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Herpesviruses, including α-herpesvirus and herpes simplex virus (HSV-1), are masters of immune evasion. Previously we demonstrated that CD1d-restricted NKT cells are required for optimal anti-HSV-1 immune responses and HSV-1 efficiently downregulates CD1d to suppress NKT cell function. To delineate how the virus evades NKT cell function and establishes infection in vivo , we screened an HSV-1 expression library to identify the viral gene(s) downregulating CD1d and discovered that a leaky late gene, UL56, most efficiently suppresses CD1d expression by degrading the protein, apparently via both proteasome- and lysosome-dependent pathways. To investigate the molecular mechanism of UL56 suppression of CD1d expression, we purified and identified UL56-associated proteins by mass spectrometry. The most abundant associated proteins were members of NEDD4 E3 ubiquitin ligase family. Interestingly overexpression of one member, NEDD4L is sufficient to downregulate CD1d expression. However, different from the K5 protein from Kaposi sarcoma's herpesvirus (KSHV), UL56 and NEDD4L did not directly ubiquitinate CD1d. CD1d protein lacking the key lysine residue in its cytoplasmic tail is similarly downregulated by UL56 and NEDD4L protein. Co-expression of UL56 and NEDD4L synergistically reduced the CD1d expression, suggesting that UL56 collaborates with NEDD4L to downregulate CD1d. During in vivo infection, UL56-deficient mutant virus showed significantly weaker virulence in NKT-sufficient mice but demonstrated higher virulence in mutant mice lacking NKT cells. All our results supported that at least one of the pathogenesis functions of UL56 is its suppression of NKT cell function during infection., Importance: In the large DNA genomes of herpeviruses, there are many genes encoding associate proteins. Most of these proteins are not essential for viral replication but play key roles in viral pathogenesis, in particular, modulating the host immune system to allow efficient viral replication in vivo and latency. The HSV-1 UL56 gene is one of such genes, and its exact pathogenic roles have remain elusive. After we demonstrated the essential roles of CD1d-restricted NKT cells in anti-HSV-1 immunity during HSV-1 ocular infection (P. Rao, X. Wen, J. H. Lo, S. Kim, X. Li, et al., J Virol 92:e01490-18, 2018, https://doi.org/10.1128/jvi.01490-18), we now screened the HSV-1 expression library and identified UL56 is a key factor downregulating CD1d and suppressing NKT cell function. In this manuscript, we are reporting our molecular mechanism study of how UL56 evades CD1d antigen presentation and NKT cell function.

Bone fractures due to osteoporosis are a significant problem. Limited accuracy of standard bone mineral density (BMD) for fracture risk assessment, combined with low adherence to bone health screening precludes identification of those at risk of fracture. Because of the wide availability of digital breast tomosynthesis (DBT) imaging, bone screening using a DBT scanner at the time of breast screening has been proposed. Earlier studies have shown that BMD, microstructure, and stiffness of the distal radius can be calculated using digital tomosynthesis imaging of the wrist (DWT). However, strength and stress/strain parameters, which are more relevant to structural failure, and have the potential to enhance the utility of DWT, were not examined previously. Therefore, this study aimed to examine the ability of DWT to discriminate patients with and without fragility fracture using DWT based finite element (DWT-FE) derived strength and stress/strain distribution properties, and to determine in vivo repeatability of these biomechanical properties. Twenty-two postmenopausal women with any fragility fracture (included spine, hip, distal radius, humerus and tibia fractures) and 68 without were recruited. Each participant's nondominant arm (dominant arm if history of fracture in the nondominant arm) was scanned with DWT and compressive loading was simulated using FE modeling. Six additional patients were DWT-scanned thrice, with repositioning, to determine the repeatability of the study variables. Age and T-score were not different between fracture and nonfracture groups (p > 0.1), but strength and stress/strain parameters were significant predictors of fracture status (AUC = 0.64-0.74). Standard deviation of tensile strain was the most discriminatory variable for fracture status (AUC = 0.74) and was independent from stiffness. Repeatability error of DWT biomechanical properties was 0.7 % to 5.8 %. This study demonstrated that DWT-FE based strength and standard deviation of tensile strain were reproducible and predict fracture status independent from BMD and stiffness. The results suggest that the accuracy of fracture risk screening can be improved in the highly accessible environment of mammographic imaging., Competing Interests: Declaration of competing interest All authors confirm that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The impact of cardiac resynchronization therapy (CRT) in patients receiving durable left ventricular assist device (LVAD) implantation remains unclear and there is no consensus regarding postoperative management. We sought to determine the impact of postoperative management of CRT on clinical outcomes following LVAD implantation. A total of 789 patients underwent LVAD implantation at our institution from 2007 to 2022 including 195 patients (24.7%) with preoperative CRT. Patients with preoperative CRT were significantly older and more frequently received an LVAD as destination therapy compared to patients without preoperative CRT. After LVAD implantation, 85 patients had CRT programmed "off" and 74 patients had CRT programmed "on." The risk of mortality was significantly increased amongst patients with preoperative CRT that was turned "on" following LVAD implantation compared to patients with preoperative CRT turned "off" following implant (subdistribution hazard ratio [sdHR] = 1.54; 1.06-2.37 95% confidence interval [CI]; p = 0.036). There was no significant difference between incidence of ventricular arrhythmias in patients with and without postoperative CRT "on" (35.1% vs . 48.2%; p = 0.095). Additional clinical trials are warranted to determine the best CRT programming strategy following LVAD implantation., Competing Interests: Disclosure: F.H.S. has received institutional research support and honorarium for educational conferences from Abbott. