1st-3rd Quartiles Research Articles

Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium–glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7–31.2) vs. 55.9 (51.0–64.5), STZ: 83.4 (53.7–91.7) vs. 121.2 (57.0–136.0) μL·min−1·kg−1, median (1st–3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8–18.4) vs. 10.5 (2.9–19.0), STZ: 36.9 (25.7–54.9) vs. 32.8 (15.1–37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA–AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Adjustment of segmental rotations to achieve both racket speed and accuracy at various impact heights during a two-handed backhand stroke

ABSTRACT This study investigated the influence of impact height and competitive level on racket speed and stroke accuracy by analysing segmental angular kinematics under a random ball condition. High- (HQ, n = 7) and low-quality (LQ, n = 7) groups were determined by k-means clustering of the ratio of ball landing in the target (accuracy) and racket speed decrease. HQ showed higher accuracy (48.3% vs. 32.4%), less speed decrease at lower impact heights (−4.4% vs. −10.3%) and better competitive level ranking [median (1st–3rd quartiles); 4 (2–7)] than LQ [10 (8–13)]. HQ produced greater racket speed (24.4 vs. 21.6 m/s), especially with a notable horizontal velocity (23.8 vs. 20.8 m/s) of the racket at lower impact height, which was attributed to the central role of greater angular velocity of pelvis and thorax in the hitting direction. Both groups showed similar adjustment mechanisms that due to the decrease in angular velocity of pelvis, players increased the relative rotation angle between pelvis and thorax to maintain angular velocity of thorax when transitioning from low to high impact heights. Our findings suggest that players should emphasise the coordination between pelvic and thoracic rotations according to impact heights to maintain racket speed while controlling ball landing position.

Is It Safe to Treat Stable Patients with Bacteremic Urinary Tract Infections with High-Resistant-Rate Antibiotics?

In most areas of the world, urine bacteria have high resistance rates to third-generation cephalosporins, and it is unclear if it is safe to treat stable patients with bacteremic urinary tract infections (UTI) with those antibiotics. There are recommendations that empiric therapy for a suspected UTI should include only antibiotics with resistance rates less than 10%. In this historical observational single center study, we selected 180 stable internal medicine patients hospitalized between January 2019 and December 2021, with identical bacteria isolated from blood and urine cultures. Charts were reviewed to determine if deaths and readmissions up to 30 days after discharge were due to bacterial resistance to initial antibiotic therapy (BRIAT). The patient's median age was 82 years (1st-3rd quartiles, 73-87 years). A total of 54.4% were female. There were 125 patients treated with ceftriaxone. A total of 38 (30.3%) had BRIAT. Four patients died, but none were because of a delay in appropriate treatment. The median days of hospitalization for all patients was 7 days, and 9 days versus 6 days in those with and without BRIAT. There were no re-hospitalizations for a UTI in patients with BRIAT. We conclude that, despite high resistance rates, empiric ceftriaxone in stable hospitalized patients with a bacteremic UTI is safe. There was no urosepsis-related mortality during the hospitalization or on follow-up. The treatment of all patients with wider-spectrum antibiotics might have decreased the median hospital stay by only one day. The potential effect would be even lower if all patients with a suspected systemic UTI were treated with wide-spectrum antibiotics, because some patients do not have an infection of the urinary tract. A reassessment of the recommendation that empiric therapy for a suspected systemic urinary tract infection should include only wider-spectrum antibiotics is warranted.

The real time to surgery: Limited delay after medical optimization does not impact hip fracture surgery outcomes

IntroductionCurrent U.S./Canadian guidelines recommend hip fracture surgery within 48 h of injury to decrease morbidity/mortality. Multiple studies have identified medical optimization as the key component of time to surgery, but have inherent bias as patients with multiple co-morbidities often take longer to optimize. This study aimed to evaluate time from medical optimization to surgery (TMOS) to determine if “real surgical delay” is associated with: 1) mortality and 2) complications for geriatric hip fracture patients. MethodsA retrospective chart review of geriatric hip fractures treated from 2015–2018 at a single, level-1 trauma center was conducted. Univariate logistic regression was performed to identify association between TMOS and post-operative complication rates. For mortality, the Wilcoxon test was used to compare TMOS for patients discharged following surgery to those who were not. ResultsA total of 884 hip fractures were treated operatively, with median TMOS 16.2 h (5.0–22.5, 1st-3rd quartiles). Univariate logistic regression models did not identify an association between TMOS and complication rates. For patients successfully discharged, median TMOS was 16.2 h (5.0–22.3, 1st-3rd quartiles). For the cohort of patients not successfully discharged, median TMOS was 19.1 h (10.1–25.9, 1st-3rd quartiles, p = 0.16). Conclusion“Real surgical delay”, or TMOS is not associated with increased complications or with inpatient mortality for geriatric hip fracture patients. With few exceptions, our institution adhered to the 48-hour time window from injury to hip surgery. We maintain the belief timely surgery following optimization plays a crucial role in the geriatric hip fracture patient outcomes.

