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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.)

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: 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.)

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.)

The impact of preoperative end-diastolic left ventricular dimension (preLVEDD) on long-term outcomes with centrifugal continuous-flow left ventricular assist device (CF-LVAD) is not well established. Accordingly, we performed an analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry to study this relationship. All patients with centrifugal CF-LVAD in the INTERMACS registry from June 2006 to December 2017 were screened. The final study group consisted of 3,304 patients. After a median follow-up of 9.0 months (interquartile range [IQR], 4.2-18.8 months), 2,596 (79%) patients were alive. After adjusting for significant covariates, increased preLVEDD was associated with lower mortality (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84-0.98; p = 0.01), stroke (HR, 0.85; 95% CI, 0.77-0.93; p < 0.001), and gastrointestinal bleeding (HR, 0.88; 95% CI, 0.80-0.97; p = 0.01), although there were more arrhythmias (HR, 1.14; 95% CI, 1.05-1.24; p = 0.003). Our study suggests that preLVEDD is an independent predictor of mortality and adverse events in patients treated with centrifugal CF-LVAD. preLVEDD should be considered an important preimplant variable for risk stratification when considering a CF-LVAD., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Context: Primary hyperparathyroidism (PHPT) results from the hypersecretion of parathyroid hormone from parathyroid tumors. A transcription factor, namely Paired box1 (PAX1), is active in parathyroid gland development., Objective: We aimed to study potential epigenetic-mediated mechanism of PAX1 gene in sporadic parathyroid adenomas., Methods: In parathyroid adenomas tissues, we analyzed the DNA methylation via bisulfite-specific polymerase chain reaction (BSP) and histone modifications via chromatin immunoprecipitation in regulating the differential expression of PAX1., Results: The results showed that mRNA and protein expression of PAX1 was significantly reduced in parathyroid adenomas. Bisulfite sequencing demonstrated hypermethylation in the promoter region of PAX1 (35%; 14/40) and lower levels of histone 3 lysine 9 acetylation (H3K9ac) were observed on the promoter region of PAX1 (6-fold; P < .004) in parathyroid adenomas. Furthermore, upon treatment with a pharmacologic inhibitor, namely 5'aza-2 deoxycytidine, in rat parathyroid continuous cells, we found re-expression of PAX1 gene., Conclusion: Our study not only reveals expression of PAX1 is epigenetically deregulated but also paves a way for clinical and therapeutic implications in patients with PHPT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Primary hyperparathyroidism (PHPT) in India is mostly symptomatic with renal and skeletal complications. Evidence on mortality outcomes following parathyroidectomy from India, where the disease is predominantly symptomatic is limited., Material and Methods: This was a prospective study to evaluate mortality outcomes in the Indian PHPT registry over the past 25 years (n = 464). Pre- and postoperative parameters and mortality data were obtained from medical records and/or by verbal autopsy, a method validated by WHO for data collection in settings where several deaths are noninstitutional. Patients were divided into survivor (SG) and nonsurvivor groups (NSG) to ascertain differences in presentation and the effect of parathyroidectomy., Results: The overall mortality was 8.8% at a median follow-up of 8 years (IQR 1-13) after parathyroidectomy. Chronic kidney disease was the most common background cause of death (43.5%), followed by pancreatitis (28.2%). NSG had significantly more frequent renal dysfunction (91.9% vs 73.9%), anaemia (50 vs 16.6%) and pancreatitis (24.3 vs 6.4%). PTH (61.9 vs 38.3 pmol/l) and baseline creatinine (97.2 vs 70.7 µmol/l) were significantly higher and eGFR lower (66.7 vs 90.7 ml/min/1.73m 2 ) in the NSG than SG. By Cox proportional modelling, renal dysfunction [HR 2.88 (1.42-5.84)], anaemia [HR 2.45 (1.11-5.42)] and pancreatitis [HR 2.65 (1.24-5.66)] on univariate and renal dysfunction [HR 3.33 (1.13-9.77)] on multivariate analysis were significant for mortality. Survival curves demonstrated a significantly higher mortality with lower eGFR values., Conclusions: Nonsurvivors in PHPT had greater prevalence and more severe baseline renal dysfunction than survivors. Survival after parathyroidectomy was significantly associated with estimated glomerular filtration rate at baseline., (© 2021. The Japanese Society Bone and Mineral Research.)