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Vertebral fractures are a common and debilitating consequence of osteoporosis. Bone mineral density (BMD), measured by dual energy x-ray absorptiometry (DXA), is the clinical standard for assessing overall bone quantity but falls short in accurately predicting vertebral fracture. Fracture risk prediction may be improved by incorporating metrics of microstructural organization from an appropriate imaging modality. Digital tomosynthesis (DTS)-derived textural and microstructural parameters have been previously correlated to vertebral bone strength in vitro, but the in vivo utility has not been explored. Therefore, the current study sought to establish the extent to which DTS-derived measurements of vertebral microstructure and size discriminate patients with and without vertebral fracture. In a cohort of 93 postmenopausal women with or without history of vertebral fracture, DTS-derived microstructural parameters and vertebral width were calculated for T12 and L1 vertebrae, as well as lumbar spine BMD and trabecular bone score (TBS) from DXA images. Fracture patients had lower BMD and TBS, while DTS-derived degree of anisotropy and vertebral width were higher, compared to nonfracture (p < 0.02 to p < 0.003) patients. The addition of DTS-derived parameters (fractal dimension, lacunarity, degree of anisotropy and vertebral width) improved discriminative capability for models of fracture status (AUC = 0.79) compared to BMD alone (AUC = 0.67). For twelve additional participants who were imaged twice, in vivo repeatability errors for DTS parameters were low (0.2 % - 7.3 %). The current results support the complementary use of DTS imaging for assessing bone quality and improving the accuracy of fracture risk assessment beyond that achievable by DXA alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Primary hyperparathyroidism (PHPT), the third most common endocrine disorder, was so eloquently described first by Fuller Albright as a polymorphic condition in his classic paper and monograph as early as 1934. Over the decades, the clinical presentation of PHPT in developed countries has shifted significantly from a disease primarily affecting the bones and kidneys to an asymptomatic condition often discovered incidentally. In developing countries, the high prevalence of vitamin D deficiency is one of the main factors influencing the clinical presentation of PHPT. In Europe and North America, PHPT is predominantly asymptomatic. In South America, China, and Eastern parts of Europe, such as Turkey, Bulgaria, and Russia, there is an ongoing transition from symptomatic to asymptomatic cases. Asia shows variability: symptomatic cases dominate in the Indian subcontinent, Middle East, and Southeast Asia, while transitional patterns with predominant asymptomatic cases have now been reported in China, and Japan reports mostly asymptomatic cases. Factors influencing these changes include advancements in diagnostic technologies, detection of incidental parathyroid adenomas during thyroid ultrasonography, regional differences in vitamin D deficiency, dietary habits, and genetic polymorphisms in vitamin D and calcium-sensing receptors. A higher prevalence of nephrolithiasis in certain climates contributes to regional variations. This review examines the dynamic nature of PHPT's clinical presentation, shaped by geographic, genetic, and environmental influences. Also, this review highlights the importance of addressing global disparities in an attempt to optimize patient outcomes., (Copyright © 2025. Published by Elsevier Ltd.)

Background: In critically ill patients, delirium is a prognostic indicator of morbidity and mortality., Objective: This study investigates the impact of a delirium diagnosis on outcomes after left ventricular assist device (LVAD) implantation., Methods: This retrospective study included all adult patients who received LVADs at our institution between January 2016 and December 2020. We compared preimplantation characteristics between the two groups, with and without a diagnosis of delirium, and compared their outcomes, including 1-month, 6-month, and in-hospital mortality, as well as reintubation rate, length of stay, discharge disposition, and readmission rates., Results: In total, 361 patients (26.7% women and 75.8% African American) received durable LVADs. Ninety-four patients (26.1%) were diagnosed with delirium during the index admission. Preimplantation demographic characteristics, past medical and psychiatric conditions, Interagency Registry for Mechanically Assisted Circulatory Support Profile, and laboratory values did not differ between the two groups with and without a diagnosis of delirium; older age (59 vs 56; P = 0.03) was associated with delirium. Delirium diagnosis was associated with higher 1-month (P = 0.007), 6-month (P = 0.004), and in-hospital mortality (P < 0.001), unplanned reintubations (P < 0.001), and a lower likelihood of discharge home (P = 0.03). Total hospital and intensive care unit length of stay were higher in patients with a diagnosis of delirium, though these results were not statistically significant. Readmission to the hospital after index admission was quicker in patients with a diagnosis of delirium, but this result was not statistically significant., Conclusions: In this study, a diagnosis of delirium during the LVAD implantation admission was associated with higher mortality, adverse postsurgical outcomes, and unfavorable discharge dispositions. Future prospective research is needed to validate the prognostic implications of delirium in both the short and long term. Additionally, there is a need to identify modifiable risk factors associated with delirium to promote early diagnosis and implement evidence-based management strategies to enhance outcomes within this population., (Copyright © 2024 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Reduced bone mineral density (BMD) and microarchitectural deterioration contribute to increased fracture risk. Although the effects of anti-fracture medications (AFMs) on BMD are well-documented, their impact on bone material properties (BMPs) remains poorly characterized. Accordingly, we conducted a systematic review and meta-analysis to evaluate the effects of AFMs on BMPs. Based on data availability, we further categorized AFMs into anti-resorptives, bisphosphonates alone, and strontium ranelate subgroups to perform additional analyses of BMPs in osteoporotic patients., Methods: We did a comprehensive search of three databases, namely, PubMed, Web of Science, and Google Scholar, using various permutation combinations, and used Comprehensive Meta-Analysis software to analyze the extracted data., Results: The 15 eligible studies (randomized and non-randomized) compared the following: (1) 301 AFM-treated patients with 225 on placebo; (2) 191 patients treated with anti-resorptives with 131 on placebo; (3) 86 bisphosphonate-treated patients with 66 on placebo; and (4) 84 strontium ranelate-treated patients with 70 on placebo. Pooled analysis showed that AFMs significantly decreased cortical bone crystallinity [standardized difference in means (SDM) -1.394] and collagen maturity [SDM -0.855], and collagen maturity in cancellous bone [SDM -0.631]. Additionally, anti-resorptives (bisphosphonates and denosumab) significantly increased crystallinity [SDM 0.387], mineral-matrix ratio [SDM 0.771], microhardness [SDM 0.858], and contact hardness [SDM 0.952] of cortical bone. Anti-resorptives increased mineral-matrix ratio [SDM 0.543] and microhardness [SDM 0.864] and decreased collagen maturity [SDM -0.539] in cancellous bone. Restricted analysis of only bisphosphonate-treated studies showed a significant decrease in collagen maturity [SDM -0.650] in cancellous bone and an increase in true hardness [SDM 1.277] in cortical bone. In strontium ranelate-treated patients, there was no difference in BMPs compared to placebo., Conclusion: Collectively, our study suggests that AFMs improve bone quality, which explains their anti-fracture ability that is not fully accounted for by increased BMD in osteoporosis patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sharma, Shankar, Rajender, Mithal, Rao and Chattopadhyay.)

