation, along with 48 outpatients exhibiting sinus rhythm or non-atrial fibrillation arrhythmias. Using the time-domain analysis method for atrial fibrillation detection, we achieved a sensitivity of 94.8% [95% confidence interval (CI), 90.08-97.75%] and a specificity of 98.6% (95% CI, 95.07-99.83%). Similarly, utilizing the frequency-domain analysis method resulted in a sensitivity of 91.6% (95% CI, 86.08-95.46%) and specificity of 94.4% (95% CI, 89.35-97.57%)., Conclusions: These findings suggest that AViTA BPM63B, which integrates two novel algorithms for atrial fibrillation diagnosis, demonstrates high sensitivity and specificity. Utilizing the AViTA BPM63B for BP monitoring could aid in the early detection of atrial fibrillation among outpatients in cardiology clinics., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: ST2 receptor is a member of toll-like/interleukin-1 receptor family. After the activation of IL-33/ST2 signaling pathway clinically detectable amount of soluble form of ST2 (sST2) is released into the circulation. Previous studies showed that sST2 levels were significantly higher in hypertension patients than in controls. In this prospective study, we aimed to analyze this relation and test the predictive accuracy of the sST2 level in diagnosis of nondipping hypertension in newly diagnosed hypertension patients., Methods: Three hundred thirty-seven patients (150 normal, 187 hypertension) who presented with symptoms of hypertension were included in the study. All patients underwent 24-h ambulatory blood pressure monitoring and sST2 measurement., Results: Of 187 hypertension patients, 92 of them had nondipping and 95 of them had dipping pattern. sST2 level was significantly higher in nondipping group compared to dipping group and control group (40.79 ± 7.77 vs. 32.47 ± 6.68; P  < 0.0001 and 40.79 ± 7.77 vs. 20.09 ± 7.09; P  < 0.0001 respectively). Binary logistic regression analysis revealed that; only sST2 level was an independent risk factor for hypertension [ P  < 0.0001, β : 1.258, odds ratio (OR) (95% confidence interval (CI)): 1.158-1.366]. and also nondipping hypertension [ P  < 0.0001, β : 1.208, OR (95% CI): 1.108-1.317]., Conclusion: Based on the present study it could be concluded that sST2 level is significantly associated with the newly diagnosed hypertension and nondipping hypertension. Hence it could reliably be used to diagnose hypertension and nondipping hypertension with high sensitivity and specificity., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Despite their high health care use, it is unclear whether the health care needs of people with MS are being met and what their priorities are. We assessed priorities for access to, and affordability of care, by people living with MS in the United States. We also tested the association between perceived inadequate access to care and health-related quality of life (HRQoL)., Methods: In Fall 2022, we conducted a cross-sectional survey of participants in the North American Research Committee on Multiple Sclerosis Registry about access to care and HRQoL (Health Utilities Index Mark III). We used multivariable polytomous logistic regression to test sociodemographic and clinical factors associated with access to care. We used multivariable linear regression analysis to test the association between access to care and HRQoL., Results: We included 4,914 respondents in the analysis, of whom 3,974 (80.9%) were women, with a mean (SD) age 64.4 (9.9) years. The providers who were most reported as needed but inaccessible were complementary providers (35.5%), followed by allied health providers (24.2%), occupational therapists (22.7%), and mental health providers (20.7%). Over 80% of participants reported that it was important or very important to be able to get an appointment with their primary MS health care provider when needed, to have sufficient time in their appointments to explain their concerns, to see their neurologist if their status changed, and that their health care providers communicated to coordinate their care. Participants who reported needing to see the provider but not having access or seeing the provider but would like to see them more often had lower HRQOL (ranging from -0.059 to -0.176) than participants who saw the provider as much as needed., Discussion: Gaps in access to care persist for people with MS in the United States and substantially affect HRQoL. Improving access to care for people with MS should be a health system priority., Competing Interests: R.A. Marrie receives research funding from