Effect of automated head-thorax elevation during chest compressions on lung ventilation: a model study

Our goal was to investigate the effects of head-thorax elevation (HUP) during chest compressions (CC) on lung ventilation. A prospective study was performed on seven human cadavers. Chest was automatically compressed-decompressed in flat position and during progressive HUP from 18 to 35°. Lung ventilation was measured with electrical impedance tomography. In each cadaver, 5 sequences were randomly performed: one without CC at positive end-expiratory pressure (PEEP) 0cmH2O, 3 s with CC at PEEP0, 5 or 10cmH2O and 1 with CC and an impedance threshold device at PEEP0cmH2O. The minimal-to-maximal change in impedance (VTEIT in arbitrary unit a.u.) and the minimal impedance in every breathing cycle (EELI) the) were compared between flat, 18°, and 35° in each sequence by a mixed-effects model. Values are expressed as median (1st–3rd quartiles). With CC, between flat, 18° and 35° VTEIT decreased at each level of PEEP. It was 12416a.u. (10,689; 14,442), 11,239 (7667; 13,292), and 6457 (4631; 9516), respectively, at PEEP0. The same was true with the impedance threshold device. EELI/VTEIT significantly decreased from − 0.30 (− 0.40; − 0.15) before to − 1.13 (− 1.70; − 0.61) after the CC (P = 0.009). With HUP lung ventilation decreased with CC as compared to flat position. CC are associated with decreased in EELI.

Integrated myocardial flow reserve (iMFR) assessment: diffuse atherosclerosis and microvascular dysfunction are more strongly associated with mortality than focally impaired perfusion.

Although treatment of ischemia-causing epicardial stenoses may improve symptoms of ischemia, current evidence does not suggest that revascularization improves survival. Conventional myocardial ischemia imaging does not uniquely identify diffuse atherosclerosis, microvascular dysfunction, or nonobstructive epicardial stenoses. We sought to evaluate the prognostic value of integrated myocardial flow reserve (iMFR), a novel noninvasive approach to distinguish the perfusion impact of focal atherosclerosis from diffuse coronary disease. This study analyzed a large single-center registry of consecutive patients clinically referred for rest-stress myocardial perfusion positron emission tomography. Cox proportional hazards modeling was used to assess the association of two previously reported and two novel perfusion measures with mortality risk: global stress myocardial blood flow (MBF); global myocardial flow reserve (MFR); and two metrics derived from iMFR analysis: the extents of focal and diffusely impaired perfusion. In total, 6867 patients were included with a median follow-up of 3.4 years [1st-3rd quartiles, 1.9-5.0] and 1444 deaths (21%). Although all evaluated perfusion measures were independently associated with death, diffusely impaired perfusion extent (hazard ratio 2.65, 95%C.I. [2.37-2.97]) and global MFR (HR 2.29, 95%C.I. [2.08-2.52]) were consistently stronger predictors than stress MBF (HR 1.62, 95%C.I. [1.46-1.79]). Focally impaired perfusion extent (HR 1.09, 95%C.I. [1.03-1.16]) was only moderately related to mortality. Diffusely impaired perfusion extent remained a significant independent predictor of death when combined with global MFR (p < 0.0001), providing improved risk stratification (overall net reclassification improvement 0.246, 95%C.I. [0.183-0.310]). The extent of diffusely impaired perfusion is a strong independent and additive marker of mortality risk beyond traditional risk factors, standard perfusion imaging, and global MFR, while focally impaired perfusion is only moderately related to mortality.

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

Photoplethysmography waveform analysis for classification of vascular tone and arterial blood pressure: Study based on neural networks

To test whether a Shallow Neural Network (S-NN) can detect and classify vascular tone dependent changes in arterial blood pressure (ABP) by advanced photopletysmographic (PPG) waveform analysis. PPG and invasive ABP signals were recorded in 26 patients undergoing scheduled general surgery. We studied the occurrence of episodes of hypertension (systolic arterial pressure (SAP) >140 mmHg), normotension and hypotension (SAP < 90 mmHg). Vascular tone according to PPG was classified in two ways: 1) By visual inspection of changes in PPG waveform amplitude and dichrotic notch position; where Classes I-II represent vasoconstriction (notch placed >50% of PPG amplitude in small amplitude waves), Class III normal vascular tone (notch placed between 20-50% of PPG amplitude in normal waves) and Classes IV-V-VI vasodilation (notch <20% of PPG amplitude in large waves). 2) By an automated analysis, using S-NN trained and validated system that combines seven PPG derived parameters. The visual assessment was precise in detecting hypotension (sensitivity 91%, specificity 86% and accuracy 88%) and hypertension (sensitivity 93%, specificity 88% and accuracy 90%). Normotension presented as a visual Class III (III-III) (median and 1st-3rd quartiles), hypotension as a Class V (IV-VI) and hypertension as a Class II (I-III); all p < .0001. The automated S-NN performed well in classifying ABP conditions. The percentage of data with correct classification by S-ANN was 83% for normotension, 94% for hypotension, and 90% for hypertension. Changes in ABP were correctly classified automatically by S-NN analysis of the PPG waveform contour.

