Notes

An added value of the particular electrocardiogram throughout Noonan affliction.
Two (6.1%) of 33 "at-risk" patients (patients with≥10 EDs plus patients who developed inhibitors) developed high-titer inhibitors and were withdrawn. No other safety concerns, including thromboembolic events, were identified. In the prophylaxis group (n=28), 67.9% were bleed free; all bleeds (n=15) were treated with one N9-GP injection; and overall, spontaneous, and traumatic ABRs were low (median ABRs of 0.0, 0.0, and 0.0, respectively; modeled mean ABRs of 0.31, 0.08, and 0.23, respectively). Estimated mean FIX trough activity was 15.0%.

We report an inhibitor incidence of 6.1%, which is within the expected range for PUPs with hemophilia B. No other safety concerns were identified; moreover, N9-GP provided effective hemostatic coverage.
We report an inhibitor incidence of 6.1%, which is within the expected range for PUPs with hemophilia B. No other safety concerns were identified; moreover, N9-GP provided effective hemostatic coverage.Hemostasis is a complex process involving the concerted action of molecular and vascular components. Its basic understanding as well as diagnostic and therapeutic aspects have greatly benefited from the use of monoclonal antibodies. Interestingly, camelid-derived single-domain antibodies (sdAbs), also known as VHH or nanobodies, have become available during the previous 2 decades as alternative tools in this regard. Compared to classic antibodies, sdAbs are easier to produce and their small size facilitates their engineering and functionalization. It is not surprising, therefore, that sdAbs are increasingly used in hemostasis-related research. In addition, they have the capacity to recognize unique epitopes unavailable to full monoclonal antibodies. This property can be used to develop novel diagnostic tests identifying conformational variants of hemostatic proteins. Examples include sdAbs that bind active but not globular von Willebrand factor or free factor VIIa but not tissue factor-bound factor VIIa. Finally, sdAbs have a high therapeutic potential, exemplified by caplacizumab, a homodimeric sdAb targeting von Willebrand factor that is approved for the treatment of thrombotic thrombocytopenic purpura. In this review, the various applications of sdAbs in thrombosis and hemostasis-related research, diagnostics, and therapeutic strategies will be discussed.Accounts of the numerous negative effects caused by COVID-19 are pervasive, but few perspectives have identified any positive impacts of this massive societal shift. This forum examines potentially positive changes that have occurred within the scientific community amid the chaotic pandemic. Among these positives are the formation of virtual supergroups and an interdisciplinary brain trust. In forcing scientists away from their lab benches, COVID-19 has created time and space for more conversations about science and experimental design. Being away from the lab in this time of social unrest has also given scientists time to directly address institutional racism and its suppression of diversity in science. Although COVID-19 has been an unforeseen disaster of epic proportions, some of the resulting changes in our scientific community should remain in place after the pandemic is over. By leveraging these small wins, we will undoubtedly return to our laboratories stronger, smarter, and more efficient.
Correct diagnosis of the cause of thrombocytopenia is crucial for the appropriate management of patients. Hyposialylation/desialylation (characterized by abnormally high β-galactose exposure) accelerates platelet clearance and can lead to thrombocytopenia. However, the reference range for β-galactose exposure in healthy individuals has not been defined previously.

The objective of the present study was to develop a standardized assay of platelet β-galactose exposure for implementation in a clinical laboratory.

β-Galactose exposure was measured in platelet-rich plasma by using flow cytometry and
agglutinin (RCA). A population of 120 healthy adults was recruited to study variability.

We determined an optimal RCA concentration of 12.5μg/mL. The measure was stable for up to 4hours (mean fluorescence intensity [MFI]-RCA 1233±329 at 0 hour and 1480±410 at 4 hours). The platelet count did not induce a variation of RCA and the measure of RCA was stable when tested up to 24hours after blood collection (MFI-RCA 1252±434 at day 0 and 1140±297 24hours after blood sampling). To take into account the platelet size, results should be expressed as RCA/forward scatter ratio. We used the assay to study variability in 120 healthy adults, and we found that the ratio is independent of sex and blood group.