Background: Although sustained ventricular arrhythmias (VAs) are a common complication after durable left ventricular assist device (LVAD) implantation, the incidence, risk factors, and prognostic implications of postoperative early VAs (EVAs) in contemporary patients with LVAD are poorly understood., Methods and Results: A single-center retrospective analysis was performed of patients who underwent LVAD implantation from October 1, 2006, to October 1, 2022. EVA was defined as an episode of sustained VA identified ≤30 days after LVAD implantation. A total of 789 patients underwent LVAD implantation (mean age 62.9 ± 0. years 5, HeartMate 3 41.4%, destination therapy 43.3%). EVAs occurred in 100 patients (12.7%). A history of end-stage renal disease (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.45-21.70), preoperative electrical storm (OR 2.82, 95% CI 1.11-7.16), and appropriate implantable cardiac defibrillator therapy before implantation (OR 2.8, 95% CI 1.26-6.19) are independently associated with EVAs. EVA was associated with decreased 30-day survival (hazard ratio 3.02, 95% CI 1.1-8.3, P = .032). There was no difference in transplant-free survival time between patients with and without EVAs (hazard ratio 0.82, 95% CI 0.5-1.4, P = .454)., Conclusions: EVAs are common after durable LVAD implantation and are associated with an increased risk of 30-day mortality., Competing Interests: CONFLICT OF INTEREST Farooq H. Sheikh reports institutional research support and honorarium for speaking at educational conferences from Abbott. No company or agency had any role in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atypical femur fractures (AFFs) are a well-established complication of long-term bisphosphonate (BP) therapy, but their pathogenesis is not fully understood. Although many patients on long-term BP therapy have severe suppression of bone turnover (SSBT), not all such patients experience AFF, even though SSBT is a major contributor to AFF. Accordingly, we evaluated tissue level properties using nano-scratch testing of trans-iliac bone biopsy specimens in 12 women (6 with and 6 without AFF matched for age and race). Nano-scratch data were analyzed using a mixed-model ANOVA with volume-normalized scratch energy as a function of AFF (Yes or No), region (periosteal or endosteal), and a first-order interaction between region and AFF. Tukey post hoc analyses of the differences of least squared means of scratch energy were performed and reported as significant if p <.05. The volume-normalized scratch energy was 10.6% higher in AFF than in non-AFF patients ( p =.003) and 17.9 % higher in the periosteal than in the endosteal region ( p =.004). The differences in normalized scratch energy are suggestive of a higher hardness of the bone tissue after long-term BP therapy. The results of this study are consistent with other studies in the literature and demonstrate the efficacy of using Nano-Scratch technique to evaluate bone tissue that exhibits SSBT and AFF. Further studies using nano-scratch may help quantify and elucidate underlying mechanisms for the pathogenesis of AFF., Competing Interests: None of the authors have any conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain., Objective: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing., Methods: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D., Results: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity., Conclusion: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2 -/- ) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2 -/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH., (© 2024. The Author(s).)