Myocardial late gadolinium enhancement using delayed 3D IR-FLASH in the pediatric population: feasibility and diagnostic performance compared to single-shot PSIR-bSSFP

BackgroundThis study compares three-dimensional (3D) high-resolution (HR) late gadolinium enhancement (LGE; 3D HR-LGE) imaging using a respiratory navigated, electrocardiographically-gated inversion recovery gradient echo sequence with conventional LGE imaging using a single-shot phase-sensitive inversion recovery (PSIR) balanced steady-state free precession (bSSFP; PSIR-bSSFP) sequence for routine clinical use in the pediatric population. MethodsPediatric patients (0–18 years) who underwent clinical cardiovascular magnetic resonance (CMR) with both 3D HR-LGE and single-shot PSIR-bSSFP LGE between January 2018 and June 2020 were included. Image quality (0–4) and detection of LGE in the left ventricle (LV) (per 17 segments), in the right ventricle (RV) (per 3 segments), as endocardial fibroelastosis (EFE), at the hinge points, and at the papillary muscles was analyzed by two blinded readers for each sequence. Ratios of the mean signal intensity of LGE to normal myocardium (LGE:Myo) and to LV blood pool (LGE:Blood) were recorded. Data is presented as median (1st–3rd quartiles). Wilcoxon signed rank test and chi-square analyses were used as appropriate. Inter-rater agreement was analyzed using weighted κ-statistics. Results102 patients were included with median age at CMR of 8 (1–13) years-old and 44% of exams performed under general anesthesia. LGE was detected in 55% of cases. 3D HR LGE compared to single-shot PSIR-bSSFP had longer scan time [4:30 (3:35–5:34) vs 1:11 (0:47–1:32) minutes, p < 0.001], higher image quality ratings [3 (3–4) vs 2 (2–3), p < 0.001], higher LGE:Myo [23.7 (16.9–31.2) vs 5.0 (2.9–9.0), p < 0.001], detected more segments of LGE in both the LV [4 (2–8) vs 3 (1–7), p = 0.045] and RV [1 (1–1) vs 1 (0–1), p < 0.001], and also detected more cases of LGE with 13/56 (23%) of patients with LGE only detectable by 3D HR LGE (p < 0.001). 3D HR LGE specifically detected a greater proportion of RV LGE (27/27 vs 17/27, p < 0.001), EFE (11/11 vs 5/11, p = 0.004), and papillary muscle LGE (14/15 vs 4/15, p < 0.001). Inter-rater agreement for the recorded variables ranged from 0.42 to 1.00. Conclusions3D HR LGE achieves greater image quality and detects more LGE than conventional single-shot PSIR-bSSFP LGE imaging, and should be considered an alternative to conventional LGE sequences for routine clinical use in the pediatric population.

Neuroimaging evaluation of unilateral asymptomatic carotid plaque ulceration: preliminary results of the Carotid Artery Multimodality imaging Prognostic study

Abstract Background Carotid plaque ulceration has been associated with imaging characteristics of high risk of future events (plaque vulnerability) in patients with a significant degree of stenosis, while little is known about its role in patients with a lesser degree of stenosis and its association with markers of vascular inflammation. Purpose We evaluated the association between imaging characteristics of plaque vulnerability and vascular inflammation detected by different imaging tests. Methods One hundred and seven patients with unilateral asymptomatic carotid artery stenosis (40–60% detected by Doppler ultrasound (DUS)), enrolled in the ongoing Carotid Artery Multimodality Prognostic (CAMP) study were prospectively evaluated with computed tomography angiography (CTA), contrast-enhanced magnetic resonance imaging (CEMRA) and, in a subgroup of patients, with 18-F-fluorodeoxyglucose positron emission tomography (PET). Plaque ulceration was detected by CTA. Variables are expressed as median (1st–3rd quartiles) and number (percentages).The Student's t-test or Mann-Whitney and Chi square or Fisher's exact test were used to study associations among variables. Results An ulcerated plaque was present in 35% patients (n=33) of those undergoing CTA (n=94), while intraplaque hemorrhage and lipid-rich necrotic core were present in 9% and 15% of those undergoing CEMRA. Compared with patients with non-ulcerated plaques, those with an ulcerated plaque had a significant higher degree of stenosis at DUS, a higher target to background ratio (TBR) at 18F-FDG-PET and a higher high-sensitivity cardiac troponin (cTn) T. Conclusions Plaque ulceration is common and associated with higher degree of stenosis, higher indices of wall inflammation and higher serum markers of myocardial injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Regione Toscana