Gene expression noise can reduce cellular fitness or facilitate processes such as alternative metabolism, antibiotic resistance, and differentiation. Unfortunately, efforts to study the impacts of noise have been hampered by a scaling relationship between noise and expression level from individual promoters. Here, we use theory to demonstrate that mean and noise can be controlled independently by expressing two copies of a gene from separate inducible promoters in the same cell. We engineer low and high noise inducible promoters to validate this result in Escherichia coli, and develop a model that predicts the experimental distributions. Finally, we use our method to reveal that the response of a promoter to a repressor is less sensitive with higher repressor noise and explain this result using a law from probability theory. Our approach can be applied to investigate the effects of noise on diverse biological pathways or program cellular heterogeneity for synthetic biology applications., (© 2021. The Author(s).)

Type 2 diabetes mellitus (T2DM) adversely affects the normal functioning, intrinsic material properties, and structural integrity of many tissues, including bone. It is well known that the clinical utility of areal bone mineral density (aBMD) is limited to assess bone strength in individuals with T2DM. Therefore, there is a need to explore new diagnostic techniques that can better assist and improve the accuracy of assessment of bone tissue quality. The present study investigated the link between bone and fingernail material/compositional properties in type 2 diabetes mellitus (T2DM). For that, femoral head and fingernail samples were obtained from twenty-five adult female patients (with/without T2DM) with fragility femoral neck fractures undergoing hemi/total hip arthroplasty. Cylindrical cores of trabecular bone were subjected to micro-CT, and lower bone volume fraction was observed in the diabetic group than the non-diabetic group due to fewer and thinner trabeculae in individuals with T2DM. The material and compositional properties of bone/fingernail were estimated using nanoindentation and Fourier Transform Infrared Spectroscopy, respectively. Both bone/fingernails in T2DM had lower reduced modulus (Er), hardness (H), lower Amide I and Amide II area ratio (protein content), higher sugar-to-matrix ratio, and relatively high carboxymethyl-lysine (CML) content compared with non-diabetic patients. Sugar-to-matrix ratio and relative CML content were strongly and positively correlated with HbA1c for both bone/fingernail. There was a positive correlation between bone and fingernail glycation content. Our findings provide evidence that the degradation pattern of bone and fingernail properties go hand-in-hand in individuals with T2DM. Hence, the fingernail compositional/material properties might serve as a non-invasive surrogate marker of bone quality in T2DM; however, further large-scale studies need to be undertaken., Competing Interests: The authors have declared that no competing interests exist.

Context: Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of the parathyroid glands., Objective: We sought to identify whether the epigenetic alterations in GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices., Methods: Messenger RNA (mRNA) and protein expression of GCM2 were analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of the GCM2 promoter were measured by bisulfite sequencing and chromatin immunoprecipitation-qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in parathyroid (PTH)-C1 cells by treating with 5-aza-2'-deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels., Results: mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P < .001) and higher H3K9me3 levels in the GCM2 promoter (P < .04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a nonsignificant change in GCM2 transcription., Conclusion: These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be a promising avenue of research for parathyroid adenoma therapeutics., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: There is controversy over the adverse effect of vitamin D deficiency on bone mineralization. The purpose of this study was to determine the ethnical differences in vitamin D and bone mineralization as well as the association between vitamin D deficiency and bone mineralization defects., Materials and Methods: We examined serum 25-hydroxyvitamin D (25(OH)D) levels and transiliac bone biopsies in 92 healthy black and white women, aged 20-73 years. The major bone mineralization indices include osteoid volume per bone volume (OV/BV), osteoid surfaces per bone surface (OS/BS), osteoid thickness (O.Th) and mineralization lag time (Mlt)., Results: 25(OH)D levels were significantly lower and prevalence of 25(OH)D deficiency was significantly higher in blacks than in whites. However, none of the mineralization indices showed significant difference between the two groups. In addition, there was no significant correlation between 25(OH)D levels and mineralization indices in both black and white cohorts. Only one case had O.Th marginally greater than 12.5 µm, which is the cutoff value for identifying bone mineralization defects. OV/BV and OS/BS, but not O.Th, were significantly positively correlated with activation frequency (Ac.f)., Conclusions: Our study indicated: (1) vitamin D deficiency is common, but bone mineralization is not impaired in black women, and (2) there are no significant correlations between serum 25(OH)D levels and bone mineralization indices, suggesting that vitamin D deficiency may not be an independent factor contributing to bone mineralization defects and osteomalacia., (© 2021. The Japanese Society Bone and Mineral Research.)