Background: Invasive hemodynamics are fundamental in assessing patients with advanced heart failure (HF). Several novel hemodynamic parameters have been studied; however, the relative prognostic potential remains ill-defined., Hypothesis: Advanced hemodynamic parameters provide additional prognostication beyond the standard hemodynamic assessment., Methods: Patients from the PRognostic Evaluation During Invasive CaTheterization for Heart Failure (PREDICT-HF) registry who underwent right heart catheterization (RHC) were included in the analysis. The primary endpoint was survival to orthotopic heart transplant (OHT) or durable left ventricular assist device (LVAD), or death within 6 months of RHC., Results: Of 846 patients included, 176 (21%) met the primary endpoint. In a multivariate model that included traditional hemodynamic variables, pulmonary capillary wedge pressure (PCWP) (OR: 1.10, 1.04-1.15, p < .001), and cardiac index (CI) (OR: 0.86, 0.81-0.92, p < .001) were shown to be predictive of adverse outcomes. In a separate multivariate model that incorporated advanced hemodynamic parameters, cardiac power output (CPO) (OR: 0.76, 0.71-0.83, p < .001), aortic pulsatility index (API) (OR: 0.94, 0.91-0.96, p < .001), and pulmonary artery pulsatility index (OR: 1.02, 1.00-1.03, p .027) were all significantly associated with the primary outcome. Positively concordant API and CPO afforded the best freedom from the endpoint (94.7%), whilst negatively concordant API and CPO had the worst freedom from the endpoint (61.5%, p < .001). Those with discordant API and CPO had similar freedom from the endpoint., Conclusion: The advanced hemodynamic parameters API and CPO are independently associated with death or the need for OHT or LVAD within 6 months. Further prospective studies are needed to validate these parameters and elucidate their role in patients with advanced HF., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n = 20) and without (n = 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17 yr. Despite the matched range of treatment duration (4-17 yr), AFF patients received alendronate for significantly longer time (10.7 yr) than non-AFF patients (8.0 yr) (P = .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6 mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Sheehan's syndrome (SS) is a rare but well-characterized cause of hypopituitarism. Data on skeletal health is limited and on microarchitecture is lacking in SS patients., Purpose: We aimed to explore skeletal health in SS with bone mineral density (BMD), turnover, and microarchitecture., Methods: Thirty-five patients with SS on stable replacement therapy for respective hormone deficiencies and 35 age- and BMI-matched controls were recruited. Hormonal profile and bone turnover markers (BTMs) were measured using electrochemiluminescence assay. Areal BMD and trabecular bone score were evaluated using DXA. Bone microarchitecture was assessed using a second-generation high-resolution peripheral quantitative computed tomography., Results: The mean age of the patients was 45.5 ± 9.3 years with a lag of 8.3 ± 7.2 years prior to diagnosis. Patients were on glucocorticoid (94%), levothyroxine (94%), and estrogen-progestin replacement (58%). None had received prior growth hormone (GH) replacement. BTMs (P1NP and CTX) were not significantly different between patients and controls. Osteoporosis (26% vs. 16%, p = 0.01) and osteopenia (52% vs. 39%, p = 0.007) at the lumbar spine and femoral neck (osteoporosis, 23% vs. 10%, p = 0.001; osteopenia, 58% vs. 29%, p = 0.001) were present in greater proportion in SS patients than matched controls. Bone microarchitecture analysis revealed significantly lower cortical volumetric BMD (vBMD) (p = 0.02) at the tibia, with relative preservation of the other parameters., Conclusion: Low areal BMD (aBMD) is highly prevalent in SS as compared to age- and BMI-matched controls. However, there were no significant differences in bone microarchitectural measurements, except for tibial cortical vBMD, which was lower in adequately treated SS patients., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Despite effective therapies for those at risk of osteoporotic fracture, low adherence to screening guidelines and limited accuracy of bone mineral density (BMD) in predicting fracture risk preclude identification of those at risk. Because of high adherence to routine mammography, bone health screening at the time of mammography using a digital breast tomosynthesis (DBT) scanner has been suggested as a potential solution. BMD and bone microstructure can be measured from the wrist using a DBT scanner. However, the extent to which biomechanical variables can be derived from digital wrist tomosynthesis (DWT) has not been explored. Accordingly, we measured stiffness from a DWT based finite element (DWT-FE) model of the ultra-distal (UD) radius and ulna, and correlate these to reference microcomputed tomography image based FE (μCT-FE) from five cadaveric forearms. Further, this method is implemented to determine in vivo reproducibility of FE derived stiffness of UD radius and demonstrate the in vivo utility of DWT-FE in bone quality assessment by comparing two groups of postmenopausal women with and without a history of an osteoporotic fracture (Fx; n = 15, NFx; n = 51). Stiffness obtained from DWT and μCT had a strong correlation (R 2  = 0.87, p < 0.001). In vivo repeatability error was <5 %. The NFx and Fx groups were not significantly different in DXA derived minimum T-scores (p > 0.3), but stiffness of the UD radius was lower for the Fx group (p < 0.007). Logistic regression models of fracture status with stiffness of the nondominant arm as the predictor were significant (p < 0.01). In conclusion this study demonstrates the feasibility of fracture risk assessment in mammography settings using DWT imaging and FE modeling in vivo. Using this approach, bone and breast screening can be performed in a single visit, with the potential to improve both the prevalence of bone health screening and the accuracy of fracture risk assessment., Competing Interests: Declaration of competing interest The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Invasive hemodynamic measurement via right heart catheterization has shown divergent data in its role in the treatment of patients with heart failure (HF) and cardiogenic shock. We hypothesized that variation in data acquisition technique and interpretation might contribute to these observations. We sought to assess differences in hemodynamic acquisition and interpretation by operator subspecialty as well as level of experience., Methods and Results: Individual-level responses to how physicians both collect and interpret hemodynamic data at the time of right heart catheterization was solicited via a survey distributed to international professional societies in HF and interventional cardiology. Data were stratified both by operator subspecialty (HF specialists or interventional cardiologists [IC]) and