HDL functionality in type 1 diabetes: enhancement of cholesterol efflux capacity in relationship with decreased HDL carbamylation after improvement of glycemic control

BackgroundReduced cholesterol efflux capacity (CEC) of HDLs is likely to increase cardiovascular risk in type 1 diabetes (T1D). We aimed to assess whether improvement of glycemic control in T1D patients is associated with changes in CEC in relation with changes in carbamylation of HDLs.MethodsIn this open-label trial, 27 uncontrolled T1D patients were given a three-month standard medical intervention to improve glycemic control. HDL fraction was isolated from plasma, and CEC was measured on THP-1 macrophages. Carbamylation of HDLs was evaluated by an immunoassay. Control HDLs from healthy subjects were carbamylated in vitro with potassium cyanate.ResultsHbA1c decreased from 11.4% [10.2–12.9] (median [1st–3rd quartiles]) at baseline to 8.1% [6.6–9.0] after the three-month intervention (P < 0.00001). The CEC of HDLs increased after intervention in 19 (70%) patients (P = 0.038). At the same time, the carbamylation of HDLs decreased in 22 (82%) patients after intervention (P = 0.014). The increase in CEC significantly correlated with the decrease in carbamylated HDLs (r = −0.411, P = 0.034), even after adjustment for the change in HbA1c (β = −0.527, P = 0.003). In vitro carbamylation of control HDLs decreased CEC by 13% (P = 0.041) and 23% (P = 0.021) using 1 and 10 mmol/L of potassium cyanate, respectively.ConclusionsThe improvement of CEC in relation to a decrease in the carbamylation of HDLs may likely contribute to the beneficial cardiovascular effect of glycemic control in T1D patients.Trial registration: NCT02816099 ClinicalTrials.gov.

Sodium Intake and Salt Taste Preference During Adolescence: Followup of a Randomized Controlled Field Trial

ObjectivesDetermine whether dietary counseling on breastfeeding and healthy eating for mothers during the early postpartum period interacted with or was independent of sodium intake and pubertal development in predicting the concentration of salty taste most preferred by adolescents. MethodsWe conducted follow-up assessments of children aged 12 years (n = 202) whose mothers participated in a randomized controlled field trial when they were infants; the trial was designed to determine the impact of the dietary counseling for low-income mothers during the early postpartum period. Sodium intake was assessed using two, 24-hour dietary recalls from which we focused on sodium from processed and ultra-processed foods, classified according to the “NOVA” system; the most preferred level of salt was evaluated by the Monell two-series, forced-choice, paired comparison tracking method; and pubertal development was classified according to the Tanner stages. The associations of the randomization group, tanner stage, and sodium intake from processed and ultra-processed foods (4th quartile vs 1st–3rd quartiles) with the most preferred level of salt were assessed using multivariate linear regression. Variables such as birth weight, duration of exclusive breastfeeding, household income, skin color, BM-for-age Z, and height-for-age Z score were also included in the multivariate model for adjustment. ResultsIndependent of randomized groups (p = 0.14), children in Tanner stages 1–3 most preferred significantly higher concentrations of salty taste than those in later stages (β = 0.43; p = 0.02). Higher intakes of sodium from processed and ultra-processed foods were also associated with a preference for higher concentrations of salty taste (β = 0.52; p = 0.01). ConclusionsPrior to the cessation of puberty children most prefer higher concentration of salty of puberty adolescents prefer higher salt concentrations, evidencing that biological needs play an important role in driving salty-taste preferences. Therefore, it is relevant to promote healthy food habits among adolescents to prevent the excessive consumption of processed and ultra-processed foods which are not only rich in sodium, but also in sugar and fat. Funding SourcesBrazil National Council for Scientific and Technological Development; NIH Grant R01DC016616 to JAM.