Atypical femur fractures (AFFs) are well-established serious complication of long-term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case-control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue-level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty-two full-thickness transiliac bone biopsies were obtained from age- and sex-matched patients on long-term bisphosphonate therapy with ( n  = 16) and without an AFF ( n  = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface-based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non-AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non-AFF groups or between cortical and cancellous bone of non-AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non-AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long-term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Purpose of Review: The pathogenesis of bone fragility in diabetes has not been fully characterized. The antifracture efficacy of available therapies remains unproven in patients with diabetes. We aim to collate current evidence of the treatment of diabetic bone fragility, and to provide a rationale for considering optimal therapeutic option in patients with diabetes., Recent Findings: The antifracture efficacy of antiresorptive and anabolic therapies is well established in patients without diabetes. Studies in patients with osteoporosis have shown that anabolic therapies lead to faster and larger benefits to bone mineral density and offer greater protection against fracture than antiresorptive therapies. Available data suggest that antiresorptive and anabolic therapies have similar effect on bone density and fracture risk reduction in patients with and without diabetes. However, the evidence in diabetes is limited to observational studies and post hoc analyses of osteoporosis studies., Summary: There are no specific guidelines for the treatment of bone fragility in patients with diabetes. We offer a rationale for use of anabolic therapies in diabetes which is a low bone formation state, in contrast to postmenopausal osteoporosis that is characterized by increased bone turnover. Prospective studies evaluating the effect of available therapies on bone quality and fracture outcomes in patients with diabetes are needed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents., Methods: A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity., Results: Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P =0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points., Conclusions: In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.

Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT., Methods: A retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry., Results: Of the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P = .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P = .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P = .02) and median alkaline phosphatase (202 vs 145 pg/mL; P = .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P = .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status., Conclusion: PHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women., (Copyright © 2020 American Association of Clinical Endocrinologists. All rights reserved.)

The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India., Purpose: In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines, the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country., Methods: The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians, researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guidelines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India., Results: Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diagnostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice. Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential, which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy., Conclusions: Implementation of the position statement in clinical practice is expected to improve the overall care of patients with osteoporosis in India.

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n = 26) and without (n = 26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p = .001), which remained so after adjusting for treatment duration (p = .007), and showed a trend in cancellous bone (+1.6%, p = .05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Introduction: Primary hyperparathyroidism (PHPT), a third common endocrine disorder, varies from asymptomatic disease, mostly seen in the West where routine biochemical screening is practiced, to the classical symptomatic disease mostly seen in the Eastern countries. We aimed to compare the demographic, clinical, biochemical measurements in patients with asymptomatic and symptomatic PHPT from the Indian PHPT registry., Material and Methods: Data of PHPT patients from the last 25 years (1995-2019) were analyzed for demographic, clinical presentation and biochemical measurements, and compared these characteristics between asymptomatic and symptomatic PHPT patients., Results: Of the 554 patients, 54 (10%) patients had asymptomatic PHPT. There was a sharp rise in the proportion of asymptomatic PHPT patients of 3% in the first decade to 13% in the second decade of the century (p = 0.003). Patients with asymptomatic PHPT were significantly older (50 vs. 42 years; p < 0.0001) and had higher mean body mass index (27.8 vs. 23.5 kg/m 2 ; p < 0.0001) compared to the symptomatic PHPT group. In addition, asymptomatic PHPT patients had significantly lower median plasma iPTH (180 vs. 370 pg/mL; p < 0.0001), serum alkaline phosphatase (119 vs. 172 IU/L; p < 0.0001), and parathyroid adenoma weight (1.0 vs. 2.62 g; p = 0.006) compared to the symptomatic PHPT group., Conclusion: Although symptomatic PHPT is still most prevalent (> 90%) in India with higher indices of the disease and tumor weights, there is a progressive rise in the prevalence of asymptomatic PHPT patients in the last decade. Improvements in calcium and vitamin D nutrition might account for this change as in the Western series.

