Glycated hemoglobin (HbA
) is an important measure of glycemia in diabetes. HbA
is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a ...genome-wide association study (GWAS) for HbA
in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (
) were associated with HbA
in FinnDiane at genome-wide significance
< 5 × 10
). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA
also in the meta-analysis with RASS
< 5 × 10
), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA
in an East Asian population without diabetes (
≤ 0.013). A weighted genetic risk score created from 55 HbA
-associated variants from the literature was associated with HbA
in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA
may lead to better prevention of diabetes complications.
Vaginal vault brachytherapy is a common treatment for endometrial cancer. Historically, applicator insertion has been the domain of a radiation oncologist (RO). This commentary outlines a project to ...improve efficiency and workforce utilisation by introducing a competency framework and training module allowing entitled radiation therapists to perform single‐channel cylinder applicator insertions and treatment delivery under RO supervision for fraction one and without supervision for subsequent fractions. The rationale, relevant regulations, implementation process and barriers are explored.
This commentary outlines a project to improve efficiency and workforce utilisation by introducing a competency framework and training module allowing entitled radiation therapists to perform single‐channel cylinder applicator insertions for vaginal vault brachytherapy.
Aims/hypothesis
An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect ...genetic variation associated with elevated AER in patients with type 1 diabetes.
Methods
The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a
p
value <10
−4
were followed up in 3,750 additional patients with type 1 diabetes from seven studies.
Results
The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the
GLRA3
gene were strongly associated with albuminuria (
p
< 5 × 10
−8
). In the replication group, a nominally significant association (
p
= 0.035) was observed between albuminuria and rs1564939 in
GLRA3
, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in
GLRA3
. The strongest replication (
p
= 0.026) was obtained for rs2410601 between the
PSD3
and
SH2D4A
genes. Pathway analysis highlighted natural killer cell mediated immunity processes.
Conclusions/interpretation
This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
Iron deficiency anemia (IDA) has been implicated in the etiology of transient ischemic attack and ischemic stroke. This study aimed to: 1) document IDA prevalence in patients ≥ 65 years of age ...admitted to hospital with transient ischemic attack or first ischemic stroke, and 2) investigate dietary intake as a predictor of iron status.
Ninety-four patients were enrolled. An algorithm containing values for hemoglobin, ferritin, total iron binding capacity, transferrin saturation, and serum transferrin receptor measured at admission was used to identify IDA. Usual dietary intake was assessed with the Clue II food frequency questionnaire.
Prevalence estimates were 6.4% for IDA, 2.1% for iron deficiency without anemia, and 6.4% for anemia from other causes. IDA prevalence was significantly higher than published National Health and Nutrition Examination Survey III (NHANES III) estimates for gender-specific age groups ≥ 70 years (One-Sample Proportion Test; males p = 0.038 n= 37; females p = 0.002 n=44). A comparison of IDA prevalence against selected controls from the NHANES III database yielded an odds ratio (OR) of 6.3, 95% confidence interval (CI) 0.8 to 53.7, which was not statistically significant (Fisher's Exact Test; n=94; p = 0.118). Multivariate linear regression analysis of dietary intake with indicators of iron status (n=58) revealed only iron supplements (p = 0.013) and heme iron intake (p = 0.038) as negative predictors of total iron binding capacity (p<0.05).
These findings support the initiation of a prospective case control study to investigate IDA as a risk factor for ischemic stroke in elderly patients.
Background
Most studies of post‐transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and ...HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups.
Methods
Patients were followed up for 30 months in a 6‐center prospective cohort study. Data on demographics, CMV infections, tissue‐invasive disease, recurrences, rejection, and immunosuppression were recorded.
Results
The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P = .0706). Tissue‐invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P = .087). Median time to CMV infection was longer in the lung transplant group (236 vs 40 days, P < .0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350 mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P = .008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group.
Conclusions
Current CMV prevention strategies have resulted in a low incidence of tissue‐invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era.
Introduction
The aim of this study was to investigate the dosimetric differences between surface mould high‐dose‐rate (HDR) brachytherapy and external beam volumetric‐modulated arc therapy (VMAT) for ...two treatment sites.
Methods
Previously treated HDR brachytherapy surface mould scalp (n = 4) and lower leg (n = 3) treatments were retrospectively analysed. The VMAT plans were optimised using an additional 3‐mm setup margin on the clinical target volume (CTV) of the previously treated HDR plans. The HDR plans were calculated and normalised using the TG‐43 formalism and recalculated with Acuros BV (AC).
Results
On average, the mean brain and normal tissue doses were reduced by 44.8% and 27.4% for scalp and lower leg VMAT cases, respectively, when compared to AC calculated HDR plans. For VMAT plans, the average dose to a 1‐mm thick skin structure deep to the target volume was not any lower than that in AC HDR plans. On average, the CTV coverage was 13.8% and 9.6% lower for scalp cases with AC dose calculation than with TG‐43 and 8.3% and 5.3% lower for lower leg cases if 0‐ or 1‐cm backscatter material was applied above the catheters, respectively.