High concentration of symmetric dimethylarginine is associated with low platelet reactivity and increased bleeding risk in patients with acute coronary syndrome

BackgroundDual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs). ObjectivesOur study evaluated the role of SDMA in predicting bleeding events in patients after ACS treated with DAPT. MethodsWe compared plasma concentrations of NO-related pathway metabolites in patients with ACS (n = 291) and investigated the prognostic value of SDMA as a bleeding predictor during 1-year follow-up. We measured the metabolites concentration using ultra performance liquid chromatography. Platelet reactivity was determined using impedance aggregometry. ResultsPatients with the highest quartile (4th) of SDMA concentration had significantly lower platelet aggregation compared to those in the 1st-3rd quartiles of SDMA, based on ADP + PGE1-, AA-, and ADP-induced platelet reactivity tests (p = 0.0004, p = 0.002, p = 0.014, respectively). Patients with major or minor bleeding events had significantly higher concentrations of SDMA as compared to those without bleeding events or to those with minimal bleeding events (p = 0.019, p = 0.019, respectively). ConclusionHigher SDMA concentration is associated with lower platelet reactivity and is associated with major and minor bleeding events in patients with ACS on DAPT. Therefore, SDMA stands as a potential biomarker for individualization of duration and potency of antiplatelet therapies in the ACS population at high risk of bleeding complications.

High Patient Satisfaction with Examination by Advanced Practice Physiotherapists in an Orthopaedic Outpatient Shoulder Clinic: A Cross-Sectional Study Using Quantitative and Qualitative Methods.

Purpose: To evaluate patients' satisfaction with being examined and diagnosed in an orthopaedic outpatient shoulder clinic, determine whether a difference exists between levels of satisfaction among patients examined by advanced practice physiotherapists (APPs) and orthopaedic surgeons (OSs), and explore patients' experiences with being examined by APPs. Method: One hundred and thirty-three patients participated in a cross-sectional questionnaire study using the Visit-Specific Satisfaction Instrument (VSQ-9). Primary outcome was satisfaction with "The visit overall" (item 9). Nine patients participated in semi-structured interviews, which were thematically analyzed. Results:There was no significant difference in satisfaction with "The visit overall" between patients examined by an OS (median: 75, 1st-3rd quartiles: 75-100) and an APP (median: 100, 1st-3rd quartiles: 75-100). The VSQ-9 total score was not significantly different between groups, but some items regarding direct interaction with the health provider were scored significantly higher in the APP group. Patients were particularly satisfied with APPs' ability to explain during the consultation. Conclusions: The results showed high levels of satisfaction with examinations performed by both OSs and APPs with no difference between groups concerning "The visit overall." From a patient perspective, the results support the use of APPs to examine and diagnose selected patients in an orthopaedic outpatient shoulder clinic.

Aberrant ARID5B Expression and Its Association with Ikaros Dysfunction in Acute Lymphoblastic Leukemia

Background: AT-rich interactive domain-containing protein 5B (ARID5B) forms a complex with PHD finger protein 2 (PHF2) and the ARID5B-PHF2 complex then induces the demethylation of di-methylated 'Lys-9' of histone H3 (H3K9me2) leading to transcription activation target genes. Mutations and single nucleotide polymorphisms of ARID5B are associated with the development of acute lymphoblastic leukemia (ALL) and treatment outcome. So far there have been no reports about ARID5B expression in ALL and the clinical significance of ARID5BlowPHF2low expression in ALL patients. Ikaros, the product of the IKZF1 gene, plays a critical role in lymphocyte development and functions as a tumor suppressor of leukemia. ChIP-seq data show the obvious Ikaros binding peaks in promoter of ARID5B, which suggested the regulatory role of Ikaros on ARID5B expression in ALL cells. Methods: 164 Subjects with newly-diagnosed ALL (107 B-cell and 57 T-cell ALL; 12-77 years old) between June 2008 and June 2016 were studied at the First Affiliated Hospital of Nanjing Medical University and Zhongda Hospital Southeast University. The study was approved by the Ethics Committee of the institutes. Subjects were allocated in a high or low ARID5B expression cohort (4th quartile vs . 1st-3rd quartiles) with a cut-off value determined by SPSS 20.0. The qChIP assays were performed by incubating chromatin with antibodies against Ikaros, H3K4me3 or normal rabbit IgG as a control. The Nalm6 and CEM cells were transfected with human IKZF1 shRNA or Scrambled shRNA constructs in the GFP vector (pGFP-v-RS) by Neon system. Median differences between the cohorts were evaluated using a Mann-Whitney U-test. Frequency differences were analyzed using uni- and multivariate Cox model. Relapse-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. Results: We observed the ARID5B mRNA level is significantly down-regulated in subset of ALL patients. Low ARID5B mRNA levels were associated with leukemic cell proliferation and poor prognostic indicators. Particularly ARID5B expression is positively correlated with PHF2 expression in ALL. The ARID5BlowPHF2low was associated with a higher percentage of bone marrow blasts (91.2% vs. 82.4%, P =0.000), stem cell marker CD34+ (88.2% vs. 55.6%, P =0.000), myeloid marker CD33+ (50.9% vs. 28.6%, P =0.036), splenomegaly (50.0% vs. 22.9%, P =0.008), a complete remission(CR) time ≥4 weeks (53% vs. 21%, P =0.003) and higher frequency of Ik 6(+) (49.3% vs. 15.8%, P =0.001) and lower median PLT count (109/L) (32.0 vs. 58.5, P =0.020) compared to patients with non- ARID5BlowPHF2low cohort. The multivariable analysis confirmed the association with bone marrow blasts, Ik 6(+) and a CR time ≥4 weeks. ChIP-seq data shows Ikaros binding peaks in the ARID5B promoter region in Nalm6 B-ALL and primary B-cell ALL cells and the bindings wereconfirmed by individual qChIP assay. Moreover, expression of Ikaros promotes ARID5B expression, while efficient Ikaros knockdown decreased ARID5B expression in Nalm6 and CEM cells. We also found ARID5B expression was significantly lower in B-ALL with Ik6(+) (0.3153 ± 0.0938 vs. 1.2052 ± 0.58441, P =0.02439). Treatment of Nalm6 and CEM cells with CX-4945, which functions as IKAROS activator, promotes expression of ARID5B mRNA in a dose-dependent manner in ALL cell lines and patients' samples, and Ikaros knockdown significantly blocked this effect. Moreover,CX-4945 treatment significantly increases binding of Ikaros and enrichment of H3K4me3 to the ARID5B promoter region in Nalm6 and CEM ALL cells, as well as in patients' samples. Conclusion: We identified that ARID5Blow, particularly ARID5BlowPHF2low expression is associated with leukemia proliferation and poor prognostic markers. Our results also revealed the oncogenic effect of ARID5BlowPHF2low expression in ALL, and identified a high-risk subgroup of ALL characterized by Ikaros dysfunction and ARID5BlowPHF2low expression. DisclosuresDovat:ELF Zone Inc: Membership on an entity's Board of Directors or advisory committees.