Dynamical properties of gene regulatory networks are tuned to ensure bacterial survival. In mycobacteria, the MprAB-σ E network responds to the presence of stressors, such as surfactants that cause surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e., different responses to identical stressor levels for prestressed and unstressed cells. Here, we show that hysteresis does not occur in nonpathogenic Mycobacterium smegmatis but does occur in Mycobacterium tuberculosis However, the observed rapid temporal response in M. tuberculosis is inconsistent with the model predictions. To reconcile these observations, we implement a recently proposed mechanism for stress sensing, namely, the release of MprB from the inhibitory complex with the chaperone DnaK upon the stress exposure. Using modeling and parameter fitting, we demonstrate that this mechanism can accurately describe the experimental observations. Furthermore, we predict perturbations in DnaK expression that can strongly affect dynamical properties. Experiments with these perturbations agree with model predictions, confirming the role of DnaK in fast and sustained response. IMPORTANCE Gene regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches that enable bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood. In this paper, combining quantitative experiments and mathematical modeling, we uncover how interactions between two master regulators of stress response-the MprAB two-component system (TCS) and the alternative sigma factor σ E -shape the dynamical properties of the surface stress network. The result show hysteresis (history dependence) in the response of the pathogenic bacterium M. tuberculosis to surface stress and lack of hysteresis in nonpathogenic M. smegmatis Furthermore, to resolve the apparent contradiction between the existence of hysteresis and fast activation of the response, we utilize a recently proposed role of chaperone DnaK in stress sensing. These result leads to a novel system-level understanding of bacterial stress response dynamics., (Copyright © 2021 Rao et al.)

Osteoporosis is a disease with a high burden of morbidity. For its accurate diagnosis, using indigenous data as reference standards is needed. However, normative data on bone density is lacking in India. Therefore, we aimed to determine the reference range for bone density for the healthy population of north India., Introduction: Osteoporosis is a major public health problem around the globe including India, resulting in significant morbidity, mortality, and health care burden. However, the reference values used for its diagnosis are largely based on data from the western population, which may lead to over- or underdiagnosis of osteoporosis in Indians. Our study aimed to determine the reference range for bone mineral density for the healthy population of India., Methods: This is a cross-sectional study of 825 subjects (men 380, women 445) (median age: 41 years, IQR 32-55 years), recruited by a house-to-house survey. The population was stratified into decade-wise groups and biochemical measurements including renal and liver function tests, glycated hemoglobin, serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density were performed in all the subjects. The T-scores for men aged > 50 years and post-menopausal women were calculated based on the data generated from this study in young men and women aged 20-40 years., Results: According to the BMD manufacturer's data, which is based on the western population, 70% of the Indian men (> 50 years) and 48% of the post-menopausal Indian women had osteopenia while 18% of the men and 25% of the women had osteoporosis. However, according to the re-calculated T-scores from the current study, only 56% and 7.2% of men and 33% and 5% of women had osteopenia and osteoporosis, respectively. An age-related decline in bone mineral density, as seen in the western population, was also seen in both Indian men and women., Conclusion: We have established a reference database for BMD in healthy Indian adult population, which may have clinical implications for the diagnosis and intervention strategies for the management of osteoporosis.

Bacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression in response to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their expression when activated. Escherichia coli Mg2+ -sensing TCS, PhoPQ, in addition to the positive feedback, includes a negative feedback loop via the upregulation of the MgrB protein that inhibits PhoQ. How the interplay of these feedback loops shapes steady-state and dynamical responses of PhoPQ TCS to change in Mg2+ remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady-state response to decreasing Mg2+ is biphasic, i.e. plateaus over a range of Mg2+ concentrations, and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose a novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+ and MgrB. Finally, we show how the interplay of positive and negative feedback loops affects the network's steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results improve the understanding of TCS signaling and other networks with overlaid positive and negative feedback., Competing Interests: The authors have declared that no competing interests exist.

Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tissues. It is a major intracellular divalent anion, participates in many genetic, energy and intermediary metabolic pathways, and is important for bone health. Although we usually think of phosphate mostly in terms of its level in the serum, it is needed for many biological and structural functions of the body. Availability of adequate calcium and inorganic phosphate in the right proportions at the right place is essential for proper acquisition, biomineralization, and maintenance of mass and strength of the skeleton. The three specialized mineralized tissues, bones, teeth, and ossicles, differ from all other tissues in the human body because of their unique ability to mineralize, and the degree and process of mineralization in these tissues also differ to suit the specific functions: locomotion, chewing, and hearing, respectively. Biomineralization is a dynamic, complex, and lifelong process by which precipitations of inorganic calcium and inorganic phosphate divalent ions form biological hard tissues. Understanding the biomineralization process is important for the management of diseases caused by both defective and abnormal mineralization. Hypophosphatemia results in mineralization defects and osteomalacia, and hyperphosphatemia is implicated in abnormal excess calcification and/or ossification, but the exact mechanisms underlying these processes are not fully understood. In this review, we summarize available evidence on the role of phosphate in biomineralization. Other manuscripts in this issue of the journal deal with other relevant aspects of phosphate homeostasis, phosphate signaling and sensing, and disorders resulting from hypo- and hyperphosphatemic states.

