Incidence,Predictors, and Prognostic Value of Acute Kidney Injury Among Patients Undergoing Left Atrial Appendage Closure

Objectives

The aims of this registry were to determine the incidence, predictors, and prognostic value of periprocedural acute kidney injury (AKI) after left atrial appendage closure (LAAC).

Characterization of the GBoV1 Capsid and Its Antibody Interactions

Human bocavirus 1 (HBoV1) has gained attention as a gene delivery vector with its ability to infect polarized human airway epithelia and 5.5 kb genome packaging capacity. Gorilla bocavirus 1 (GBoV1) VP3 shares 86% amino acid sequence identity with HBoV1 but has better transduction efficiency in several human cell types. Here, we report the capsid structure of GBoV1 determined to 2.76 Å resolution using cryo-electron microscopy (cryo-EM) and its interaction with mouse monoclonal antibodies (mAbs) and human sera. GBoV1 shares capsid surface morphologies with other parvoviruses, with a channel at the 5-fold symmetry axis, protrusions surrounding the 3-fold axis and a depression at the 2-fold axis. A 2/5-fold wall separates the 2-fold and 5-fold axes. Compared to HBoV1, differences are localized to the 3-fold protrusions. Consistently, native dot immunoblots and cryo-EM showed cross-reactivity and binding, respectively, by a 5-fold targeted HBoV1 mAb, 15C6. Surprisingly, recognition was observed for one out of three 3-fold targeted mAbs, 12C1, indicating some structural similarity at this region. In addition, GBoV1, tested against 40 human sera, showed the similar rates of seropositivity as HBoV1. Immunogenic reactivity against parvoviral vectors is a significant barrier to efficient gene delivery. This study is a step towards optimizing bocaparvovirus vectors with antibody escape properties.     

Reclassification of adolescent hypertension by ambulatory blood pressure monitoring using adult norms and association with left ventricular hypertrophy

2017 pediatric blood pressure (BP) guidelines applied adult BP norms to define clinic hypertension (HTN) in patients ≥ 13 years. 2014 pediatric ambulatory BP monitor (ABPM) guidelines recommend age‐ and sex‐specific percentile norms for patients < 18 years. The authors evaluated reclassification of HTN when applying adult ABPM norms in patients ≥ 13 years and assessed the association of left ventricular hypertrophy (LVH) with HTN. Charts of patients 13–17 years with ABPM 9/2018–5/2019 were reviewed for sex, age, height, weight, BP medication, ABPM results, and left ventricular mass index (LVMI). American Heart Association 2005 (AHA 2005), AHA 2017 (AHA 2017), and European Society of Hypertension 2018 (ESH 2018) guidelines for adult ABPM were compared with 2014 AHA pediatric norms (pABPM). HTN was defined by each guideline using only ABPM. ABPM and clinic BP were used to classify white coat hypertension (WCH) and masked hypertension (MH). LVH was defined as LVMI > 51 g/m^2.7. 272 patients had adequate ABPM. 124 patients also had echocardiogram. All adult norms resulted in significant reclassification of HTN. LVMI correlated significantly with systolic BP only. The odds of a patient with HTN having LVH was significant using AHA 2005 (OR: 8.75 [2.1, 36.4], p = .03) and ESH 2018 (OR: 4.94 [1, 24.3], p = .002). Significant reclassification of HTN occurs with all adult norms. HTN is significantly associated with LVH using AHA 2005 and ESH 2018. Applying pediatric norms for ABPM while using adult norms for clinic BP causes confusion. Guideline selection should balance misdiagnosis with over‐diagnosis.     

