Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease

Erythropoiesis-stimulating agents (ESAs) are effective in ameliorating anemia in chronic kidney disease (CKD). A recent trial in diabetic patients with CKD, however, suggested a greater risk of stroke associated with full correction of anemia with ESAs. Using national Veterans Affairs data we performed a case-control study examining the association of incident ESA use with acute stroke in patients with estimated glomerular filtration rate < 60 cm3/min per 1.73?m2 and outpatient hemoglobin <12?g/dl. Using diagnosis codes, we identified 2071 acute hospitalized stroke cases and matched them 1:5 with controls without stroke, resulting in 12,426 total patients for analysis. Conditional logistic regression was used to estimate the association of ESA use with stroke, adjusting for potential confounders. After multivariate adjustment, ESA use in 1026 patients was associated with greater odds of stroke (odds ratio 1.30). There was significant interaction between ESA use and cancer, with greater odds of stroke among ESA-treated cancer patients (odds ratio 1.85), but not in ESA-treated patients without cancer (odds ratio 1.07). ESA-treated patients with cancer received a median initial dose 2.5-4 times greater than ESA-treated patients without cancer, but pre-ESA hemoglobin and its rate of change did not differ between these groups. Hence, in a large national sample of anemic patients with CKD, ESA treatment was associated with an increased risk of acute stroke with the greatest effect among patients with cancer.     

The complement cascade as a mediator of tissue growth and regeneration

Recent evidence has demonstrated that the complement cascade is involved in a variety of physiologic and pathophysiologic processes in addition to its role as an immune effector. Research in a variety of organ systems has shown that complement proteins are direct participants in maintenance of cellular turnover, healing, proliferation and regeneration. As a physiologic housekeeper, complement proteins maintain tissue integrity in the absence of inflammation by disposing of cellular debris and waste, a process critical to the prevention of autoimmune disease. Developmentally, complement proteins influence pathways including hematopoietic stem cell engraftment, bone growth, and angiogenesis. They also provide a potent stimulus for cellular proliferation including regeneration of the limb and eye in animal models, and liver proliferation following injury. Here, we describe the complement cascade as a mediator of tissue growth and regeneration.     

Mortality and morbidity after aortic root replacement: 10-year experience

Aortic root reconstruction remains a challenging surgical procedure. This retrospective study was carried out to evaluate the early and long-term outcomes of aortic root replacement over a 10-year period. There were 83 patients with a mean age of 43.2 +/- 14 years (range, 10 to 78 years). Type A aortic dissection and Marfan syndrome were found in 28% and 24%, respectively. The most common technique used for repair of this condition was the Bentall operation. The mean duration of follow-up was 29.6 +/- 28 months, ranging from 1 to 120 months. Hospital (30-day) mortality was 13.3% (11 patients). Two patients died during the late follow-up. The mortality was significantly higher in patients presenting with cardiogenic shock, those with long cardiopulmonary bypass and crossclamp times, and the group who had concomitant coronary artery bypass grafting. Emergency operation was not a significant risk factor for early death in our patients. The most common complications were bleeding and neurological sequelae. Aortic root replacement can be achieved with acceptable mortality and morbidity in a high-risk group of patients. Improvements in the outcome may be achieved by faster transport of patients in cardiogenic shock, and by reducing the cardiopulmonary bypass and crossclamp times.     

Bilateral Optic Nerve Head Angiomas and Retrobulbar Haemangioblastomas in von Hippel-Lindau Disease

A 39-year-old man presented with progressive visual loss in both eyes. His past medical history was remarkable for biopsy-proven bilateral adrenal phaeochromocytomas. Ophthalmoscopy revealed an optic nerve head angioma and macular lipid exudates in the right eye and a regressed optic nerve head angioma in the left eye. A fluorescein angiogram revealed a lobulated pattern of leakage and venous staining from the optic nerve head angioma. Brain and orbital magnetic resonance imaging showed haemangioblastomas of the right intraorbital and left paraclinoid optic nerves and in the left cerebellopontine angle area. These findings were consistent with a clinical diagnosis of von Hippel-Lindau disease.     

Trajectory of Growth of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Houston,Texas, January through May 2021, Based on 12,476 Genome Sequences

Certain genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of substantial concern because they may be more transmissible or detrimentally alter the pandemic course and disease features in individual patients. SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist health care system diagnosed from January 1 through May 31, 2021 are reported here. Prevalence of the B.1.1.7 (Alpha) variant increased rapidly and caused 63% to 90% of new cases in the latter half of May. Eleven B.1.1.7 genomes had an E484K replacement in spike protein, a change also identified in other SARS-CoV-2 lineages. Compared with non–B.1.1.7-infected patients, individuals with B.1.1.7 had a significantly lower cycle threshold (a proxy for higher virus load) and significantly higher hospitalization rate. Other variants [eg, B.1.429 and B.1.427 (Epsilon), P.1 (Gamma), P.2 (Zeta), and R.1] also increased rapidly, although the magnitude was less than that in B.1.1.7. Twenty-two patients infected with B.1.617.1 (Kappa) or B.1.617.2 (Delta) variants had a high rate of hospitalization. Breakthrough cases (n = 207) in fully vaccinated patients were caused by a heterogeneous array of virus genotypes, including many not currently designated variants of interest or concern. In the aggregate, this study delineates the trajectory of SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, TX, and heralds the arrival of B.1.617 variants in the metroplex.