Clinical Significance of Phd Finger Protein 2 As a Novel Ikaros Target in Acute Lymphoblastic Leukemia

Background: PHD finger protein 2 (PHF2) mediates demethylation of dimethylated ‘Lys-9‘ of histone H3 (H3K9me2), followed by transcription activation of target genes. PHF2 is a positive epigenetic regulator and is associated with tumor suppression in several types of cancer. Until now, there have been no reports about the PHF2 expression in leukemia patients and its roles in acute lymphoblastic leukemia (ALL).Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high risk B-progenitor ALL and are associated with poor outcome. However, it is still undetermined whether and how IKAROS regulates PHF2 expression. Methods: The 164 patients with newly-diagnosed ALL (107 B-ALL and 57 T-ALL; 12-77 years old) were recruited between June 2008 and June 2016 at the First Affiliated Hospital of Nanjing Medical University and Zhongda Hospital Southeast University. The study was approved by the Ethics Committee of the two hospitals. Patients were allocated into high or low PHF2 expression cohorts (4th quartile vs . 1st-3rd quartiles) with a cut-off value determined by SPSS 20.0. The genomic amplification combined direct sequencing was used for detection of IKZF1 deletion. PHF2 expression was determined by qPCR in cells . The enrichment of IKAROS binding and H3K4me3 in the promoter of PHF2 was determined by the chromatin-immunoprecipitation assay combined qPCR (qChIP). IKZF1 knockdown was achieved in cells by transfection of human IKZF1 shRNA constructs in the GFP vector using the Neon Transfection System and with scrambled shRNA as a control. Median differences between the cohorts were evaluated using a Mann-Whitney U-test. Frequency differences were analyzed using univariate and multivariate Cox models. Relapse-free survival and overall survival were estimated by the Kaplan-Meier method and compared by log-rank test. Statistical analyses used SPSS version 20.0. Results: PHF2 mRNA levels in bone marrow samples from adults with ALL, especially those with B-cell ALL (B-ALL), were significantly lower than those in normals. The B-ALL cohort with low PHF2 mRNA levels was associated with a higher median bone marrow blast percentage (90.4% vs. 82.4%; P=0.001), a higher percentage of stem cell marker CD34+ (82.3% vs. 60.0%; P=0.021), myeloid marker CD33+ (48.5% vs. 25.0%; P=0.046), splenomegaly (46.8% vs. 23.1%, P=0.034) and delayed remission more than 4 weeks (48.7% vs. 19.0%; P=0.015), also a higher frequency of Ik6 (+) (46.3% vs. 8.0%, P=0.001) and a lower median PLT count in comparison to the high PHF2 expression cohort. Moreover, ChIP-seq data identified IKAROS binding peaks in the PHF2 promoter region in Nalm6 B-ALL and primary B-ALL cellsand the bindings were confirmed by the qChIP assay . IKAROS overexpression promotes PHF2 mRNA levels, conversely, IKZF1 knockdown decreased PHF2 expression in Nalm6 and CEM cells. These data indicate a direct effect of IKAROS on PHF2 transcription. The patients with IKZF1 deletion (Ik 6) have significantly lower PHF2 expression (0.03201 ± 0.000527 vs. 0.11331± 0.05773; P=0.033), which suggests that the IKZF1 deletion may contribute to low PHF2 expression in ALL patients. Treatment of Nalm6 and CEM cells with CK2 inhibitor CX-4945, which functions as IKAROS activator, promoted expression of PHF2 mRNA in ALL cell lines and primary cells and IKZF1 knockdown blocks this effect. CX-4945 treatment also increases the binding of IKAROS and H3K4me3 enrichment to the PHF2 promoter region in Nalm6 and CEM ALL cells as well as in primary ALL cells. Conclusion: PHF2 low expression was significantly associated with leukemia proliferation and several poor prognostic indicators in adult ALL patients. IKAROS directly regulates PHF2 transcription, and that CK2 inhibitor promotes PHF2 transcription through histone modification in an IKAROS dependent manner. Our data demonstrates the oncogenic effects of IKAROS dysfunction induced decreases in PHF2 expression. This is the first report to demonstrate that low PHF2 expression is significantly associated with Acute Lymphoblastic Leukemia. We suggest that PHF2 expression levelsmay be integrated into future adult ALL risk-stratification models. DisclosuresDovat:ELF Zone Inc: Membership on an entity's Board of Directors or advisory committees.