Association of Interleukin-1β-31C/T, -511T/C and -3954C/T Single Nucleotide Polymorphism and Their Blood Plasma Level in Acquired Aplastic Anemia

Aplastic anemia (AA) is an immune-mediated disorder in which hematopoietic stem and progenitor cells are targeted by a number of cellular and molecular pathways. This case control study aims to investigate the association of interleukin-1beta (IL-1β) gene polymorphisms, (IL-1β-31, IL-1β-511 and IL-1β-3954) and their plasma levels with acquired AA. Genotyping was done by Restricted Fragment Length Polymorphism (PCR–RFLP) method and IL-1β plasma levels were evaluated in peripheral blood using ELISA. Increased level of IL-1β was reported to be significant in cases as compared to controls. The susceptibility of developing AA was higher in the cases for IL-1β-3954 genotype. IL-1β-511 genotype showed significant association with the severity groups of AA. No significant association was noticed in responder versus non-responder group. Plasma level of IL-1β gene was found to be significantly higher in severe and very-severe group of AA versus control group. Our findings suggest that IL-1β gene and its genotypes might be involved in the pathophysiology of AA and play a central role in the etiopathogenesis of AA.     

Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia

Background

C-type lectin-like molecule-1 is a transmembrane receptor expressed on myeloid cells, acute myeloid leukemia blasts and leukemic stem cells. To validate the potential of this receptor as a therapeutic target in acute myeloid leukemia, we generated a series of monoclonal antibodies against the extracellular domain of C-type lectin-like molecule-1 and used them to extend the expression profile analysis of acute myeloid leukemia cells and to select cytotoxic monoclonal antibodies against acute myeloid leukemia cells in preclinical models.

Design and Methods

C-type lectin-like molecule-1 expression was analyzed in acute myeloid leukemia cell lines, and in myeloid derived cells from patients with acute myeloid leukemia and healthy donors. Anti-C-type lectin-like molecule-1 antibody-mediated in vitro cytotoxic activity against acute myeloid leukemia blasts/cell lines and in vivo anti-cancer activity in a mouse xenograft model were assessed. Internalization of C-type lectin-like molecule-1 monoclonal antibodies upon receptor ligation was also investigated.

Results

C-type lectin-like molecule-1 was expressed in 86.5% (45/52) of cases of acute myeloid leukemia, in 54.5% (12/22) of acute myeloid leukemia CD34⁺/CD38⁻ stem cells, but not in acute lymphoblastic leukemia blasts (n=5). Selected anti-C-type lectin-like molecule-1 monoclonal antibodies mediated dose-dependent complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity specifically against acute myeloid leukemia-derived cell lines. Exogenous expression of the transmembrane receptor in HEK293 cells rendered the cells susceptible to antibody-mediated killing by monoclonal antibodies to the receptor. Furthermore, these monoclonal antibodies demonstrated strong complement-dependent cytotoxicity against freshly isolated acute myeloid leukemia blasts (15/16 cases; 94%). The monoclonal antibodies were efficiently internalized upon binding to C-type lectin-like molecule-1 in HL-60 cells. Moreover, a lead chimeric C-type lectin-like molecule-1 monoclonal antibody reduced the tumor size in xenograft mice implanted with HL-60 cells.

Conclusions

Our results demonstrate that targeting C-type lectin-like molecule-1 with specific cytotoxic monoclonal antibodies is an attractive approach which could lead to novel therapies for acute myeloid leukemia.     

Prevalence of non-convulsive seizure and other electroencephalographic abnormalities in ED patients with altered mental status

Four to ten percent of patients evaluated in emergency departments (ED) present with altered mental status (AMS). The prevalence of non-convulsive seizure (NCS) and other electroencephalographic (EEG) abnormalities in this population is unknown.ObjectivesTo identify the prevalence of NCS and other EEG abnormalities in ED patients with AMS.MethodsA prospective observational study at 2 urban ED. Inclusion: patients ≥ 13 years old with AMS. Exclusion: An easily correctable cause of AMS (e.g. hypoglycemia). A 30-minute standard 21-electrode EEG was performed on each subject upon presentation. Outcome: prevalence of EEG abnormalities interpreted by a board-certified epileptologist. EEGs were later reviewed by 2 blinded epileptologists. Inter-rater agreement (IRA) of the blinded EEG interpretations is summarized with κ. A multiple logistic regression model was constructed to identify variables that could predict the outcome.ResultsTwo hundred fifty-nine patients were enrolled (median age: 60, 54% female). Overall, 202/259 of EEGs were interpreted as abnormal (78%, 95% confidence interval [CI], 73-83%). The most common abnormality was background slowing (58%, 95% CI, 52-68%) indicating underlying encephalopathy. NCS (including non-convulsive status epilepticus [NCSE]) was detected in 5% (95% CI, 3-8%) of patients. The regression analysis predicting EEG abnormality showed a highly significant effect of age (P < .001, adjusted odds ratio 1.66 [95% CI, 1.36-2.02] per 10-year age increment). IRA for EEG interpretations was modest (κ: 0.45, 95% CI, 0.36-0.54).ConclusionsThe prevalence of EEG abnormalities in ED patients with undifferentiated AMS is significant. ED physicians should consider EEG in the evaluation of patients with AMS and a high suspicion of NCS/NCSE.     