Historically, rickets and osteomalacia have been synonymous with vitamin D deficiency dating back to the 17th century. The term osteomalacia, which literally means soft bone, was traditionally applied to characteristic radiologically or histologically documented skeletal disease and not just to clinical or biochemical abnormalities. Osteomalacia results from impaired mineralization of bone that can manifest in several types, which differ from one another by the relationships of osteoid (ie, unmineralized bone matrix) thickness both with osteoid surface and mineral apposition rate. Osteomalacia related to vitamin D deficiency evolves in three stages. The initial stage is characterized by normal serum levels of calcium and phosphate and elevated alkaline phosphatase, PTH, and 1,25-dihydroxyvitamin D [1,25(OH) 2 D]-the latter a consequence of increased PTH. In the second stage, serum calcium and often phosphate levels usually decline, and both serum PTH and alkaline phosphatase values increase further. However, serum 1,25(OH) 2 D returns to normal or low values depending on the concentration of its substrate, 25-hydroxyvitamin D (25OHD; the best available index of vitamin D nutrition) and the degree of PTH elevation. In the final stage, hypocalcemia and hypophosphatemia are invariably low with further exacerbation of secondary hyperparathyroidism. The exact,or even an approximate, prevalence of osteomalacia caused by vitamin D deficiency is difficult to estimate, most likely it is underrecognized or misdiagnosed as osteoporosis. Signs and symptoms include diffuse bone, muscle weakness, and characteristic fracture pattern, often referred to as pseudofractures, involving ribs, scapulae, pubic rami, proximal femurs, and codfish-type vertebrae. The goal of therapy of vitamin D-deficiency osteomalacia is to alleviate symptoms, promote fracture healing, restore bone strength, and improve quality of life while correcting biochemical abnormalities. There is a need for better understanding of the epidemiology of osteomalacia. Simplified tools validated by concurrent bone histology should be developed to help clinicians promptly diagnose osteomalacia. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

This study has established the normal reference intervals for bone histomorphometric measurements derived from healthy premenopausal women, which is rarely available. We presented the static and dynamic bone histomorphometric data from trans-iliac bone biopsies in 62 healthy premenopausal women (19 blacks and 43 whites, ages 20-53 years). There were no significant differences in age and BMI between black and white women. Since there was no significant difference in bone remodeling between the two ethnic groups, we pooled data of all 62 premenopausal women to establish normal reference intervals for bone histomorphometry. The results provide normal reference intervals for both static and dynamic histomorphometric variables in cancellous and cortical bone of the ilium. None of the bone remodeling-related variables correlated with age or BMI. This study provides reference intervals for bone histomorphometric measurements in both cancellous and cortical bone of the ilium, which would be helpful in the evaluation of bone health in women.

Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8's N terminus contains a disordered region of ∼160 amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins., Competing Interests: Declaration of Interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Impella (Abiomed Inc, Danvers, MA) is a temporary mechanical support device positioned across the aortic valve, and can be used to support patient before LVAD implantation. There are no data on the incidence of aortic insufficiency (AI) in patients supported with Impella as a bridge to durable LVAD implantation. We sought to assess the incidence of AI in patients with Impella support as a bridge to durable left ventricular assist device (LVAD) implantation., Methods: We reviewed all patients undergoing primary LVAD implantation at the University of Pennsylvania from January 2015 onward, comparing those supported with Impella as temporary mechanical support with those supported by either venoarterial extracorporeal life support or an intra-aortic balloon pump. We reviewed transthoracic echocardiography preoperatively, as well as at 1 week, 1, 3, 6, 9, and 12 months after LVAD implantation., Results: A total of 215 echocardiograms were analyzed in 41 patients. Eleven patients were supported with Impella before LVAD implant-6 patients with Impella alone (5 with Impella CP, 1 with Impella 5.0) and 5 with Impella in conjunction with venoarterial extracorporeal life support (2 with Impella 2.5, 2 with Impella CP, and 1 with Impella 5.0). After LVAD implant, mild or moderate AI developed in 82% of patients supported with Impella (9 of 11) compared with 43% of those without Impella (13 of 30) (P = .038)., Conclusions: Patients supported by Impella as a bridge to durable LVAD have a higher risk of developing AI. Further studies are needed to assess this risk as the use of the Impella increases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Reduced calcium sensing receptor (CaSR) expression has been implicated in parathyroid tumorigenesis, but the underlying mechanism remains elusive. Accordingly, we aimed to explore the epigenetic changes (DNA methylation and histone modifications) involved in CaSR regulation in sporadic parathyroid adenomas and correlate epigenetic state with disease indices., Experimental Design: Forty sporadic parathyroid adenomas and 10 control parathyroid tissues were studied. Real-time quantitative PCR (qPCR) for mRNA and immunohistochemistry for protein expression of CaSR were performed. The methylation status of the CaSR promoter 2 was determined by bisulphite sequencing analysis of sodium bisulphite-converted DNA. To determine the role of histone modifications in the CaSR regulation, chromatin immunoprecipitation-qPCR assay was performed., Results: Real-time qPCR revealed reduced CaSR mRNA expression with a fold reduction of 0.12 (P < 0.0001) in parathyroid adenomas. Immunohistochemistry revealed reduced protein expression of CaSR in 90% (36/40) of adenomas. The promoter 2 region of CaSR displayed significant hypermethylation in 45% (18/40) of the adenomas compared with the controls (6.7%; 1 of 10) (P < 0.002). Bisulphite sequencing analysis revealed maximum methylated CpG at glial cell missing 2 binding site on the CaSR promoter 2 compared to other CpG sites. The methylation status of CaSR correlated directly with plasma intact parathyroid hormone levels in patients with parathyroid adenoma. With chromatin immunoprecipitation-qPCR analysis, H3K9me3 levels showed increased enrichment by 10-fold in adenomas and correlated with CaSR-mRNA expression (r = 0.61; P < 0.003). Treatment with 5-aza-2'deoxycytidine restored the expression of CaSR in a parathyroid cell line., Conclusion: Our data suggest that hypermethylation and increased H3K9me3 of the CaSR promoter 2 are involved in silencing CaSR expression in sporadic parathyroid adenoma., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Canonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4 + and CD8 + T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals.

Background: Dysphagia is a complication following radiation therapy (RT) for head and neck cancers (HNC). Radiologic findings of posterior pharyngeal wall thickening (PPWT) after RT has not been quantified and correlated to swallowing outcomes. Aims/objective: To evaluate PPWT and its impact on swallowing function following RT. Material and methods: Retrospective analysis of pre- and three-month post-RT PPWT, demographics, oncologic history, and swallowing parameters of patients undergoing RT for HNC. Multivariate analysis of variance was performed to evaluate the effect of PPWT on swallowing outcomes. Results: The mean age of the cohort ( n  = 207) was 61.8 (± 11.29) years. The mean PPWT increased by 0.28 (± 0.19) cm ( p  = .00) three-months after RT. A significant difference in PPWT score between tumor subsites, χ 2 (2) = 45.883, p  = .00, with the highest mean rank score of 135.97 for nasopharynx and 103.46 for oropharynx. PPWT was significantly associated with increased pyriform sinus retention, higher Penetration-Aspiration Scale (PAS) scores and post-deglutitive aspiration ( p  < .05). Conclusions and significance: PPWT increase significantly after RT for HNC. Increased PPWT was associated with mean radiation dose to the nasopharynx and oropharynx and was an independent risk factor for increased pharyngeal residue, higher PAS scores, and timing of aspiration ( p  < .05).

Aortic insufficiency (AI) is a frequent problem after continuous-flow left ventricular assist device (LVAD) implantation and results in increased morbidity and mortality. Advances in transcatheter aortic valve replacement (TAVR) technology have resulted in this being discussed as a potential option for LVAD patients with AI. While small case series have been published, we report the first case of TAVR thrombosis in an LVAD patient. This case highlights a major diagnostic and management dilemma that should become more present if this strategy becomes more widespread., (© 2020 Wiley Periodicals, Inc.)

