Citations

AbstractIntroductionAs hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain.MethodsA total of 1086 dementia‐free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population‐based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016–2017) and magnetic resonance imaging of the brain (2011–2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts.ResultsHearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus.ConclusionOur results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes.

Objectives: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting: Thirty-three hospital sites in the United States ( n = 32) and Jordan ( n = 1). Patients: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions: None. Measurements and Main Results: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851–5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4–18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16–1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Objectives: To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. Design: Multicenter prospective cohort study between September 2017 and February 2018. Settings: Thirty-four hospitals in the United States and Jordan. Patients: Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. Interventions: None. Measurement and Main Results: Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, −0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45−2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19−0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27−2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63−1.18). Conclusions: The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) EL 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very high-risk features, a new dual action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis.

Abstract Background. Recent clinical trials based on immunotherapies targeting the PD-1/PD-L1 pathway have shown striking durable responses in a subset of patients with solid cancers. The Programmed death 1 (PD-1) protein is a key immune checkpoint inhibitor expressed by activated T cells. Its ligand, PD-L1, was reported highly expressed by tumor cells in some diffuse large B-cell lymphomas (DLBCL) of non-Germinal Center phenotype. We recently reported on the French multicenter GOELAMS075 trial that pre-treatment soluble PD-L1 (sPD-L1) in plasma was elevated in DLBCL patients compared to controls, and that elevated sPD-L1 was associated with inferior overall survival (OS), independent of the International Prognostic Index (IPI) and other clinical factors (Rossille et al., Leukemia 2014). Here, we replicate and extend these findings in two independent studies from Australia and the US. Methods. The protein expression of sPD-L1 was evaluated using a commercial ELISA kit. The French discovery cohort consisted of 288 adults with newly diagnosed aggressive DLBCL, age 18 to 60 years, and treated with R-CHOP or high dose chemotherapy plus rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379); there were also 60 controls. The Australian study consisted of 51 DLBCL patients age 18 to 71 years, all stages, treated with R-CHOP14, along with 57 controls. The US study was an observational cohort from the Iowa/Mayo Lymphoma SPORE and consisted of 225 DLBCLs, age 19 to 92 years, all stages, treated with immunochemotherapy, along with 98 controls. Plasma samples were collected pre-treatment using EDTA tubes for the Australian and the US cohorts, BDª P100 tubes for the French cohort. sPD-L1 expression was measured in Rennes, France (French & US samples) and in Brisbane, Australia (Australian samples).The Kaplan-Meier method and Cox regression were used to model the association of sPD-L1 with OS. The 95th percentile of the sPD-L1 levels in each matched control group was used as the cutoff point to define elevated sPD-L1 levels. Results. Replicating the French findings, sPD-L1 levels were significantly higher for DLBCL patients compared to controls in both the US (P<0.0001) and Australian (P<0.0001) studies (Figure 1). The odds ratios for elevated sPD-L1 among patients compared to controls were 10.7 (95% CI 3.3-22.0), 8.9 (95% CI 3.1-25.3) and 12.6 (95% CI 2.7-28.0) for the French, US and Australian studies, respectively. In the French cohort, elevated sPD-L1 levels were associated with inferior OS (Hazard Ratio (HR)=2.05; 95% CI 1.18-3.57), and this was replicated in the US cohort (HR=1.71; 95% CI 0.97-3.01) (Figure 2). Due to the similarity of the results, we next pooled the French and US cohorts to increase power for multivariate and subset analyses. The median age at diagnosis of the 513 patients was 54 years; 29% were more than 60 years old; 69% of the patients had stage III-IV disease; 56% were IPI intermediate-risk and 9% were IPI high-risk patients. The median follow-up was 48 months (range, 0.5-126) overall, and 66 months for the patients still alive; there were 102 deaths. Using a cutpoint of 1729 pg/mL from the combined studies, patients with elevated sPD-L1 had inferior OS compared to patients without elevated sPD-L1, with 3-year OS rates estimated at 78% (95% CI 71.8-84.9) vs. 87.8% (95%CI 84.5-91.4) (P<0.01). In multivariate analysis, elevated sPD-L1 (HR=1.75; 95%CI 1.16-2.64), age (HR=1.03; 95%CI 1.02-1.05), high-risk IPI score (HR=3.71; 95%CI 1.91-7.21) and ALC ² 1 G/L (HR=2.19; 95%CI 1.44-3.33) were all significant at P<0.01. In analyses stratified by IPI, the 3-year OS rates among high-risk patients (IPI 4-5) was 40.9% (95% CI 23.6-71.0) for elevated sPD-L1 vs. 82.1% (95% CI 69.1-97.6) for not elevated sPD-L1 (P<0.01). There was no association of sPD-L1 with 3-year OS among low risk (IPI 0-1) or intermediate-risk (IPI 2-3) patients. Conclusion. We confirmed that sPD-L1 levels are higher in pre-treatment plasma samples of newly diagnosed DLBCL patients compared to controls, and that elevated levels of sPD-L1 are associated with inferior OS in DLBCL patients treated with immunochemotherapy, and this is independent of IPI and other clinical factors. Among high risk patients, we identified a subgroup with less than 50% survival. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Hereditary atransferrinemia is a rare but instructive disorder that has previously been reported in only 8 patients in 6 families. It is characterized by microcytic anemia and by iron loading, and can be treated effectively by plasma infusions. We now report the first case known in the United States. We determined the sequences flanking the exons of the human transferrin gene and sequenced all of the exons and some of the flanking regions of the patient's DNA and that of her parents. The patient's DNA revealed a 10-base pair (bp) deletion, followed by a 9-bp insertion of a duplicated sequence. There was also a G→C transversion at complementary DNA (cDNA) nt 1429, predicting that a proline was substituted for the alanine in amino acid position 477 (Ala 477 Pro). The latter mutation occurs at an evolutionarily highly conserved site; 704 control alleles were screened and this point mutation was not found. Each of the patient's transferrin genes contains one mutation, ie, the patient is a compound heterozygote for these mutations, because one was found in each of her parents. In addition to these mutations, which we regard to be causative in the patient's atransferrinemia, a silent polymorphism at cDNA 1572 G→C was found in exon 13 as well as 2 previously unreported polymorphisms at IVS8 + 62 c→t and IVS14-4 c→a. The mutation in nt 1572 and that in intron 8 were common in the general population; the intron 14 mutation is rare.