Conclusions
VMAT is a feasible treatment option in the case of extensive skin malignancies of the scalp and lower leg. Uncertainties related to delivered dose with HDR brachytherapy when using the TG‐43 dose calculation model or possible air gaps between the mould and skin favour the use of VMAT. The potential soft tissue deformation needs to be considered if VMAT is used.
Dosimetric differences between surface mould high‐dose‐rate (HDR) brachytherapy and volumetric‐modulated arc therapy (VMAT) for extensive skin lesions. Organ at risk dose was significantly lower in VMAT plans than in the HDR plans. Acuros BV (Varian Medical Systems, Palo Alto, US) calculations for HDR plans revealed a significant dose reduction in the target volume and the dose was comparable to VMAT dose.
Abstract
Background
Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from ...several countries with CP-Ec isolates obtained from a prospective cohort.
Methods
Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture.
Results
Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non–MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non–MBL-Ec was 62% (95% CI: 48.2–74.3%). Among infected patients, non–MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec.
Conclusions
Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non–MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.
Carbapenemase-producing Escherichia coli (CP-Ec) are concerning given the global prevalence of E. coli in many infection sites and limited available treatment options. We observed regional variation in CP-Ec, often among high-risk genotypes. Mortality was lower in those infected with metallo-β-lactamase producers.
To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) of the retinal pigment epithelium (RPE) in two families.
Two families with autosomal-dominant PD were identified. Eight ...members of family 1 (five affected) were subjected to whole-genome SNP genotyping; multipoint genome-wide linkage analysis identified 7 regions of potential linkage, and genotyping four additional individuals from family 1 resulted in a maximum logarithm of odds score of 2.09 observed across four chromosomal regions. Exome sequencing of two affected family 1 members identified 15 shared non-synonymous rare coding sequence variants within the linked regions; candidate genes were prioritised and further analysed. Sanger sequencing confirmed a novel heterozygous missense variant (E79K) in orthodenticle homeobox 2 (OTX2) that segregated with the disease phenotype. Family 2 with PD (two affected) harboured the same missense variant in OTX2. A shared haplotype of 19.68 cM encompassing OTX2 was identified between affected individuals in the two families. Within the two families, all except one affected demonstrated distinct 'patterns' at the macula. In vivo structural retinal imaging showed discrete areas of RPE-photoreceptor separation at the macula in all cases. Electroretinogram testing showed generalised photoreceptor degeneration in three cases. Mild developmental anomalies were observed, including optic nerve head dysplasia (four cases), microcornea (one case) and Rathke's cleft cyst (one case); pituitary hormone levels were normal.
This is the first report implicating OTX2 to underlie PD. The retinal disease resembles conditional mice models that show slow photoreceptor degeneration secondary to loss of Otx2 function in the adult RPE.
The British Association for Psychopharmacology and the National Association of Psychiatric Intensive Care and Low Secure Units developed this joint evidence-based consensus guideline for the clinical ...management of acute disturbance. It includes recommendations for clinical practice and an algorithm to guide treatment by healthcare professionals with various options outlined according to their route of administration and category of evidence. Fundamental overarching principles are included and highlight the importance of treating the underlying disorder. There is a focus on three key interventions: de-escalation, pharmacological interventions pre-rapid tranquillisation and rapid tranquillisation (intramuscular and intravenous). Most of the evidence reviewed relates to emergency psychiatric care or acute psychiatric adult inpatient care, although we also sought evidence relevant to other common clinical settings including the general acute hospital and forensic psychiatry. We conclude that the variety of options available for the management of acute disturbance goes beyond the standard choices of lorazepam, haloperidol and promethazine and includes oral-inhaled loxapine, buccal midazolam, as well as a number of oral antipsychotics in addition to parenteral options of intramuscular aripiprazole, intramuscular droperidol and intramuscular olanzapine. Intravenous options, for settings where resuscitation equipment and trained staff are available to manage medical emergencies, are also included.
Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and ...promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects.
Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma.
In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.
Display omitted
•Apoptotic lymphoma cells promote tumor growth, angiogenesis, and TAM accumulation•Unbiased “in situ transcriptomics” analysis shows TAMs promote pro-tumor pathways•Apoptotic tumor cells express and process matrix remodeling proteins•The oncogenic potential of apoptotic tumor cells extends beyond lymphoma
Apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. Ford et al. demonstrate apoptotic lymphoma cells can promote tumor growth, angiogenesis, TAM accumulation, and TAM activation to potentiate cancer progression. These results have important implications for apoptosis-inducing anti-cancer therapies.
PDF