In patients with primary hyperparathyroidism, the size of the adenoma is a major determinant of biochemical indices, disease severity, and manner of presentation. However, the large variation in adenoma weight, both within and between populations and a steady decline in parathyroid adenoma weights over time remain largely unexplained. Based on the results in a small number of patients almost two decades ago we proposed that vitamin D nutritional status of the patient explains both the disease manifestations and much of the variation in adenoma size. Accordingly, we examined the relationship between vitamin D nutrition, as assessed by serum levels of 25-hydroxyvitamin D, and parathyroid gland weight, the best available index of disease severity, in a large number of patients (n = 440) with primary hyperparathyroidism. A significant inverse relationship was found between serum 25-hydroxyvitamin D level and log adenoma weight (r = -0.361; p < 0.001). Also, the adenoma weight was significantly related directly to serum PTH, calcium, and alkaline phosphatase as dependent variables. In patients with vitamin D deficiency (defined as serum 25-hydroxyvitamin D levels 15 ng/mL or lower), gland weight, PTH, AP, and adjusted calcium were each significantly higher than in patients with 25-hydroxyvitamin D levels of 16 ng/mL or higher, but serum 1,25-dihydroxyvitamin D levels were similar in both groups. We interpret this to mean that suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to 1,25-dihydroxyvitamin D deficiency. We conclude that variable vitamin D nutritional status in the population may partly explain the differences in disease presentation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial., Methods: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C₁₆) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%)., Results: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15)., Conclusions: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission., Trial Registration: ClinicalTrials.gov identifier: NCT01421342., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Objective: We assessed our experience with Afirma gene expression classifier (GEC) combined with sono-graphic risk assessment, using both the American Thyroid Association (ATA) and the Thyroid Imaging Reporting and Data System (TI-RADS) in evaluating indeterminate thyroid nodules. Methods: We identified 98 patients with 101 nodules who had a second fine needle aspiration biopsy (FNA) between January 1, 2014, and September 30, 2017, and sent to Veracyte for cytopathology and subsequent Afirma GEC testing. A second FNA biopsy was performed if the initial cytopathology was either Bethesda III or IV (n = 94) or nondiagnostic (n = 7). We correlated cytopathology, histopathology, and Afirma GEC results with sonographic risk assessment using both the ATA system and TI-RADS. Results: The mean age of the cohort was 57.4 ± 12.3 years; 84% women and 60% white. Repeat FNA was benign in 51 of 101 nodules, and of the remaining 50 nodules, 18 (36%) were GEC-benign and 32 (64%) GEC-suspicious. Eighteen of the 32 GEC-suspicious nodules underwent surgery with the following results: 7 benign (39%), 1 follicular thyroid carcinoma (6%), 6 follicular variant of papillary thyroid cancer (33%), and 4 noninvasive follicular tumor with papillary-like nuclear features (22%). The malignancy rate among the surgical cohort was 39% (without noninvasive follicular tumor with papillary-like nuclear features [NIFTP]) and 61% (with NIFTP) and about 50% and 20% of this group scored in the high suspicion category by ATA and TR5 by TI-RADS, respectively. Conclusion: Afirma GEC was useful in avoiding surgery in one-third of indeterminate nodules and performed similarly to ATA and TI-RADS. However, the use of echogenicity in scoring may underestimate the risk of malignancy in patients with indeterminate nodules. Abbreviations: ATA = American Thyroid Association; AUS = Atypia of Undetermined Significance; FLUS = Follicular Lesion of Undetermined Significance; FN = follicular neoplasm; FNA = fine needle aspiration; FTC = follicular thyroid cancer; FVPTC = follicular variant of papillary thyroid cancer; GEC = Gene Expression Classifier; ND = nondiagnostic; NIFTP = noninvasive follicular tumor with papillary-like nuclear features; TI-RADS = Thyroid Imaging Reporting and Data System; TR = TI-RADS.

The development of pulmonary hypertension (PH) in patients with heart failure is associated with increased morbidity and mortality. In this article, the authors examine recent changes to the definition of PH in the setting of left heart disease (PH-LHD), and discuss its epidemiology, pathophysiology and prognosis. They also explore the complexities of diagnosing PH-LHD and the current evidence for the use of medical therapies, promising clinical trials and the role of left ventricular assist device and transplantation., Competing Interests: Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2020, Radcliffe Cardiology.)

Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller "ASC-independent" inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes., (© 2020 Ball et al.)