Abstract Mutations in the hemojuvelin gene (HJV) are a cause of juvenile hemochromatosis (JH), but do they influence the phenotype of patients with adult-onset hemochromatosis with or without mutations of the HFE gene? We sequenced the coding region of the HJV gene of 133 subjects with primary iron overload (75 whites: 50 HFE, 25 non-HFE associated; 51 blacks: 1 HFE-associated; 7 Asians). A 63 year old white woman with non-HFE iron overload was found to be a compound heterozygote for HJV mutations: one previously identified (G320V); the other novel (C321W). The patient was diagnosed at age 30 (SI 223 μg/100 mL, TIBC 293 μg/100 mL, TS 76%, hepatic iron 31,154 μg/g, hepatic iron index 19.2). She had 2 healthy children, developed amenorrhea at age 23, had a history of hypothyroidism and developed Type 2 diabetes at age 59. She was iron depleted after 66 phlebotomies. Among 74 other white subjects with iron overload we found 3 polymorphisms: IVS2-6 C>G (3 subjects); nt 165 T>A (G55G), and IVS4-50 C>T (1 subject, each). Among 51 black iron overloaded and 132 black control subjects, the most notable polymorphism was a DNA triplet insert predicting an insertion of glycine. This was found in 2 subjects, one with and one without iron storage disease. Among the iron overloaded black subjects, we also found IVS2-6 C>G (1 subject), nt -140 G>C (3 subjects), nt 792 G>C (S264S) (1 subject), nt 828 C>A (I275I) (1 subject), and nt 929 C>G (A310G) (2 subjects). These polymorphisms, excluding S264S and I275I, were found in control subjects as well. No coding region mutations or polymorphisms were found in the 7 Asian iron overloaded subjects. We also determined the gene frequency of the HJV I222N and G320V mutations in adult control subjects from central Alabama, where a JH index case had been found with these mutations. Allele frequencies of I222N and G320V were 0.002 (n=240) and 0 (n=241) respectively in control whites. A white control female heterozygous for the I222N was also heterozygous for HFE C282Y but had normal iron measures. No I222N and G320V mutations were found in 124 and 118 black subjects respectively. We conclude that: 1) iron overloaded patients without HFE mutations, with or without a JH phenotype should be screened for HJV; 2) HJV mutations do not account for most cases of increased penetrance of HFE-associated hemochromatosis; 3) double heterozygosity for HFE C282Y and HJV I222N does not necessarily cause iron overload.

