FGF23 metabolism, a new paradigm for chronic kidney disease

Introduction:  Fibroblast growth factor-23 (FGF23) is a major regulator of phosphate metabolism often elevated in genetic hypophosphataemic disorders and in chronic kidney disease. Recent studies have identified relationships between FGF23 and various markers of iron status including ferritin. New assays measuring the intact form of FGF23 have been released.  Objective:  To determine the relationship between ferritin and C-terminal and intact FGF23 concentrations in blood.  Method:  FGF23 concentrations were measured using the 2nd generation, two-site enzyme-linked immunosorbent assay for either C-terminal or intact FGF23 (Immutopics Inc., Ca, USA). Ferritin was measured on a COBAS 6000 (Roche Diagnostics). Assay accuracy and precision were monitored using kit controls supplied by the manufacturers.  Results:  We observe a weak negative correlation between measurements of C-terminal and intact FGF23 (Pearson’s rho=0.85 p<0.0001). We observed no statistically significant correlation of ferritin concentrations with either FGF23 C-terminal or intact. However high concentrations of ferritin were observed in samples showing low concentrations of C-terminal FGF23 (<140RU/mL) and intact FGF23 (<122pg/mL).  Conclusion:  Although not statistically significant, we observe a negative relationship between concentrations of ferritin and FGF23. High level of C-terminal FGF23 is found in patients with chronic kidney disease, especially in patients with end-stage renal disease usually regarded as a compensatory response to hyperphosphatemia or phosphate overload. We observed a cluster of patients with retention of both C-terminal and intact FGF23 associated with low levels of ferritin suggesting that metabolism and/or excretion of FGF23 in CDK patients might be an iron dependent mechanism

El uso de los animales en las expresiones idiomáticas del rumano: estudio de sus equivalencias al inglés y al español y análisis aplicado a la traducción

El siguiente trabajo tiene como foco principal la recopilación de expresiones idiomáticas rumanas referentes al campo semántico de los animales, además del estudio de sus equivalencias al inglés y al español. El corpus abarca unas 350 unidades fraseológicas, de las cuales ofreceremos fichas descriptivas de cien expresiones, junto con sus equivalentes, clasificadas mediante un criterio semántico. Finalmente, seleccionaremos un corpus reducido de veinte fichas, que serán objeto de un estudio empírico dirigido a hablantes nativos de rumano, inglés y español, para determinar frecuencias de uso y preferencia de variante

Assessment of vitamin D status using MitraTM volumetric absorptive microsampling (VAMS) device

Introduction: The use of dried blood spot (DBS) sampling for general wellness assessment and in clinical diagnostics has gained popularity as a convenient and less invasive alternative to venous sampling. Collection of blood samples from a finger/heel prick using conventional filter paper suffers from variability in sample volume and spot sizes which undermine the quality of results. We describe the use of a volumetric absorptive microsampler (VAMS), called MitraTM (Torrance, CA, USA) for measurement of 25OHD3 and interpretation of vitamin D status according to current international guidelines.  Method: A liquid-chromatography mass spectrometry (LC-MS/MS) method was used for measurement of 25OHD3 (Tang et al. ASBMR 2015, LB-MO0026). We compared results from patient samples (n=97) collected by VAMS and Whatman® 903 cards extracted as whole spot (wDBS) and sub-punches (spDBS) against plasma 25OHD3 concentration. We investigated the volume displacement effects of haematocrit (Hct) on DBS 25OHD3 measurements and described the use of DBS-to-plasma equivalence value (PEV) to allow accurate interpretation of vitamin D status.  Results: VAMS showed the best assay precision CV (<8.2%) compared to wDBS (<16.6%) and spDBS (<15.1%) across the assay range of 0.1-125 nmol/L, the least variability in recovery and lowest LLoQ (Figure 1). We observed a decrease in DBS 25OHD3 concentration in proportion to the reduction in plasma volume and increase in packed cell volume. The displacement effect of Hct resulted in a strong but negatively biased correlation (r2=0.893, -39.3%) between raw DBS values and plasma concentrations, that was dependent upon the level of Hct present in sample. We demonstrated the use of simple linear regression model to transform raw DBS values into PEVs. In a subsequent cohort of patient samples (n=70), PEVVAMS produced the most accurate interpretation of vitamin D status compared to PEVwDBS and PEVspDBS.  Discussion: We present data supporting the use of VAMS for measurement of 25(OH)D3, particularly in circumstances where venesection may be impossible or difficult and where sample volume may be limited. Although the recovery of analyte remains Hct-dependent, the use of DBS-to-plasma equivalence values improves the clinical applicability and broadens the utility of DBS as a sampling technique