Physical Activity, Sleep, and Sedentary Behavior among Successful Long-Term Weight Loss Maintainers: Findings from a U.S. National Study.

Despite adults’ desire to reduce body mass (weight) for numerous health benefits, few are able to successfully lose at least 5% of their starting weight. There is evidence on the independent associations of physical activity, sedentary behaviors, and sleep with weight loss; however, this study provided insight on the combined effects of these behaviors on long-term body weight loss success. Hence, the purpose of this cross-sectional study was to evaluate the joint relations of sleep, physical activity, and sedentary behaviors with successful long-term weight loss. Data are from the 2005–2006 wave of the National Health and Examination Survey (NHANES). Physical activity and sedentary behavior were measured with an accelerometer, whereas sleep time was self-reported. Physical activity and sleep were dichotomized into meeting guidelines (active/not active, ideal sleep/short sleep), and sedentary time was categorized into prolonged sedentary time (4th quartile) compared to low sedentary time (1st–3rd quartiles). The dichotomized behaviors were combined to form 12 unique behavioral combinations. Two-step multivariable regression models were used to determine the associations between the behavioral combinations with (1) long-term weight loss success (≥5% body mass reduction for ≥12-months) and (2) the amount of body mass reduction among those who were successful. After adjustment for relevant factors, there were no significant associations between any of the independent body weight loss behaviors (physical activity, sedentary time, and sleep) and successful long-term weight loss. However, after combining the behaviors, those who were active (≥150 min MVPA weekly), regardless of their sedentary time, were significantly (p < 0.05) more likely to have long-term weight loss success compared to the inactive and sedentary referent group. These results should be confirmed in longitudinal analyses, including investigation of characteristics of waking (type, domain, and context) and sleep (quality metrics) behaviors for their association with long-term weight loss success.

Simultaneous ventilation in the Covid-19 pandemic. A bench study

COVID-19 pandemic sets the healthcare system to a shortage of ventilators. We aimed at assessing tidal volume (VT) delivery and air recirculation during expiration when one ventilator is divided into 2 test-lungs. The study was performed in a research laboratory in a medical ICU of a University hospital. An ICU (V500) and a lower-level ventilator (Elisée 350) were attached to two test-lungs (QuickLung) through a dedicated flow-splitter. A 50 mL/cmH2O Compliance (C) and 5 cmH2O/L/s Resistance (R) were set in both A and B test-lungs (A C50R5 / B C50R5, step1), A C50-R20 / B C20-R20 (step 2), A C20-R20 / B C10-R20 (step 3), and A C50-R20 / B C20-R5 (step 4). Each ventilator was set in volume and pressure control mode to deliver 800mL VT. We assessed VT from a pneumotachograph placed immediately before each lung, pendelluft air, and expiratory resistance (circuit and valve). Values are median (1st-3rd quartiles) and compared between ventilators by non-parametric tests. Between Elisée 350 and V500 in volume control VT in A/B test- lungs were 381/387 vs. 412/433 mL in step 1, 501/270 vs. 492/370 mL in step 2, 509/237 vs. 496/332 mL in step 3, and 496/281 vs. 480/329 mL in step 4. In pressure control the corresponding values were 373/336 vs. 430/414 mL, 416/185 vs. 322/234 mL, 193/108 vs. 176/ 92 mL and 422/201 vs. 481/329mL, respectively (P<0.001 between ventilators at each step for each volume). Pendelluft air volume ranged between 0.7 to 37.8 ml and negatively correlated with expiratory resistance in steps 2 and 3. The lower-level ventilator performed closely to the ICU ventilator. In the clinical setting, these findings suggest that, due to dependence of VT to C, pressure control should be preferred to maintain adequate VT at least in one patient when C and/or R changes abruptly and monitoring of VT should be done carefully. Increasing expiratory resistance should reduce pendelluft volume.