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that began in early 2020 has been challenging for every academic health center and health system, hospital, and public health system in the United States and countries worldwide.1, 2, 3, 4, 5, 6, 7 The pandemic has also provided unprecedented opportunities for basic and translational research in all biomedical fields. Molecular population genomics of SARS-CoV-2 were systematically analyzed in the ethnically and socioeconomically diverse metropolitan Houston, TX, area (population 7 million) since the first coronavirus disease 2019 (COVID-19) cases were reported in early March 2020.8, 9, 10, 11 These studies are facilitated by a central molecular diagnostic laboratory that comprehensively identifies and retains all COVID-19 diagnostic specimens from our large health care system, which includes eight hospitals, emergency care clinics, and outpatient centers distributed throughout the metropolitan region. In addition, the longstanding interest in pathogen genomics and sequencing infrastructure was leveraged to investigate the spread of SARS-CoV-2 in metropolitan Houston.8, 9, 10, 11, 12, 13, 14, 15, 16 SARS-CoV-2 viruses causing infections in the earliest phase of the pandemic affecting Houston had substantial genomic diversity and are progeny of strains derived from several continents, including Europe and Asia.^8,9 These findings indicated that SARS-CoV-2 was introduced into our region many times independently by individuals who had traveled from different parts of the country and the world. Subsequently, sequence analysis of 5085 genomes causing the first disease wave and massive second disease wave in Houston showed that all strains in the second wave had a D614G amino acid replacement in the spike protein.⁹ The D614G polymorphism increases human transmission and infectivity in vitro and in vivo in animal infection models.17, 18, 19, 20, 21, 22 More importantly, this was the first study to analyze the molecular architecture of SARS-CoV-2 in two infection waves in any major metropolitan region.One of the key goals since the start of the pandemic has been to sequence all positive SARS-CoV-2 specimens from patients in our hospital system and rapidly identify mutations that may be associated with detrimental patient outcome, including therapeutic or vaccine failure. Similarly, with the recognition of an increasing number of SARS-CoV-2 variants of interest (VOIs) and variants of concern (VOCs) by public health agencies, such as the US CDC, World Health Organization, and Public Health England (https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html, last accessed June 8, 2021; and https://www.gov.uk/government/collections/new-sars-cov-2-variant, last accessed June 8, 2021), there is now substantial domestic and international need to identify these virus genotypes rapidly and understand their velocity and patterns of dissemination. In particular, VOC B.1.1.7 (also termed Alpha), first identified in the United Kingdom, is of special interest because it has the ability to transmit effectively, it can spread through populations rapidly, and has been reported to have a significantly higher mortality rate than non-B.1.1.7 infections (Virological, https://virological.org/t/preliminary-genomic-characterisation- of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563, last accessed June 8, 2021; Public Health England, https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/947048/technical_briefing_voc_sh_njl2_sh2.pdf, last accessed June 8, 2021; New and Emerging Respiratory Virus Threats Advisory Group, https://app.box.com/s/3lkcbxepqixkg4mv640dpvvg978ixjtf/file/756963730457, last accessed June 8, 2021; Centre for Mathematical Modelling of Infectious Diseases, https://cmmid.github.io/topics/covid19/uk-novel-variant.html, last accessed June 8, 2021; and https://virological.org/t/lineage-specific-growth-of-sars-cov-2-b-1-1-7-during-the-english-national-lockdown/575, last accessed June 8, 2021).23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 VOCs B.1.351 (β) and P.1 (Gamma), found to cause widespread disease in South Africa and Brazil, respectively, have sequence changes in spike protein that make them less susceptible to host and some therapeutic antibodies.37, 38, 39, 40 Recently, two additional VOIs, B.1.427 and B.1.429 (Epsilon), were recognized by the CDC in part because of their rapid transmission in many California communities⁴¹ (Outbreak.info, https://outbreak.info/situation-reports?pango=b.1.427, last accessed June 8, 2021; and https://outbreak.info/situation-reports?pango=b.1.4279, last accessed June 8, 2021).Based on sequencing 20,453 SARS-CoV-2 genomes causing COVID-19 disease in Houston, all named VOIs and VOCs are circulating in the metropolitan region, making it the first community to document their presence.¹⁰ A follow-up study reported rapid increase of VOC UK B.1.1.7 in Houston¹¹; cases infected with the variant were estimated to have a doubling time of approximately 7 days. This rapid B.1.1.7 growth trajectory raised the possibility that this variant would cause nearly all new COVID-19 cases in metropolitan Houston by the end of March or early April 2021, a time frame similar to an estimate made in late January by the CDC.³³This study reports integrated virus genome and patient data for 12,476 unique COVID-19 cases identified between January 1, 2021, and May 31, 2021, including 3276 patients with the B.1.1.7 VOC. In the latter half of May, depending on the day, 63% to 90% of all new COVID-19 cases in metropolitan Houston were caused by B.1.1.7. Linked medical record information, available for virtually all sequenced genomes, was used to study the relationship between virus genotypes and patient phenotypes. Patients infected with B.1.1.7 had significantly lower cycle threshold (C_T) values in nasopharyngeal specimens (considered to be a proxy for higher virus load) and a significantly higher hospitalization rate compared with non-B.1.1.7 patients. There was no difference between these two groups in hospital length of stay or mortality. Of the 3276 B.1.1.7 genomes, 11 (0.3%) had an E484K change in spike protein that reduces binding by some neutralizing antibodies. Unexpectedly, five cases of B.1.1.7 were detected from samples collected in early December, resulting in a revised time frame for the introduction of this variant to Houston. Twenty-two patients were identified with COVID-19 caused by B.1.617.1 (Kappa) or B.1.617.2 (Delta) variants reported to be causing widespread disease and extensive public health problems in India, other Southeast Asian countries, and many regions of the United Kingdom (World Health Organization, https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-june-2021, last accessed June 9, 2021).42, 43, 44, 45, 46, 47, 48, 49 These patients also had a high rate of hospitalization. Vaccine breakthrough cases (n = 207) were caused by diverse virus genotypes, many of which were not VOCs or VOIs. Our genome data show that VOCs and VOIs now account for the great majority of all new COVID-19 cases in this region, identify B.1.1.7 as the major cause of new cases in Houston, and document the arrival and spread of B.1.617 variants in the Houston metroplex.     