Reference intervals for serum 24,25-Dihydroxyvitamin D and the ratio with 25-Hydroxyvitamin established using a newly developed LC-MS/MS method

24,25(OH)2D is the product of 25(OH)D catabolism by CYP24A1.The measurement of serum 24,25(OH)2D concentration may serve as an indicator of vitamin D catabolic status and the relative ratio with 25(OH)D can be used to identify patients with inactivating mutations in CYP24A1. We describe a LC-MS/MS method to determine: 1) the relationships between serum 24,25(OH)2D and 25(OH)D; 2) serum reference intervals in healthy individuals; 3) the diagnostic accuracy of 24,25(OH)2D measurement as an indicator for vitamin D status; 4) 24,25(OH)2D cut-off value for clinically significant change between inadequate and sufficient 25(OH)D status. Serum samples of healthy participants (n=1996) from Army recruits and patients (n=294) were analysed. The LC-MS/MS assay satisfied industry standards for method validation. We found a positive, concentration-dependent relationship between serum 24,25(OH)2D and 25(OH)2D concentrations. The 25(OH)D:24,25(OH)2D ratio was significantly higher (p4.2 nmol/L was identified as a diagnostic cut-off for 25(OH)D replete status. One patient sample with an elevated 25(OH)D:24,25(OH)2D ratio of 32 and hypercalcaemia who on genetic testing confirmed to have a biallelic mutation of CYP24A1. Our study demonstrated the feasibility of a combined 24,25(OH)2D and 25(OH)D assessment profile. Our established cut-off value for 24,25(OH)2D and ratio reference ranges can be useful to clinicians in the investigation of patients with an impaired calcium/phosphate metabolism and may point towards the existence of CYP24A1 gene abnormalities

Calpain system protein expression and activity in ovarian cancer

Purpose: Expression of members of the calpain system are associated with clinical outcome of patients with, amongst others, breast and ovarian cancer, with calpain-2 expression in ovarian cancer being implicated in chemo-resistance and survival. This study aimed, using a large patient cohort and in vitro models, to verify its importance and further investigate the role in ovarian cancer chemoresponse. Methods: Calpain-1, calpain-2, calpain-4 and calpastatin expression were evaluated in primary ovarian carcinomas (n=575) by immunohistochemistry. Protein expression was assessed, via Western blotting, in 5 ovarian cancer cell lines with various sensitivities towards cisplatin/carboplatin. In vitro calpain activity was inhibited by calpeptin treatment to assess changes in platinum-sensitivity by proliferation assay, with expression of genes associated with epithelial-mesenchymal transition being examined by RT² Profiler™ PCR Array.Results: The current study confirmed previous data that high calpain-2 expression is associated with poor overall survival (P=0.026) and that calpain-1 was not associated with overall survival or progression free survival. Low expression of calpastatin (P=0.010) and calpain-4 (P=0.003) were also associated with adverse survival. Such prognostic associations do not seem to be linked with altered tumour sensitivity towards platinum-based chemotherapy. Interestingly, low calpain-1 expression was more frequent in patients with confined-tumours (stage 1) (χ2=11.310, d.f.=1, P=0.001). Calpains and calpastatin expression varied among ovarian cancer cell lines yet their expression levels were similar between chemo-sensitive cells and resistant counterparts. Moreover, calpeptin treatment did not alter cellular response to platinum based chemotherapy or epithelial-mesenchymal transition related gene expression.Conclusions: The conventional calpains and calpastatin have been confirmed to play an important role in ovarian cancer however the precise mechanisms whereby they exert effects remain to be elucidated

Improving Social Justice in COVID-19 Health Research: Interim guidelines for reporting health equity in observational studies

The COVID-19 pandemic has highlighted the global imperative to address health inequities. Observational studies are a valuable source of evidence for real-world effects and impacts of implementing COVID-19 policies on the redistribution of inequities. We assembled a diverse global multi-disciplinary team to develop interim guidance for improving transparency in reporting health equity in COVID-19 observational studies. We identified 14 areas in the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist that need additional detail to encourage transparent reporting of health equity. We searched for examples of COVID-19 observational studies that analysed and reported health equity analysis across one or more social determinants of health. We engaged with Indigenous stakeholders and others groups experiencing health inequities to co-produce this guidance and to bring an intersectional lens. Taking health equity and social determinants of health into account contributes to the clinical and epidemiological understanding of the disease, identifying specific needs and supporting decision-making processes. Stakeholders are encouraged to consider using this guidance on observational research to help provide evidence to close the inequitable gaps in health outcomes

Global assessment of marine plastic exposure risk for oceanic birds

Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years