N-terminal pro–B-type natriuretic peptide is a specific predictor of appropriate device therapies in patients with primary prevention implantable cardioverter-defibrillators

Sudden death risk stratification of patients with left ventricular systolic dysfunction remains challenging. Retrospective studies have suggested N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be a useful risk stratification tool. The purpose of this study was to ascertain the utility of NT-proBNP as a predictor of appropriate implantable cardioverter-defibrillator (ICD) therapies in primary prevention ICD recipients. This was a prospective study of 342 stable patients with left ventricular ejection fraction ≤40% who received a primary prevention ICD. NT-proBNP assay was performed at the time of device implant and used as a dichotomized variable (1st-3rd NT-proBNP quartiles vs 4th NT-proBNP quartile) to predict primary (appropriate ICD therapies) and secondary (death, ICD-deactivation, chronic inotropic support, transplant) outcomes. Median follow-up was 35.0 months (interquartile range 15.2-55.3). In unadjusted analyses, NT-proBNP predicted both primary (hazard ratio [HR] 1.89; 95% confidence interval [CI] 1.00-3.56); P = .049) and secondary outcomes (HR 2.13; 95% CI 1.18-3.85; P =.012). Multivariable analysis reaffirmed NT-proBNP as a primary outcome predictor (HR 4.31; 95% CI 1.92-9.70; P<.001) but not as a secondary outcome predictor (HR 1.23; 95% CI 0.61-2.50; P = .564). Instead, secondary outcome was predicted by patient age and renal function. In an unadjusted subanalysis limited to patients with blood urea nitrogen <30 mg/dL, NT-proBNP remained a primary endpoint predictor (HR 2.51; 95% CI 1.25-5.05; P = .010) but not a secondary endpoint predictor (HR 1.34; 95% CI 0.52-3.44; P = .541). Receiver operating analyses at 2- and 3-year follow-up timepoints confirmed that NT-proBNP significantly improved the performance of multivariable models designed to predict future appropriate ICD therapies. In multivariable analysis, NT-proBNP is a reasonable and specific predictor of future appropriate device therapies in primary prevention ICD recipients. In contrast, adjusted NT-proBNP does not predict all-cause mortality.

Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.

Hypercoagulability and endotheliopathy reported in patients with coronavirus disease 2019 (COVID-19) combined with strict and prolonged immobilization inherent to deep sedation and administration of neuromuscular blockers for Acute Respiratory Distress Syndrome (ARDS) may expose critically ill COVID-19 patients to an increased risk of venous thrombosis and pulmonary embolism (PE). We aimed to assess the rate and to describe the clinical features and the outcomes of ARDS COVID-19 patients diagnosed with PE during ICU stay. From March 13th to April 24th 2020, a total of 92 patients (median age: 61 years, 1st-3rd quartiles [55–70]; males: n = 73/92, 79%; baseline SOFA: 4 [3–7] and SAPS II: 31 [21–40]; invasive mechanical ventilation: n = 83/92, 90%; ICU mortality: n = 45/92, 49%) were admitted to our 41-bed COVID-19 ICU for ARDS due to COVID-19. Among them, 26 patients (n = 26/92, 28%) underwent a Computed Tomography Pulmonary Angiography which revealed PE in 16 (n = 16/26, 62%) of them, accounting for 17% (n = 16/92) of the whole cohort. PE was bilateral in 3 (19%) patients and unilateral in 13 (81%) patients. The most proximal thrombus was localized in main (n = 4, 25%), lobar (n = 2, 12%) or segmental (n = 10, 63%) pulmonary artery. Most of the thrombi (n = 13/16, 81%) were located in a parenchymatous condensation. Only three of the 16 patients (19%) had lower limb venous thrombosis on Doppler ultrasound. Three patients were treated with alteplase and anticoagulation (n = 3/16, 19%) while the 13 others (n = 13/16, 81%) were treated with anticoagulation alone. ICU mortality was higher in patients with PE compared to that of patients without PE (n = 11/16, 69% vs. n = 2/10, 20%; p = 0.04). The low rate of lower limb venous thrombosis together with the high rate of distal pulmonary thrombus argue for a local immuno-thrombotic process associated with the classic embolic process. Further larger studies are needed to assess the real prevalence and the risk factors of pulmonary embolism/thrombosis together with its prognostic impact on critically ill patients with COVID-19.