The 2018 report of the Lancet Countdown on health and climate change: shaping the health of nations for centuries to come.

Unlabelled: The Lancet Countdown: tracking progress on health and climate change was established to provide an independent, global monitoring system dedicated to tracking the health dimensions of the impacts of, and the response to, climate change. The Countdown tracks 41 indicators across five domains: climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; finance and economics; and public and political engagement. This report is the product of a collaboration of 27 leading academic institutions, the UN, and intergovernmental agencies from every continent.

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data.

The overlap between allergy and immunodeficiency.

Purpose Of Review: The mechanisms underlying the overlap of, and relationship between, atopy and immunodeficiency are just beginning to be recognized, through the identification of novel genetic conditions and the reexamination of well known primary immunodeficiencies. The present review seeks both to frame the topic and to highlight the most recent literature combining allergy in the context of immunodeficiency.

Recent Findings: The true prevalence of atopic disorders in the setting of primary immunodeficiency as a whole is difficult to pinpoint, however there have been recent attempts to measure prevalence.

Functional characterization of phospholipase C-γ mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder.

Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ (PLCγ) gives rise to two distinct human disease states: acquired resistance of chronic lymphocytic leukemia cells (CLL) to inhibitors of Brutons´s tyrosine kinase (Btk) and dominantly inherited autoinflammation and PLCγ-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγS707Y mutation to other mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγS707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγΔ19 and PLCγΔ20-22.

The CBM-opathies-A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex.

The caspase recruitment domain family member 11 (CARD11 or CARMA1)-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed "CBM-opathies.

Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis.

Background: Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is known to be, at least in part, genetically determined. Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been shown to result in various forms of psoriasis and related disorders.

Objective: We aimed to identify rare DNA variants conferring a significant risk for AD through genetic and functional studies in a cohort of patients affected with severe AD.

Greenhouse gas emissions and water footprints of typical dietary patterns in India.

Agriculture is a major contributor to India's environmental footprint, particularly through greenhouse gas (GHG) emissions from livestock and fresh water used for irrigation. These impacts are likely to increase in future as agriculture attempts to keep pace with India's growing population and changing dietary preferences. Within India there is considerable dietary variation, and this study therefore aimed to quantify the GHG emissions and water usage associated with distinct dietary patterns.

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.

Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing.

Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.

Internet accuracy of publicly available images of meniscal tears.

Background: The Internet is an easily accessible resource for both providers and patients. Despite this, the Internet is not peer reviewed, leaving Internet searches subject to inaccuracies, especially with regards to medical information. The purpose of this study was to review Internet images of meniscus tears using three popular search engines: Google, Bing, and Yahoo.

Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.

Treatment of the autoimmune and immune-dysregulatory features of patients with STAT1 GOF or STAT3 GOF disease remains challenging. Jakinibs have been used to treat the severe immune-dysregulation in patients with either GOF or GOF mutations.

Human T9 differentiation is dependent on signal transducer and activator of transcription (STAT) 3 to restrain STAT1-mediated inhibition.

Background: Patients with loss-of-function (LOF) signal transducer and activator of transcription 3 (STAT3) mutations have dermatitis, enhanced IgE production despite a relative lack of immediate hypersensitivity, recurrent infection, and an increased rate of lymphoma in addition to a number of skeletal and connective tissue abnormalities. Patients with STAT1 gain-of-function (GOF) mutations also have susceptibility to candidiasis and sinopulmonary infection, as well as autoimmunity and squamous cell carcinoma, in addition to even more broad phenotypes.

Objective: Because of the link between T9 cells and allergic inflammation, autoimmunity, and antitumor surveillance and because evidence shows a role for either STAT3 or STAT1 in T9 differentiation conflicts, we sought to determine the status on this lineage of STAT1 GOF and STAT3 LOF mutations in human subjects.

Dual Roles for Ikaros in Regulation of Macrophage Chromatin State and Inflammatory Gene Expression.

Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. The transcription factor Ikaros has been shown to play a critical role in lymphoid cell development and differentiation; however, its function in myeloid cells and innate immune responses is less appreciated. Using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility, we describe unexpected dual repressor and activator functions for Ikaros in the LPS response of murine macrophages.

TCR Signaling Abnormalities in Human Th2-Associated Atopic Disease.

Stimulation of naïve CD4 T cells with weak T cell receptor agonists even in the absence of T helper-skewing cytokines can result in IL-4 production which can drive a Th2 response. Evidence for the consequences of such a phenomenon can be found in a number of mouse models and, importantly, a series of monogenic human diseases associated with significant atopy which are caused by mutations in the T cell receptor signaling cascade. Such diseases can help understand how Th2 responses evolve in humans, and potentially provide insight into therapeutic interventions.

The Transcription Factor Runx3 Establishes Chromatin Accessibility of cis-Regulatory Landscapes that Drive Memory Cytotoxic T Lymphocyte Formation.

T cell receptor (TCR) stimulation of naive CD8 T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naive cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 promoted accessibility to memory CTL-specific cis-regulatory regions before the first cell division and was essential for memory CTL differentiation. Runx3 was specifically required for accessibility to regions highly enriched with IRF, bZIP and Prdm1-like TF motifs, upregulation of TFs Irf4 and Blimp1, and activation of fundamental CTL attributes in early effector and memory precursor cells.

Transcriptional programming of tissue-resident memory CD8 T cells.

Tissue-resident memory CD8 T cells (T) are localized in non-lymphoid tissues throughout the body where they mediate long-lived protective immunity at common sites of pathogen exposure. As the signals controlling T differentiation are uncovered, it is becoming apparent that the dynamic activities of numerous transcription factors are intricately involved in T formation. Here, we highlight known transcriptional regulators of T differentiation and discuss how understanding the transcriptional programming of CD8 T cell residency in non-lymphoid tissues can be leveraged to prevent or treat disease.

Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry.

Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option.

Recent major advances in cardiovascular pharmacotherapy.

The field of cardiovascular pharmacotherapy remains extremely active. The aim of this review is to summarize the recent major advances in cardiovascular pharmacotherapy, with a focus on (1) the new approved drug for treatment of heart failure with reduced ejection fraction-sacubitril/valsartan; (2) proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors; (3) the novel reversal agents for non-vitamin K oral anticoagulants (NOACs); and finally, (4) new evidence on pharmacological treatment of coronary artery disease.

Do emotion regulation difficulties explain the association between executive functions and child physical abuse risk?

This study examined the associations between executive functioning problems, emotion regulation difficulties, and risk for perpetrating child physical abuse (CPA). It was hypothesized that: (a) poor executive functions (i.e.

Primary atopic disorders.

Monogenic disorders have provided fundamental insights into human immunity and the pathogenesis of allergic diseases. The pathways identified as critical in the development of atopy range from focal defects in immune cells and epithelial barrier function to global changes in metabolism. A major goal of studying heritable single-gene disorders that lead to severe clinical allergic diseases is to identify fundamental pathways leading to hypersensitivity that can be targeted to provide novel therapeutic strategies for patients with allergic diseases, syndromic and nonsyndromic alike.

The accuracy of ultrasound estimation of fetal weight in comparison to birth weight: A systematic review.

Ultrasound estimation of fetal weight is a highly influential factor in antenatal management, guiding both the timing and mode of delivery of a pregnancy. Although substantial research has investigated the most accurate ultrasound formula for calculating estimated fetal weight, current evidence indicates significant error levels. The aim of this systematic review was to identify the most accurate method, whilst identifying sources of inaccuracy in order to facilitate recommendations for future practice.