Objectives: To evaluate whether the ultrasound appearance of the deltoid muscle in diabetic patients differs from that in obese nondiabetic patients., Methods: Ultrasound images of the deltoid muscle from 137 type 2 diabetic patients (including 13 prediabetic patients) and 49 obese nondiabetic patients were blindly reviewed by 2 musculoskeletal radiologists, and by a third when arbitration was needed, to determine whether the appearance was "normal," "suspected diabetes," or "definite diabetes." Age, sex, race, body mass index (BMI), insulin use, and hemoglobin A 1c were analyzed. This retrospective study included patients presenting between October 2005 and November 2017. Statistical analyses included a 2-sided sample t test or Wilcoxon rank sum test and a χ 2 or Fisher exact test. Statistical significance was defined as P < .05., Results: The type 2 diabetic patients included 98 women and 39 men aged 29 to 92 years, and the nondiabetic patients included 19 women and 30 men aged 18 to 75 years. A consensus diagnosis of definite diabetes by the musculoskeletal radiologists based on a hyperechoic deltoid was a powerful predictor of diabetes, with a positive predictive value of 89%. A hyperechoic deltoid was also a powerful predictor of prediabetes. Of the 13 prediabetic patients, all had the same hyperechoic appearance of the diabetic deltoid, regardless of BMI. Although obese diabetic patients more often had a diagnosis of definite diabetes, the BMI alone could not explain the increased echogenicity, as obese nondiabetic patients' deltoid muscles did not appear as hyperechoic and were correctly categorized as not having definite diabetes with 82% specificity., Conclusions: The characteristic hyperechoic deltoid appearance is a strong predictor of both diabetes and prediabetes and differs from that of obese nondiabetic patients., (© 2019 by the American Institute of Ultrasound in Medicine.)

Objectives: The study was designed to evaluate expression profiling of mitogen-activated protein kinase (MAPK) signalling pathway genes in sporadic parathyroid adenoma., Methods: Expression of MAPK signalling pathway genes including activated transcription factors and cell cycle regulatory genes was analysed by real-time PCR- based array in parathyroid adenoma (N = 20) and normal parathyroid tissue (N = 4)., Results: MAPK signalling pathway as studied by PCR array revealed that a total of 22 genes were differentially expressed (≥ twofold change, p ≤ 0.05) in parathyroid adenoma. Up-regulated genes were ARAF, MAPK12, CREBBP, MYC, HSPB1, HRAS, CDK4, CCND1, and E2F1, and down-regulated genes were MAP4K1, DLK1, MAP3K4, MAPK10, MAPK8, ATF2, SMAD4, MEF2C, LAMTOR3, FOS, CDKN2A CDKN2B, and RB1. The present study revealed that ERK1/2 signalling pathway with up-regulation of HRAS, ARAF, and MEK1 genes and up-regulation of positive regulators of cell cycle (CCND1, CDK4, and E2F1) and down-regulation negative regulators of cell cycle (CDKN2A, CDKN2B, and RB1) made highly dysregulated MAPK signalling pathway in parathyroid adenoma. Expression of CDK4 was positively associated with plasma PTH level (r = 0.60, p = 0.04) and tumor weight (r = 0.80, p = 0.02) of the adenoma patients, respectively. Expression of CDKN2A was correlated negatively with PTH level (r = - 0.52, p = 0.04) of the adenoma patients., Conclusion: The current study revealed that ERK pathway and associated cell cycle regulator genes are dysregulated in sporadic parathyroid adenoma.

Purpose of Review: This article summarizes the risk factors for atypical femur fractures (AFF), discusses current and emerging imaging modalities for early identification of AFF, and offers recommendations for prevention and management of AFFs based on the current concepts., Recent Findings: Antiresorptive therapies are widely recommended for prevention and treatment of osteoporosis. Despite their well established effectiveness to reduce fracture risk, emerging concerns related to potential adverse effects have led to a substantial decline in the use of bisphosphonates. Although, the pathogenesis of AFF has not yet been elucidated, the bulk of evidence supports that the well known therapeutic benefits of bisphosphonate far outweigh the relatively low risk of AFFs. Recommendations for early identification of patients at risk for AFF using radiographic imaging have been established. Consensus on the management of AFF and osteoporosis in patients with AFF needs to be formulated., Summary: AFF is a rare event associated with long-term bisphosphonate therapy, which represents an apparent paradox in the management of osteoporosis. Improved understanding of pathogenetic mechanisms will be helpful in further refining of screening guidelines and standardization of management and treatment strategies.