CIHR, Research Manitoba, MS Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada. She holds the Waugh Family Chair in Multiple Sclerosis and serves on the editorial board of Neurology. S. Lancia has nothing to disclose. G.R. Cutter serves on Data and Safety Monitoring Boards for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc., Consulting or Advisory Boards for Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Immunic, Immunosis Pty Ltd, Klein-Buendel Incorporated, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, SAB Biotherapeutics. He is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc., a private consulting company located in Birmingham AL. R.J. Fox receives personal consulting fees from AB Science, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Immunic, INmune Bio, Janssen, Lily, Novartis, Sanofi, Siemens, and TG Therapeutics; clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. A. Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program, and is a member of editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), and Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO). She holds the Kenney Marie Dixon‐Pickens Distinguished Professorship in Multiple Sclerosis Research. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Neural crest progenitor cells give rise to neuroblasts, the growing nerve cells of the sympathetic nervous system. These cells can undergo changes leading to neuroblastoma, a malignancy responsible for 15% of all pediatric cancer-related deaths. The molecular pathogenesis of this pediatric cancer involves complex genetic alterations, such as MYCN amplification, chromosomal abnormalities, and gene expression changes. Despite aggressive therapies, survival rates for children with high-risk neuroblastoma (HRNB) have not improved significantly compared to those with less severe forms of the disease. This highlights the challenge of managing HRNB and underscores the need for new, effective treatments. A comprehensive treatment regimen, including immunotherapy, radiation therapy, myeloablative chemotherapy, and surgical removal, has been employed to achieve remission in HRNB patients. While dinutuximab beta immunotherapy is an effective and widely used treatment, it has several potential side effects that must be carefully monitored. New drugs are being developed to reduce these side effects without compromising efficacy. One such drug is DL-alpha-difluoromethylornithine (DFMO), approved by the FDA under the brand name Iwilfin. Numerous clinical trials have shown that DFMO, when used as maintenance therapy, significantly improves event-free survival and overall survival in neuroblastoma patients. However, DFMO has adverse effects that require continuous monitoring. Further research is needed to minimize these side effects and improve its efficacy, particularly in addressing resistance caused by long-term use., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Optimal medical therapy, including Beta-blockers (BB), inhibitors of the renin-angiotensin system (RAS), and statins, is recommended for patients with acute myocardial infarction (AMI) in the absence of contraindications. However, the optimal duration of these medications has not been clearly established in clinical studies. This observational study aimed to investigate the period during which these medications are associated with improved clinical outcomes. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), in-hospital survivors were selected. In a Cox-proportional hazard analysis of 12,200 patients, BB (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.57-0.95; P = .019), RAS inhibitors (HR 0.70; 95% CI = 0.55-0.89; P = .004), and statins at discharge (HR = 0.65; 95% CI = 0.48-0.87; P = .004) were all associated with lower 1-year cardiac mortality. At 1-year, 10,613 patients without all-cause death, myocardial infarction, revascularization, or re-hospitalization due to heart failure were selected for further analysis. RAS inhibitors (HR = 0.53; 95% CI = 0.37-0.76; P = .001) and statins (HR = 0.30; 95% CI = 0.14-0.61; P = .001) prescribed at 1-year were associated with lower 2-year cardiac mortality, whereas BB were not (HR = 0.79; 95% CI = 0.51-1.23; P = .23). However, none of these medications prescribed at 2-years were associated with reduced 3-year cardiac mortality among the 9232 patients who remained event-free until then. RAS inhibitors and statins were associated with reduced cardiac mortality for up to 2-years, and BB for up to 1-year after the initial attack. The