Validated SNPs for eGFR and their associations with albuminuria

Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = -0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits.     

ROPES eye plaque brachytherapy dosimetry for two models of <Superscript>103</Superscript>Pd seeds

Brachytherapy dose distributions are calculated for 15 mm ROPES eye plaque loaded with model Theragenics200 and IR06-¹⁰³Pd seeds. The effects of stainless steel backing and Acrylic insert on dose distribution along the central axis of the eye plaque and at critical ocular structure are investigated. Monte Carlo simulation was carried out with the Version 5 of the MCNP. The dose at critical ocular structure by considering the eye composition was calculated. Results are compared with the calculated data for COMS eye plaque loaded with Theragenics200 palladium-103 seeds and model 6711 iodine-125 seed. The air kerma strength of the IR06-¹⁰³Pd seed to deliver 85 Gy in apex of tumor in water medium was calculated to be 4.10 U/seed. Along the central axis of stainless steel plaque loaded with new ¹⁰³Pd seeds in Acrylic insert, the dose reduction relative to water is 6.9% at 5 mm (apex). Removal of the Acrylic insert from the plaque (replacing with water) did not make significantly difference in dose reduction results (~0.2%). The presence of the stainless steel backing results in dose enhancement near the plaque relative to water. Doses at points of interest are higher for ROPES eye plaque when compared to COMS eye plaque. The dosimetric parameters calculated in this work for the new palladium seed, showed that in dosimetry point of view, the IR06-¹⁰³Pd seed is suitable for use in brachytherapy. The effect of Acrylic insert on dose distribution is negligible and the main effect on dose reduction is due to the presence of stainless steel plaque backing.     

Uncovering the behaviors of individual cells within a multicellular microvascular community

Although individual cells vary in behavior during the formation of tissues, the nature of such variations are largely uncharacterized. Here, we tracked the morphologies and motilities of ~300 human endothelial cells from an initial dispersed state to the formation of capillary-like structures, distilling the dynamics of tissue morphogenesis into an array of ~36,000 numerical phenotypes. Quantitative analysis of population averages revealed two previously unidentified phases in which the cells spread before forming connections with neighboring cells and where the microvascular plexus stabilized before spatially reorganizing. Analysis at the single-cell level showed that in contrast to the population-averaged behavior, most cells followed distinct temporal patterns that were not reflected in the bulk average. Interestingly, some of these behavioral patterns correlated to the cells' final structural role within the plexus. Knowledge of how individual cells or groups of cells behave enhances our understanding of how native tissues self-organize and could ultimately enable more precise approaches for engineering tissues and synthesizing multicellular communities.