operator experience (early career [≤10 years from training] or late career [>10 years from training]) to determine variations in clinical practice. For the sensitivity analysis, we also look at differences in each subgroup. A total of 261 responses were received. There were 141 clinicians (52%) who self-identified as HF specialists, 99 (38%) identified as IC, and 20 (8%) identified as other. There were 142 early career providers (54%) and late career providers (119 [46%]). When recording hemodynamic values, there was considerable variation in practice patterns, regardless of subspecialty or level of experience for the majority of the intracardiac variables. There was no agreement or mild agreement among HF and IC as to when to record right atrial pressures or pulmonary capillary wedge pressures. HF cardiologists were more likely to routinely measure both Fick and thermodilution cardiac output compared with IC (51% vs 29%, P < .001), something mirrored in early career vs later career cardiologists., Conclusions: Significant variation exists between the acquisition and interpretation of right heart catheterization measurements between HF and IC, as well as those early and late in their careers. With the growth of the heart team approach to management of patients in cardiogenic shock, standardization of both assessment and management practices is needed., Competing Interests: Declaration of Competing Interests Financial Disclosure: Statistical funding via UChicago Cardiology Data Science Gift. JG is a speaker for Abbott. ADD reports research funding through his institution from the American Heart Association, Biofourmis, Bodyport, Cytokinetics, American Regent, Inc, the NHLBI, Novartis, and Story Health. He also provides consulting services for and/or receives honoraria from Abiomed, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll. He has also received nonfinancial support from Abbott for educational and research activities. All other authors have no relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Compromised bone structural and mechanical properties are implicated in the increased fracture risk in type 1 diabetes (T1D). We investigated bone structure and turnover by histomorphometry in postmenopausal women with T1D and controls without diabetes using tetracycline double-labeled transiliac bone biopsy. After in vivo tetracycline double labeling, postmenopausal women with T1D of at least 10 years and without diabetes underwent transiliac bone biopsy. An expert blinded to the study group performed histomorphometry. Static and dynamic histomorphometry measurements were performed and compared between the two groups. The analysis included 9 postmenopausal women with T1D (mean age 58.4 ± 7.1 years with 37.9 ± 10.9 years of diabetes and HbA1c 7.1% ± 0.4%) and 7 postmenopausal women without diabetes (mean age 60.9 ± 3.3 years and HbA1c 5.4% ± 0.2%). There were no significant differences in serum PTH (38.6 ± 8.1 versus 51.9 ± 23.9 pg/mL), CTX (0.4 ± 0.2 versus 0.51 ± 0.34 ng/mL), or P1NP (64.5 ± 26.2 versus 87.3 ± 45.3 ng/mL). Serum 25-hydroxyvitamin D levels were higher in T1D than in controls (53.1 ± 20.8 versus 30.9 ± 8.2 ng/mL, p  < 0.05). Bone structure metrics (bone volume, trabecular thickness, trabecular number, and cortical thickness) were similar between the groups. Indices of bone formation (osteoid volume, osteoid surface, and bone formation rate) were 40% lower in T1D and associated with lower activation frequency. However, the differences in bone formation were not statistically significant. Long-standing T1D may affect bone turnover, mainly bone formation, without significantly affecting bone structure. Further research is needed to understand bone turnover and factors affecting bone turnover in people with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

Awake patients in ventricular fibrillation is a phenomenon limited to patients who are mechanically supported. We describe a cohort of patients supported by left ventricular assist devices (LVADs) presenting to the emergency department (ED) at a high-volume LVAD center while in awake ventricular fibrillation (VF)/ventricular tachycardia (VT). Among 175 patients reviewed, a total of 19 LVAD patients presented to the ED in awake VF/VT between December 2015 and July 2021. On ED presentation, patients maintained a median mean arterial blood pressure (MAP) of 70 mm Hg with a mean LVAD flow of 3.77 L/minute. ED management included cardioversion in the majority of cases: 58% were defibrillated once, 21% were defibrillated multiple times, 68% received amiodarone, and 21% received lidocaine. Inpatient management included defibrillation, ablation, and antiarrhythmic initiation in 37%, 11%, and 84% of cases, respectively. In total, five patients (26%) died with one death attributed to recurrent VT. Our findings support the short-term tolerability of sustained ventricular arrhythmias in LVAD patients, as evidenced by the maintained MAPs and mental status. Clinical teams, however, should be aware of the potential harbinger for in-hospital mortality heralded by an awake VF/VT presentation., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Background: It has been a matter of debate for long time about the existence of two distinct phenotypes of primary hyperparathyroidism (PHPT) predisposed to either renal or skeletal manifestation., Objective: To differentiate characteristics of symptomatic PHPT patients based on the presence of skeletal or renal involvement., Design: Retrospective analysis of data from the Indian PHPT registry., Patients: PHPT patients were divided into four discrete groups: asymptomatic, presenting with renal manifestations alone, skeletal manifestations alone, and both skeletal and renal manifestations., Measurements: Clinical, biochemical, and tumour weight and histopathological characteristics of these groups were compared., Results: Of the 229 eligible patients, 45 were asymptomatic, 62 had renal manifestations, 55 had skeletal manifestations, and 67 had both skeletal and renal manifestations. Patients with both skeletal and renal manifestations had higher serum calcium levels than those with isolated skeletal involvement [12.5 (11.1-13.7) mg/dL, 11.2 (10.6-12.3) mg/dL, respectively; p < .05]. Serum alkaline phosphatase (AP), plasma parathyroid hormone (PTH) levels, and parathyroid tumour weight were significantly higher in patients with isolated skeletal, and both skeletal and renal manifestations, compared to the other two groups. A preoperative PTH and AP level of 300 pg/mL and 152 U/L, predicted the risk of developing skeletal involvement with sensitivity and specificity of 71%, 70%, and 69%, 67%, respectively., Conclusions: We observed distinct skeletal and renal phenotypic subgroups among PHPT patients with characteristic biochemical and hormonal patterns with higher parathyroid disease burden in patients with skeletal complications compared to those with isolated renal manifestation., (© 2023 John Wiley & Sons Ltd.)