Insulin lispro low mixture twice daily versus basal insulin glargine once daily and prandial insulin lispro once daily in patients with type 2 diabetes mellitus requiring insulin intensification—a randomized phase IV trial: Indian subpopulation analyses

The aim of this study was to describe the efficacy and safety of two insulin intensification strategies in patients recruited in India with type 2 diabetes mellitus inadequately controlled on basal insulin glargine with metformin and/or pioglitazone. This multinational, open-label, randomized, parallel-arm, noninferiority, phase IV clinical trial evaluated insulin lispro low mixture (LM25) and basal insulin glargine administered with prandial insulin lispro (IGL) for 24 weeks. Patients were male and female, aged ≥18 to ≤75 years, with screening glycosylated hemoglobin (HbA_1c) concentration ≥7.5 to ≤10.5 % and fasting plasma glucose ≤121 mg/dL. The primary efficacy end point was change in HbA_1c from baseline to 24 weeks of treatment. Secondary efficacy end points included change in HbA_1c from baseline to 12 weeks and change in fasting blood glucose (FBG) from baseline to 12 and 24 weeks. Safety and tolerability were measured by treatment-emergent adverse events and the incidence, rate, and severity of hypoglycemic episodes. Of 81 patients randomized to LM25 (n?=?40) or IGL (n?=?41), 80 patients completed the trial and one patient discontinued due to subject decision. Mean (SD) change in HbA_1c from baseline to week 24 was ?1.2 % (1.11) for the LM25 group and ?1.0 % (1.18) for the IGL group. Safety profile, mean (FBG), glycemic variability, hypoglycemic episodes per patient-year, and health outcome measures were numerically similar between the two groups. The results of this post hoc analysis in an Indian subpopulation were consistent with results reported for the trial-level population and provide information to the consideration of LM25 as treatment option for intensification.     

Association of microsomal epoxide hydrolase exon 3 Tyr113His and exon 4 His139Arg polymorphisms with gastric cancer in India

Background

Microsomal epoxide hydrolase, an important phase II xenobiotic enzyme, exhibits polymorphisms at exon 3 (Tyr113His [T/C]) and exon 4 (His139Arg [A/G]), which modulate enzyme activity; this may affect susceptibility to cancers. We studied association between these polymorphisms and gastric cancer (GC).

Methods

In a prospective study, 77 patients with GC, 50 with peptic ulcer, and 160 healthy controls (HC) were genotyped for exon 3 (PCR-RFLP followed by sequencing) and exon 4 (PCR-RFLP). Helicobacter pylori was considered to be present if two of three tests (histology, rapid urease test, and IgG antibody) were positive.

Results

Tyr113His and His139Arg genotypes and haplotypes were comparable among groups. 113His carriers were commoner among H. pylori-negative patients with GC than HC (p-value?=?0.019, odds ratio (OR)?=?2.5, 95 % confidence interval (CI)?=?1.2–5.4). Haplotype combination of exons 3 and 4 113Tyr-139Arg (TA) were associated with higher and reduced risk in patients with GC than HC in presence and absence of H. pylori (25 % vs. 11 %; p-value?=?0.033, OR?=?2.61, 95 % CI?=?1.08–6.3 and 11.6 % vs. 28.7 %; p-value?=?0.004, OR?=?0.33, 95 % CI?=?0.15–0.7, respectively).

Conclusions

Though 113Tyr-139Arg was associated with GC in presence of H. pylori, in its absence, it appeared to be protective. Exon 3, 113His, however, was associated with GC even in absence of H. pylori infection.