effectiveness of these medications beyond these periods remains questionable., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The association between pancreatic exocrine insufficiency (PEI) and morphologic findings in chronic pancreatitis has not yet been fully studied. Thus, the aim of this study was to investigate the correlation between PEI severity and computed tomography (CT)-based morphological severity in patients with chronic pancreatitis. This nationwide survey included 180 Korean participants with chronic pancreatitis aged 18 years or older between January 2018 and December 2021. PEI severity was measured by the PEI questionnaire (PEI-Q). Morphological severity was measured using a CT-based scoring system, which included pancreatic duct caliber, pancreatic duct stricture or intraductal obstructing calculus, pancreatic atrophy, and pancreatic calcification. In addition, 35 patients who received pancreatic enzyme replacement therapy (PERT) were evaluated by PEI-Q to determine whether PEI improved after PERT. PEI severity was normal (n = 89), mild (n = 69), moderate (n = 14), or severe (n = 8). Severities of pancreatic duct caliber and pancreatic duct stricture or intraductal obstructing calculus had small but significant associations with PEI severity (Cramer V = 0.121 and 0.141, respectively). Severities of pancreatic atrophy and pancreatic calcification were not significantly associated with PEI severity. PEI severity showed a significant improvement after PERT (P < .001). In conclusion, PEI severity had significant associations with CT-based morphological severities, including severities of pancreatic duct caliber and pancreatic duct stricture or intraductal obstructing calculus. In addition, PEI-Q could be a useful indicator for evaluating the therapeutic effect of PERT in clinical practice., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Substance use disorders (SUDs) are a significant public health concern across the United States and may pose a risk to achieving sustained viral suppression (SVS) in people with HIV (PWH). This study aims to examine the association between SUDs and SVS among PWH., Design: Using electronic health records from the South Carolina Department of Health, we conducted a retrospective study of adults diagnosed with HIV between January 2006 and December 2019., Methods: The impact of SUDs on SVS was assessed using generalized linear mixed model. Potential confounders included age, sex, chronic diseases history, etc. Stepwise selection was performed to decide the confounders included in the final model, and the optimal correlation structure was determined by Akaike information criterion., Results: Of the 9412 eligible participants, 7481 (79.48%) had reached SVS status during their follow-up periods. SUDs related to alcohol (adjusted odds ratio (AOR) = 1.70, 95% confidence interval (CI): 1.46-1.98), cannabis (AOR = 1.62, 95% CI: 1.35-1.95), cocaine (AOR = 1.95, 95% CI: 1.60-2.37), opioid (AOR = 1.91, 95% CI: 1.13-3.23), and tobacco (AOR = 1.80, 95% CI: 1.69-1.92) were negatively associated with SVS. Individuals with chronic conditions such as cardiovascular disease (AOR=0.31, 95% CI: 0.29-0.33), diabetes (AOR=0.49, 95% CI: 0.41-0.59), and cancer (AOR=0.47, 95% CI: 0.38-0.58) showed a higher likelihood of maintaining SVS., Conclusion: This large cohort study of PWH with extended follow-up highlights the negative impact of SUDs on maintaining SVS. Long-term strategies for reducing substance use could support SVS in HIV patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: With estimated global post-operative mortality rates at 1-4% leading to approximately 3-12 million deaths per year, an urgent need exists for reliable measures of perioperative risk. Existing approaches suffer from poor performance, place a high burden on clinicians to gather data, or do not incorporate intraoperative data. Prior work demonstrated that intraoperative anesthetics induce prefrontal EEG oscillations in the alpha band (8-12Hz) that correlate with post-operative cognitive outcomes., Methods: We analyzed a retrospective cohort of 1,081 patients undergoing surgery with general anesthesia at Massachusetts General Hospital with intraoperative EEG recordings. The association between EEG alpha power and adverse outcomes were characterized using statistical models that were fitted on propensity weighted data. Our primary outcome was post-operative mortality, measured from date of surgery to date of death or last follow-up. Secondary outcomes included mortality within pre-specified