We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β-galactose exposure.
We defined a normal range in a healthy population and several preanalytical and analytical variables were evaluated, together with positive and negative controls. This assay may assist in the diagnosis of thrombocytopenic diseases linked to changes in β-galactose exposure.Air pollution represents a major public health threat in India affecting 19% of the world's population at extreme levels. Despite this, research in India lags behind in large part due to a lack of comprehensive air pollution exposure assessment that can be used in conjunction with health data to investigate health effects. Our vision is to provide a consortium to rapidly expand the evidence base of the multiple effects of ambient air pollution. We intend to leapfrog current limitations of exposure assessment by developing a machine-learned satellite-informed spatiotemporal model to estimate daily levels of ambient fine particulate matter measuring less than 2.5 µm (PM2.5) at a fine spatial scale across all of India. To catalyze health effects research on an unprecedented scale, we will make the output from this model publicly available. In addition, we will also apply these PM2.5 estimates to study the health outcomes of greatest public health importance in India, including cardiovascular diseases, chronic obstructive pulmonary disease, pregnancy (and birth) outcomes, and cognitive development and/or decline. Thus, our efforts will directly generate actionable new evidence on the myriad effects of air pollution on health that can inform policy decisions, while providing a comprehensive and publicly available resource for future studies on both exposure and health effects. In this commentary, we discuss the motivation, rationale, and vision for our consortium and a path forward for reducing the enormous burden of disease from air pollution in India.Skeletal development is a tightly orchestrated process in which cartilage and bone differentiation are intricately intertwined. Recent studies have highlighted the contribution of epigenetic modifications and their writers to skeletal development. Methylated cytosine (5mC) can be oxidized to 5-hydroxymethylcytosine (5hmC) by the Ten-eleven-translocation (TET) enzymes leading to demethylation. We have previously demonstrated that 5hmC is stably accumulated on lineage-specific genes that are activated during in vitro chondrogenesis in the ATDC5 chondroprogenitors. Knockdown (KD) of Tet1 via short-hairpin RNAs blocked ATDC5 chondrogenic differentiation. Here, we aimed to provide the mechanistic basis for TET1 function during ATDC5 differentiation. Transcriptomic analysis of Tet1 KD cells demonstrated that 54% of downregulated genes were SOX9 targets, suggesting a role for TET1 in mediating activation of a subset of the SOX9 target genes. Using genome-wide mapping of 5hmC during ATDC5 differentiation, we found that 5hmC is preferentially accumulated at chondrocyte-specific class II binding sites for SOX9, as compared with the tissue-agnostic class I sites. Specifically, we find that SOX9 is unable to bind to Col2a1 and Acan after Tet1 KD, despite no changes in SOX9 levels. Finally, we compared this KD scenario with the genetic loss of TET1 in the growth plate using Tet1 -/- embryos, which are approximately 10% smaller than their WT counterparts. In E17.5 Tet1 -/- embryos, loss of SOX9 target gene expression is more modest than upon Tet1 KD in vitro. Overall, our data suggest a role for TET1-mediated 5hmC deposition in partly shaping an epigenome conducive for SOX9 function. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Persons with neurologically motor-complete spinal cord injury (SCI) have a marked loss of bone mineral density (BMD) of the long bones of the lower extremities, predisposing them to fragility fractures, especially at the knee. Denosumab, a commercially available human monoclonal IgG antibody to receptor activator of nuclear factor-κB ligand (RANKL), may provide an immunopharmacological solution to the rapid progressive deterioration of sublesional bone after SCI. Twenty-six SCI participants with subacute motor-complete SCI were randomized to receive either denosumab (60 mg) or placebo at baseline (BL), 6, and 12 months. Areal bone mineral density (aBMD) by dual energy x-ray absorptiometry (DXA) at 18 months at the distal femur was the primary outcome and aBMD of the proximal tibia and hip were the secondary outcomes analyzed in 18 of the 26 participants (denosumab, n = 10 and placebo, n = 8). The metrics of peripheral QCT (pQCT) were the exploratory outcomes analyzed in a subsample of the cohort (denosumab, nMD (vBMD) and trabecular vBMD at the 4% distal tibia region, with a significant percent loss for total bone mineral content. Thus, at 18 months after acute SCI, our findings show that denosumab maintained aBMD at the knee region, the site of greatest clinical relevance in the SCI population. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
Clinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal.

The objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal.

This retrospective cohort study was conducted at a single academic medical center.

Eighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease.

Changes in serum PSA concentrations were measured during testosterone treatment for up to 18 months.

Testosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treategree of hypogonadism.
Prediabetes, an often unrecognized precursor of type 2 diabetes (T2DM), is associated with cardiometabolic complications. Here, we investigated the utility of dexamethasone challenge in predicting incident prediabetes among normoglycemic subjects with parental T2DM enrolled in the prospective Pathobiology of Prediabetes in a Biracial Cohort study.

After documenting normoglycemic status with an oral glucose tolerance test (OGTT), participants ingested dexamethasone (2 mg) at 1000 pm, and fasting plasma glucose (FPG-Dex) and cortisol were measured at 800 am the next day. Subjects were followed quarterly for 5 years, the primary outcome being incident prediabetes. Serial assessments included body composition, blood chemistry, OGTT, insulin sensitivity, and secretion.

We analyzed data from 190 participants (107 Black, 83 white; mean age 44.7 ± 10.0 years; body mass index [BMI] 29.8 ± 6.8 kg/m
; fasting plasma glucose [FPG] 90.9 ± 5.7 mg/dL). Following dexamethasone ingestion, plasma cortisol was < 5 µg/dL; FPG-Dex levels displayed marked variability (81-145 mg/dL) as did delta FPG (-7 to +48 mg/dL).
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