Subacute groin complications associated with extracorporeal membrane oxygenation (ECMO) cannulation are well recognized, yet their effects on clinical outcomes remain unknown. This single-center, retrospective study reviewed all patients receiving venoarterial ECMO from 01/2017 to 02/2020. Cohorts analyzed included transplanted patients (TPs) and non-transplanted patients (N-TPs) who did or did not develop ECMO-related subacute groin complications. Standard descriptive statistics were used for comparisons. Logistic regressions identified associated risk factors. Overall, 82/367 (22.3%) ECMO patients developed subacute groin complications, including 25/82 (30.5%) seromas/lymphoceles, 32/82 (39.0%) hematomas, 18/82 (22.0%) infections, and 7/82 (8.5%) non-specified collections. Of these, 20/82 (24.4%) underwent surgical interventions, most of which were muscle flaps (14/20, 70.0%). TPs had a higher incidence of subacute groin complications than N-TPs (14/28, 50.0% vs. 68/339, 20.1%, P = 0.001). Seromas/lymphoceles more often developed in TPs than N-TPs (10/14, 71.4% vs. 15/68, 22.1%, P = 0.001). Most patients with subacute groin complications survived to discharge (60/68, 88.2%). N-TPs who developed subacute groin complications had longer post-ECMO lengths of stay than those who did not (34 days, IQR 16-53 days vs. 17 days, IQR 8-34 days, P < 0.001). Post-ECMO length of stay was also longer among patients who underwent related surgical interventions compared to those who did not (50 days, IQR 35-67 days vs. 29 days, IQR 16-49 days, P = 0.007). Transplantation was the strongest risk factor for developing subacute groin complications (OR 3.91, CI 95% 1.52-10.04, P = 0.005). Subacute groin complications and related surgical interventions are common after ECMO cannulation and are associated with longer hospital stays. When surgical management is warranted, muscle flaps may reduce lengths of stay compared to other surgical interventions., (© 2022. The Japanese Society for Artificial Organs.)

The continuous cell line of epithelial human parathyroid cells has been proven difficult. Previously, PTH-C1 cell line was only established rat parathyroid tissue cell line known to express the parathyroid hormone-related peptide (Pthrp) gene. The paucity of continuous cell line of human parathyroid cells secreting parathyroid hormone (PTH) has imposed hurdle in in vitro assessment of the mechanisms involved in the control of parathyroid cell function and proliferation. The primary cell cultures of human parathyroid cells were derived from parathyroid adenoma tissue biopsy ( n  = 5). The cells were subsequently subcultured to maintained primary subclones. Karyotyping analysis was performed to analyze the genotypic identity of derived subclones. The expression of calcium-sensing receptor (CaSR) and intact parathyroid hormone (iPTH) were analyzed using immunocytochemistry and immunofluorescence. In the present study, we have used a defined condition medium to generate the continuous culture of human parathyroid cells derived from patients with parathyroid adenoma due to primary hyperparathyroidism. The subcultured primary subclones were maintained epithelial and polygonal morphology, doubling time of approximately 25 h, displaying a diploid chromosome number, and secretion of PTH. This cell line produces PTH and expresses the calcium-sensing receptor (CaSR) known to be involved in parathyroid function. Altogether these findings indicate the uniqueness of the human parathyroid cell line as an in vitro model for cellular and molecular studies on parathyroid physiopathology., Competing Interests: Conflict of interestThe authors have no conflict of interest., (© King Abdulaziz City for Science and Technology 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The 24th Workshop on Vitamin D was held September 7-9, 2022 in Austin, Texas and covered a wide diversity of research in the vitamin D field from across the globe. Here, we summarize the meeting, individual sessions, awards and presentations given., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Orthotopic heart transplantation is the most effective long-term therapy for end-stage heart disease. Denervation with the loss of autonomic modulation, vasculopathy, utilization of immunosuppressant drugs, and allograft rejection may result in an increased prevalence of arrhythmias in transplanted hearts. We aim to describe the trends, distribution, and the clinical impact of arrhythmias in patients with transplanted hearts. We queried the National Inpatient Sample with administrative codes for cardiac transplant patients using procedure ICD-9-CM codes 37.5 and 33.6. Arrhythmias were extracted using validated ICD-9-CM codes. Statistical Analysis System (SAS) version 9.4 was used for analysis. There were a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States of which 1,6342 (54.4%) had an arrhythmia. The frequency of total arrhythmias increased from 53.6% (n=1,158) in 1999 to 67.3% (n=1,575) in 2014. Transplant patients with arrythmias was not associated with significantly higher inpatient mortality (7.72% vs 6.90%, P = 0.225). The most common arrythmia was atrial fibrillation ([AF]26.83%) followed by ventricular tachycardia (22.86%). Trends in mortality associated with arrhythmias following heart transplant has been decreasing from 12.3% in 1999 to 8.9% in 2014 (P = 0.04). Subgroup analysis of ventricular arrythmias (VA) following heart transplant were associated with increased mortality (8.61% vs 6.94%, P = 0.0229). Over half of patients develop 1 or more cardiac arrhythmia after heart transplant. There is an increasing secular trend in the frequency of arrhythmias post cardiac transplant with atrial fibrillation determined to be the most common arrhythmia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome. We recently reported that a dual inhibitor of the Xaa-Pro-cleaving M24B aminopeptidases PEPD and XPNPEP1 called CQ31 selectively activates the CARD8 inflammasome by inducing the build-up of Xaa-Pro peptides. Here, we performed structure-activity relationship studies on CQ31 to develop the optimized dual PEPD/XPNPEP1 inhibitor CQ80 that more effectively induces CARD8 inflammasome activation. We anticipate that CQ80 will become a valuable tool to study the basic biology and therapeutic potential of selective CARD8 inflammasome activation.

Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "giant" parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 <36years), serum calcium 11.6 ± 1.1 mg/dl, alkaline phosphatase 799 ± 487 IU/L, PTH 1440 ± 477 pg/ml, 25-hydroxyvitamin D 13.0 ± 8.9 ng/ml, 1,25-dihyroxyvitamin D 26.5 ± 13.7 pg/ml, urine calcium 562 ± 274 mg/day, and parathyroid adenoma weight 4.53 ± 2.2 g. Parathyroidectomy led to the resolution of both the biochemical indices and OFC in each patient without recurrence over >10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bhan, Athimulam, Kumari, Pal, Bhadada, Cook, Qiu and Rao.)