time windows (30-days, 90-days, 180-days, and 1-year), hospital and PACU lengths of stay, discharge to long-term care, and 30-day hospital readmission., Results: Alpha power was associated with mortality risk (HR = 0.92, 95% CI:[ 0.85, 0.99], p=0.039). Within specified time windows, alpha power was associated with 30-day mortality (OR = 0.81, 95% CI: [0.66, 0.95], p=0.010), 90-day mortality (OR = 0.68, 95% CI: [0.55, 0.79], p<0.001), 180-day mortality (OR = 0.75, 95% CI: [0.66, 0.83], p<0.001), and 1-year mortality (OR = 0.85, 95% CI: [0.79, 0.91], p<0.001). Additionally, alpha power was associated with discharge to long-term care (OR = 0.91, 95% CI: [0.86, 0.96], p<0.001). We did not find significant associations among alpha power and 30-day readmission and hospital or PACU lengths of stay., Conclusions: Intraoperative EEG alpha power is independently associated with post-operative mortality and adverse outcomes, suggesting it could represent a broad measure of post-operative physical resilience and provide clinicians with a low-burden, personalized measure of post-operative risk., Competing Interests: Declarations of Interest: PLP is a co-founder of PASCALL Systems, Inc., a start-up company developing closed-loop physiological control systems for anesthesiology. All other authors declare that they have no conflicts of interest., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Hypertrophic cardiomyopathy (HCM) is a prevalent cardiac condition that often leads to heart failure, exertional syncope, and sudden cardiac death. Despite the availability of various treatments for HCM, such as septal reduction therapy through surgical septal myectomy or alcohol septal ablation (ASA), disparities in access to care and treatment outcomes persist, particularly among marginalized racial and ethnic groups. These disparities underscore the importance of understanding the influence of race, ethnicity, and regional factors on the management and outcomes of HCM, necessitating a closer examination of whether access to ASA and its associated benefits is equitably distributed across diverse populations. A comprehensive literature search was conducted on various electronic databases aimed to identify studies evaluating the odds of undergoing ASA in HCM in racial subgroups and outcomes like all-cause mortality and stroke. Three studies were included in this meta-analysis with a total sample size of 24,939 HCM patients. Adjusted odds ratio (OR) or pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. Blacks were significantly less likely to undergo ASA for HCM (OR, 0.64; 95% CI, 0.57-0.72; P < 0.01) as compared to white patients; however, no differences in all-cause mortality (RR, 0.97; 95% CI, 0.54-1.75) and stroke (RR, 1.29; 95% CI, 0.76-2.18) were noted. In conclusion, this meta-analysis highlights a significant association between race and the likelihood of undergoing ASA among patients with HCM, with minority racial groups potentially facing barriers to accessing this advanced treatment., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the use of non-barrier contraceptives among women with HIV (WWH) compared to women from the general population (WGP) in Denmark., Design: Nationwide population-based matched cohort study., Methods: We included WWH aged 16-50, treated at an HIV specialized clinic, and included in The Danish HIV Cohort Study between 1995-2021 and an age-matched comparison cohort of WGP. We examined use of hormonal contraception (HC), intrauterine devices (IUD), and sterilization from 10 years before to 20 years after study inclusion. Additionally, we calculated age-standardized proportions and incidences over calendar time., Results: We included 1,720 WWH and 17,720 WGP. Median age was 33 years and almost half of WWH had African origin (41%). Non-barrier contraceptive use was lower among WWH (8.5%) compared to WGP (32.1%) at study inclusion. Before and after inclusion, WWH had nearly half the non-barrier contraceptive use of WGP, with notably lower HC and IUD use. Initially, fewer WWH were sterilized, but five years after inclusion, sterilization became the preferred method among WWH. HC use increased among WWH after 2010 but decreased among WGP after 2005. IUD use increased among both groups during 1995-2021 but remained lower among WWH. Incidence of sterilizations remained stable in both groups., Conclusion: Use of non-barrier contraceptives was lower among WWH compared to WGP. For WWH, sterilization became the preferred non-barrier method few years after study inclusion. HC and IUD use increased among WWH after 2010 but remained lower than for WGP. Improved contraceptive counseling is recommended to support reproductive health among WWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

