Iron supplementation to treat anaemia in adult critical care patients: a systematic review and meta-analysis

Anaemia affects 60-80 % of patients admitted to intensive care units (ICUs). Allogeneic red blood cell (RBC) transfusions remain the mainstay of treatment for anaemia but are associated with risks and are costly. Our objective was to assess the efficacy and safety of iron supplementation by any route, in anaemic patients in adult ICUs.Electronic databases (CENTRAL, MEDLINE, EMBASE) were searched through March 2016 for randomized controlled trials (RCT)s comparing iron by any route with placebo/no iron. Primary outcomes were red blood cell transfusions and mean haemoglobin concentration. Secondary outcomes included mortality, infection, ICU and hospital length of stay, mean difference (MD) in iron biomarkers, health-related quality of life and adverse events.Five RCTs recruiting 665 patients met the inclusion criteria; intravenous iron was tested in four of the RCTs. There was no difference in allogeneic RBC transfusion requirements (relative risk 0.87, 95 % confidence interval (CI) 0.70 to 1.07, p = 0.18, five trials) or mean number of RBC units transfused (MD -0.45, 95 % CI -1.34 to 0.43, p = 0.32, two trials) in patients receiving or not receiving iron. Similarly, there was no difference between groups in haemoglobin at short-term (up to 10 days) (MD -0.25, 95 % CI -0.79 to 0.28, p = 0.35, three trials) or mid-term follow up (last measured time point in hospital or end of trial) (MD 0.21, 95 % CI -0.13 to 0.55, p = 0.23, three trials). There was no difference in secondary outcomes of mortality, in-hospital infection, or length of stay. Risk of bias was generally low although three trials had high risk of attrition bias; only one trial had low risk of bias across all domains.Iron supplementation does not reduce RBC transfusion requirements in critically ill adults, but there is considerable heterogeneity between trials in study design, nature of interventions, and outcomes. Well-designed trials are needed to investigate the optimal iron dosing regimens and strategies to identify which patients are most likely to benefit from iron, together with patient-focused outcomes.PROSPERO International prospective register of systematic reviews CRD42015016627 . Registered 2 March 2015

A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Hb Calgary (HBB: c.194G>T): A Highly Unstable Hemoglobin Variant with a β-Thalassemia Major Phenotype

We describe two unrelated patients, both heterozygous for an unstable hemoglobin (Hb) variant named Hb Calgary (HBB: c.194G>T) that causes severe hemolytic anemia and dyserythorpoietic, resulting in transfusion dependence and iron overload. The molecular pathogenesis is a missense variation on the β-globin gene, presumed to lead to an unstable Hb. The phenotype of Hb Calgary is particularly severe presenting as transfusion-dependent anemia in early infancy, precluding phenotypic diagnosis and highlighting the importance of early genetic testing in order to make an accurate diagnosis

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development