NLRP1 and CARD8 are related pattern-recognition receptors (PRRs) that detect intracellular danger signals and form inflammasomes. Both undergo autoproteolysis, generating N-terminal (NT) and C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the stimuli that trigger NT degradation have not been fully elucidated. Here, we show that several distinct agents that interfere with protein folding, including aminopeptidase inhibitors, chaperone inhibitors, and inducers of the unfolded protein response, accelerate NT degradation. However, these agents alone do not trigger inflammasome formation because the released CT fragments are physically sequestered by the serine dipeptidase DPP9. We show that DPP9-binding ligands must also be present to disrupt these complexes and allow the CT fragments to oligomerize into inflammasomes. Overall, these results indicate that NLRP1 and CARD8 detect a specific perturbation that induces both protein folding stress and DPP9 ligand accumulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

An apparent vitamin D paradox, characterized by lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher bone mineral density, is present in black population. In contrast, blacks have higher serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D) levels. The effect of 1,25(OH) 2 D on the skeleton is not fully understood. We examined serum 25(OH)D, 1,25(OH) 2 D and bone histomorphometry in 50 black and white women (25 each) matched for age, menstrual status, and BMI. Histomorphometric indices related to bone structure, remodeling and mineralization were measured in cancellous bone in iliac bone biopsies. Data analyses led to the following results: 1) serum 25(OH)D was significantly lower and 1,25(OH) 2 D was significantly higher in black than in white women, but neither blacks nor whites revealed significant correlation between these two vitamin D metabolites. 2) there was no significant difference in PTH levels between blacks and whites. 3) except for greater trabecular thickness (Tb.Th) in blacks, there were no significant differences in other histomorphometric variables between the two ethnic groups. 4) osteoid surface (OS/BS), unlabeled osteoid surface (ulOS/BS), and osteoblast surface (ObS/BS) significantly correlated with serum 1,25(OH) 2 D levels. We conclude that lower serum 25(OH)D levels in blacks do not impair bone structure and remodeling, nor decrease bone mineralization. Higher serum 1,25(OH) 2 D levels in blacks may help preserve bone mass by stimulating bone formation via increasing osteoblast number and function, but moderately inhibit terminal bone mineralization as shown by higher ulOS/BS., Competing Interests: All authors state no conflicts of interest., (© 2022 The Authors. Published by Elsevier Inc.)

The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.

Primary hyperparathyroidism (PHPT) is third most common endocrine disorder characterized by hypercalcemia with elevated or nonsuppressed parathyroid hormone levels by parathyroid tumors. Familial PHPT, as part of multiple endocrine type-1, occurs due to the germline mutation in the MEN1 gene. The involvement and the role of germline MEN1 variations in sporadic PHPT of Indian PHPT patients are unknown. Precise classifications of different types of MEN1 variations are fundamental for determining clinical relevance and diagnostic role. This prospective cohort study was performed on 82 patients with PHPT (with no clinical or history of MEN1) who underwent screening for MEN1 variations through Sanger sequencing. Multilevel computational analysis was performed to determine the structure-function relationship of synonymous, nonsynonymous, and variants of uncertain significance (VUS). Of the 82 PHPT patients, 42 (51%) had 26 germline MEN1 variants, including eight nonsynonymous, seven synonymous, nine VUS, one splice site, and one regulatory variation. Five most common germline variations (c.1838A>G, c.1817C>T, c.1525C>A, c.-35A>T, and c.250T>C) were observed in this study. c.-35A>T (5' untranslated region [UTR]) was associated with recurrence of PHPT (odds ratio [OR] = 5.4; p = 0.04) and subsequent detection of other endocrine tumors (OR = 13.6, p = 0.035). c.1525C>A was associated with multi glandular parathyroid tumor (OR = 13.6, p = 0.035). Align-Grantham variation and Grantham deviation (Align-GVGD), functional analysis through hidden Markov MODEL (FATHMM), and MutationTaster analysis reported the disease-specific potential of VUS and synonymous variations. Significant linkage disequilibrium was observed in c.1785G>A and c.1817C>T (r 2  = 0.3859, p = 0.0001), c.1475C>G and c.1525C>A (r 2  = 0.385, p = 0.0004), and c.1569T>C and c.1838A>G (r 2  = 0.488, p = 0.0001). The detection of MEN1 variations, especially those with disease-specific potential, can prompt early screening for other MEN1-related tumors and disease recurrence. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Objective: Vaccine hesitancy is an impediment to fighting the COVID-19 pandemic. Endocrinology clinics routinely see patients who are at high risk of a more aggressive form of COVID-19, including patients with diabetes, obesity, and hypertension. As patients with endocrine-related conditions often require multiple visits each year, endocrinology clinics provide a significant opportunity for vaccine education. The aim of our study was to evaluate patient perspectives about COVID-19 vaccination in outpatient endocrinology clinics., Methods: A pilot survey study of patients who visited 3 endocrinology clinics between May 31, 2021, and June 18, 2021. A 7-item questionnaire explored the patients' perspectives and behaviors regarding COVID-19 vaccination. Data were analyzed with descriptive statistics., Results: A total of 446 patients from 3 clinic locations (1 urban and 2 suburbans) completed our survey. There were 361 (81%) patients who indicated that they were planning to or had already received the COVID-19 vaccination, 56 (13%) reported no intent for vaccination, and 29 (7%) were unsure. Of the 85 patients who were unsure or did not intend to be vaccinated, 43 (51%) were Black, 30 (35%) were White, and 4 (5%) had other racial/ethnic identities. When asked about vaccine hesitancy, 25 (29%) wanted to wait and see how the others responded to the vaccine, 20 (24%) had concerns