How frequent and whether outcomes are worse for patients with atypical presentation in acute coronary syndrome (ACS) across the literature is not known. We conducted a systematic review of the literature on patients with ACS or acute myocardial infarction who reported whether their symptoms were atypical or typical. We determined the proportion of patients with atypical or no chest pain and used meta-analysis to evaluate predictors of atypical presentation and mortality associated with atypical presentation. A total of 43 studies were included with 1 691 401 patients (mean age: 65.4 years, 63.8% male). The proportion of patients with atypical presentation ranged from 4.6 to 74.2% while for those with no chest pain it ranged from 1.4 to 35.5%. Atypical presentation occurred in 11.6% of patients (28 studies) and no chest pain occurred in 33.6% of patients (16 studies). The three strongest factors associated with increased odds of atypical presentation or no chest pain presentation were non-ST-elevation myocardial infarction [odds ratio (OR): 2.38, 95% confidence interval (CI): 1.55-3.64], greater Killip class (OR: 2.22, 95% CI: 1.84-2.67), and prior heart failure (OR: 1.79, 95% CI: 1.76-1.82). There is a two-fold increase in odds of mortality with atypical or no chest pain presentation in ACS compared with the typical presentation (OR: 2.07, 95% CI: 1.71-2.50, I2 = 9%). Atypical presentation occurs in approximately 1 in 10 patients with ACS but can be as high as 1 in 3 in some populations. Patients who present atypically are at two-fold increased risk of mortality., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Mounting evidence points to a strong connection between cardiovascular risk during middle age and brain health later in life. The American Heart Association's Life's Essential 8 (LE8) constitutes a research and public health construct capturing key determinants of cardiovascular health. However, the overall effect of the LE8 on global, clinically relevant metrics of brain health is still unknown. We tested the hypothesis that worse LE8 profiles are associated with higher composite risk of the most important clinical endpoints related to poor brain health., Methods: We conducted a two-stage (discovery and replication) prospective study using data from the UK Biobank (UKB) and All of Us (AoU), 2 large population studies in the United Kingdom and the United States, respectively. The primary exposure was the LE8 score, a validated tool that captures 8 modifiable cardiovascular risk factors (blood pressure, glucose, cholesterol, body mass index, smoking, physical activity, diet, and sleep duration), organized in 3 categories (optimal, intermediate, and poor). The primary outcome was a composite of stroke, dementia, or late-life depression. We evaluated associations using multivariable Cox proportional hazard models., Results: The discovery stage included 316,127 UKB participants (mean age 56, 52% female). Over a mean (SD) follow-up time of 4.9 (0.4) years, the unadjusted risk of the composite outcome was 0.7% (95% CI 0.61-0.74), 1.2% (95% CI 1.11-1.22), and 1.8% (95% CI 1.70-1.91) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health hazard ratio [HR], 1.37; 95% CI 1.24-1.52, and poor vs optimal cardiovascular health HR, 2.11; 95% CI 1.88-2.36, p trend <0.001). The replication stage included 68,407 AoU participants (mean age 56, 60% female). Over a mean (SD) follow-up time of 2.9 (1.41) years, the unadjusted risk of the composite outcome was 2.8% (95% CI 2.49-3.05), 6% (95% CI 5.76-6.22), and 9.7% (95% CI 9.24-10.24) in participants with optimal, intermediate, and poor cardiovascular health, respectively ( p < 0.001). This association remained significant in multivariable Cox models (intermediate vs optimal cardiovascular health, HR 1.35; 95% CI 1.21-1.51, and poor vs optimal cardiovascular health, HR 1.94; 95% CI 1.72-2.18; p trend <0.001)., Discussion: Among middle-aged adults enrolled in 2 large population studies, poor cardiovascular health profiles were associated with two-fold higher risk of developing a composite outcome that captures the most important diseases related to poor brain health. Because the evaluated risk factors are all modifiable, our findings highlight the potential brain health benefits of using the Life's Essential 8 to guide cardiovascular health optimization.