Hereditary atransferrinemia is a rare but instructive disorder that has previously been reported in only 8 patients in 6 families. It is characterized by microcytic anemia and by iron loading, and can be treated effectively by plasma infusions. We now report the first case known in the United States. We determined the sequences flanking the exons of the human transferrin gene and sequenced all of the exons and some of the flanking regions of the patient's DNA and that of her parents. The patient's DNA revealed a 10-base pair (bp) deletion, followed by a 9-bp insertion of a duplicated sequence. There was also a G→C transversion at complementary DNA (cDNA) nt 1429, predicting that a proline was substituted for the alanine in amino acid position 477 (Ala 477 Pro). The latter mutation occurs at an evolutionarily highly conserved site; 704 control alleles were screened and this point mutation was not found. Each of the patient's transferrin genes contains one mutation, ie, the patient is a compound heterozygote for these mutations, because one was found in each of her parents. In addition to these mutations, which we regard to be causative in the patient's atransferrinemia, a silent polymorphism at cDNA 1572 G→C was found in exon 13 as well as 2 previously unreported polymorphisms at IVS8 + 62 c→t and IVS14-4 c→a. The mutation in nt 1572 and that in intron 8 were common in the general population; the intron 14 mutation is rare.

Abstract Abstract 1750 Background: Polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF) are both clonal disorders of CD34+ hematopoietic stem and progenitor cells (HSPC) that undergo inappropriate expansion. The pathological CD34+ clones from both disorders are found at increased levels in the peripheral blood of patients, indicating that the interactions between these CD34+ cells and tissue HSPC niches are different from normal HSPC. Other studies have implicated deficiencies in the CXCR4 signaling axis as a possible reason for the abnormal trafficking of HSPCs in PV and CIMF. We set out to functionally test the importance of CXCR4 for the interactions of HSPCs collected from peripheral blood of patients with PV and CIMF with the bone marrow and other tissue microenvironments. Methods: We purified CD34+ cells from peripheral blood of patients with PV or CIMF, labeled them with fluorescent trackers, and engrafted them into unmanipulated SCID mice. Using video rate, scanning confocal microscopy we tracked CD34+ cell interactions with bone marrow, spleen and liver. To functionally test the role of CXCR4 in the homing of patient CD34+ cells to different microenvironments, we treated CD34+ cells with a blocking antibody prior to engraftment. Results: Flow cytometry revealed that PV CD34+ cells had significantly lower surface expression of CXCR4 than control HSPCs (PV mean: 32.93% positive, range: 14.8–55.1; Control mean: 58.85% positive, range: 33.5–78.7; p value = 0.018) while CIMF samples had scattered CXCR4 expression (mean 61.2% positive range: 0.6–95.4) PV CD34+ cells migrated toward SDF-1 in migration assays, demonstrating that although they had lower surface CXCR4 expression, they were still able to respond to signals from the environment through this receptor. In vivo imaging of mice after engraftment revealed that PV and CIMF CD34+ cells had decreased BM homing compared to control HSPCs. However, CD34+ cells from PV and CIMF patients homed to similar areas of bone marrow vasculature as control cells. Treating CD34+ cells with a blocking antibody against CXCR4 before engraftment significantly reduced the number of PV and CIMF cells that homed to the bone marrow, indicating that their bone marrow homing still relied on CXCR4. Interestingly, there were an increased number of PV and CMF cells that homed to the spleen at baseline compared to control HSPC, suggesting that a distinct homing mechanism favored PV and CMF cell trafficking to the spleen over the BM. The number of cells that homed to the spleen increased upon antibody blockade of CXCR4, indicating that splenic homing of CD34+ cells did not depend on CXCR4/SDF-1 interactions. Conclusion: CD34+ HSPC from PV and CIMF patients and controls homed to similar areas of the BM, although PV and CIMF cells had significantly decreased BM homing. Conversely, PV and CIMF CD34+ cells homed to the spleen in significantly higher numbers than control cells. PV, CIMF and control CD34+ cells were all dependent on CXCR4 for maximal BM homing. Splenic homing was not CXCR4 dependent, however, and PV and CIMF cells homed to the spleen in higher numbers when BM homing was inhibited by CXCR4 blockade. Taken together, we conclude that unique signaling mechanisms regulate trafficking of CD34+ cells to the BM vs. the splenic microenvironments. PV and CIMF CD34+ cells have an abnormal response to these tissue signals, resulting in their preferential homing to the spleen. Molecularly targeted therapies with the Jak2 inhibitors significantly decrease splenomegaly in CIMF patients, although they do not reverse the BM disease process. Recent evidence in a mouse model suggests that the BM is in fact a sanctuary site for disease during treatment with these agents. Whether PV and CIMF CD34+ cells in patients can escape apoptosis during treatment by trafficking to more favorable microenvironments is unknown. Our study suggests that an increased understanding of the mechanisms that these cells use to engage different tissue niches could aid the treatment of these diseases. Disclosures: No relevant conflicts of interest to declare.