about the side effects, 12 (14%) did not believe in vaccines, and 11 (13%) felt that COVID-19 was not as bad as the media had portrayed it. Significantly more Black patients had vaccine hesitancy than White patients (P = .035)., Conclusion: Although most endocrinology patients were amenable to COVID-19 vaccination, a subpopulation still expressed vaccine hesitancy, indicating that endocrinology clinics may be an ideal place for targeted vaccine education., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Continuous infusion of ambulatory inotropic therapy (AIT) is increasingly used in patients with end-stage heart failure (HF). There is a paucity of data concerning the concomitant use of beta-blockers (BB) in these patients., Methods: We retrospectively reviewed all patients discharged from our institution on AIT. The cohort was stratified into 2 groups based on BB use. The 2 groups were compared for differences in hospitalizations due to HF, ventricular arrhythmias and ICD therapies (shock or antitachycardia pacing)., Results: Between 2010 and 2017, 349 patients were discharged on AIT (95% on milrinone); 74% were males with a mean age of 61 ± 14 years. BB were used in 195 (56%) patients, whereas 154 (44%) did not receive these medications. Patients in the BB group had longer duration of AIT support compared to those in the non-BB group (141 [1-2114] vs 68 [1-690] days). After adjusting for differences in baseline characteristics and indication for AIT, patients in the BB group had significantly lower rates of hospitalizations due to HF (hazard ratio [HR] 0.61 (0.43-0.86); P = 0.005), ventricular arrhythmias (HR 0.34 [0.15-0.74]; P = 0.007) and ICD therapies (HR 0.24 [0.07-0.79]; P = 0.02)., Conclusion: In patients with end-stage HF on AIT, the use of BB with inotropes was associated with fewer hospitalizations due to HF and fewer ventricular arrhythmias., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Heart transplantation is the most effective long-term therapy for end-stage heart disease. There is limited data related to sudden cardiac arrest (SCA) in postheart transplant recipients. We aimed to describe the trends, and rate of SCA following heart transplantation and thereby identify clinical predictors as well as outcomes of SCA in patients post-transplant. We queried the National Inpatient Sample (NIS) with administrative codes for SCA and heart transplant. We assessed baseline differences between SCA and non-SCA admissions, with hazard ratios adjusted for age, gender, CCI, and race. Multivariable logistic regression models were generated to identify the independent predictors for SCA. There was a total of 30,020 hospitalizations of heart transplant recipients between 1999 and 2014 in the United States and among these 1,953 patients (6.5%) suffered SCA with an increasing trend of admissions for SCA. Among the patients who suffered from SCA, 18.83% died during the same hospitalization, 19.29% were discharged to a long-term facility, and 61.38% were discharged home. Multivariate analysis demonstrated that conduction system disorders (Hazard ratio [95% confidence interval]; 7.1 [4.5-11.1]), female gender (HR:1.2 [1.1-1.3]), diabetes (HR:1.4 [1.2-1.6]), and hypertension (HR:1.2 [1.1-1.4]) were the strongest predictors for SCA. SCA hospitalizations occur in 6.5% of patients post cardiac transplant and have been increasing from 1999 to 2014. Conduction block, graft rejection, female gender, hypertension, diabetes are independent predictors for SCA in heart transplant recipients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Specific aetiologies of cardiomyopathy can significantly impact treatment options as well as appropriateness and prioritisation for advanced heart failure therapies such as ventricular assist device (VAD) or orthotopic heart transplantation (OHT). We reviewed the tissue diagnoses of patients who underwent advanced therapies for heart failure (HF) to identify diagnostic discrepancies., Methods: This study presents a retrospective cohort of the aetiology of cardiomyopathy in 118 patients receiving either durable VAD or OHT. Discrepancies between the preoperative aetiological diagnosis of cardiomyopathy with the pathological diagnosis were recorded. Echocardiographic and haemodynamic data were reviewed to examine differences in patients with differing aetiological diagnoses., Results: Twelve (12) of 118 (12/118) (10.2%) had a pathological diagnosis that was discordant with pre-surgical diagnosis. The most common missed diagnoses were infiltrative cardiomyopathy (5) and hypertrophic cardiomyopathy (3). Patients with misidentified aetiology of cardiomyopathy had smaller left ventricular (LV) dimensions on echocardiography than patients with dilated cardiomyopathy (5.8±0.9 vs 6.7±1.1 respectively p=0.01)., Conclusions: Most HF patients undergoing VAD and OHT had a correct diagnosis for their heart failure prior to treatment, but a missed diagnosis at time of intervention (VAD or OHT) was not uncommon. Smaller LV dimension on echocardiogram in a patient with a non-ischaemic cardiomyopathy warrants further workup for a more specific aetiology., Competing Interests: Disclosures SP reports consulting fees from Pfizer and Akcea Therapeutics., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Inflammasomes are multiprotein complexes that sense intracellular danger signals and induce pyroptosis. CARD8 and NLRP1 are related inflammasomes that are repressed by the enzymatic activities and protein structures of the dipeptidyl peptidases 8 and 9 (DPP8/9). Potent DPP8/9 inhibitors such as Val-boroPro (VbP) activate both NLRP1 and CARD8, but chemical probes that selectively activate only one have not been identified. Here we report a small molecule called CQ31 that selectively activates CARD8. CQ31 inhibits the M24B aminopeptidases prolidase (PEPD) and Xaa-Pro aminopeptidase 1 (XPNPEP1), leading to the accumulation of proline-containing peptides that inhibit DPP8/9 and thereby activate CARD8. NLRP1 is distinct from CARD8 in that it directly contacts DPP8/9's active site; these proline-containing peptides, unlike VbP, do not disrupt this repressive interaction and thus do not activate NLRP1. We expect that CQ31 will now become a valuable tool to study CARD8 biology., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)