Objectives: This study aimed to identify the prevalence of and factors associated with diagnostic uncertainty when critically ill children are admitted to the PICU. Understanding diagnostic uncertainty is necessary to develop effective strategies to reduce diagnostic errors in the PICU., Design: Multicenter retrospective cohort study with structured medical record review by trained clinicians using a standardized instrument to identify diagnostic uncertainty in narrative clinical notes. Diagnoses and diagnostic uncertainty were compared across time from PICU admission to hospital discharge. Generalized linear mixed models were used to determine patient, clinician, and encounter characteristics associated with diagnostic uncertainty at PICU admission., Setting: Four academic tertiary-referral PICUs., Patients: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs., Interventions: None., Measurements and Main Results: PICU admission notes for 228 of 882 patients (25.9%) indicated diagnostic uncertainty. Patients with uncertainty decreased over time but 58 (6.6%) had remaining diagnostic uncertainty at hospital discharge. Multivariable analysis showed that diagnostic uncertainty was significantly associated with off hours admission (odds ratio [OR], 1.52; p = 0.037), greater severity of illness (OR, 1.04; p = 0.025), an atypical presentation (OR, 2.14; p = 0.046), diagnostic discordance at admission between attending intensivists and resident physicians/advanced practice providers (OR, 3.62; p < 0.001), and having a neurologic primary diagnosis (OR, 1.87; p = 0.03). Older patients (OR, 0.96; p = 0.014) and those with a respiratory (OR, 0.58; p = 0.009) or trauma primary diagnosis (OR, 0.08; p < 0.001) were less likely to have diagnostic uncertainty. There were no significant associations between diagnostic uncertainty and attending intensivists' characteristics., Conclusions: Diagnostic uncertainty at PICU admission was common and was associated with off hours admission, severe illness, atypical presentation, diagnostic discordance between clinicians, and a neurologic primary diagnosis. Further study on the recognition and management of diagnostic uncertainty is needed to inform interventions to improve diagnosis among critically ill children., Competing Interests: Dr. Landrigan has consulted with and holds equity in the I-PASS (Handoff elements mnemonic: I-illness severity, P-patient summary, A-action items, S-situation awareness, S-synthesis) Institute, which seeks to train institutions in best handoff practices and aid in their implementation. In addition, Dr. Landrigan has received monetary awards, honoraria, and travel reimbursement from multiple academic and professional organizations for teaching and consulting on sleep deprivation, physician performance, handoffs, and safety; he has served as an expert witness in cases regarding patient safety and sleep deprivation; and he received funding from the Agency for Healthcare Research and Quality (AHRQ). Drs. Cifra’s, K. A. Smith’s, Bloxham’s, Hoppe’s, Miller’s, Riffe’s, Robb’s, Simone’s, Tumulty’s, Dawson’s, and Herwaldt’s institutions received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the AHRQ, and the National Center for Advancing Translational Sciences. Drs. Cifra, Bloxham, Miller, and Tumulty received funding from the AHRQ, MedStar Research Institute, and De Gruyter. Drs. Cifra, C. M. Smith, K. A. Smith, Bagdure, Bloxham, Goldhar, Hoppe, Miller, Pizzo, Riffe, Robb, Tumulty, Wolfe, Wendt, Eyck, Dawson, Reisingerr, Singh, and Herwaldt received support for article research from the National Institutes of Health. Dr. Gorga disclosed institutional grant funding. Dr. Ten Eyck disclosed work for hire. Dr. Dawson received funding from Neurosurgery, the University of Nebraska Medical Center, and IotaSoft. Dr. Singh is supported in part by the AHRQ (R01HS028595 and R18HS029347), the Houston Veterans Administration (VA) Health Services Research and Development Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413), and the VA National Center for Patient Safety; he disclosed government work. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of the VA or the U.S. government. Dr. Herwaldt’s institution received funding from the Centers for Disease Control and Prevention. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Cardiomyocytes in the adult human heart show a regenerative capacity, with an annual renewal rate of ≈0.5%. Whether this regenerative capacity of human cardiomyocytes is employed in heart failure has been controversial., Methods: We determined cardiomyocyte renewal in 52 patients with advanced heart failure, 28 of whom received left ventricular assist device support. We measured the concentration of nuclear bomb test-derived 14 C in cardiomyocyte genomic DNA and performed mathematical modeling to establish cardiomyocyte renewal in heart failure with and without LVAD unloading., Results: We show that cardiomyocyte generation is minimal in end-stage heart failure patients at rates 18 to 50× lower compared with the healthy heart. However, patients receiving left ventricle support device therapy, who showed significant functional and structural cardiac improvement, had a >6-fold increase in cardiomyocyte renewal relative to the healthy heart., Conclusions: Our findings reveal a substantial cardiomyocyte regeneration potential in human heart disease, which could be exploited therapeutically.

Competing Interests: The authors have no conflicts of interest to declare.

Competing Interests: The authors have no conflicts of interest to declare.

Competing Interests: The authors have no conflicts of interest to declare.

Purpose: In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents., Methods: Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014-2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov., Results: Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies., Conclusions: The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)