Assessment of the impact of a personalised nutrition intervention in impaired glucose regulation over 26 weeks: a randomised controlled trial.

Dietary interventions can reduce progression to type 2 diabetes mellitus (T2DM) in people with non-diabetic hyperglycaemia. In this study we aimed to determine the impact of a DNA-personalised nutrition intervention in people with non-diabetic hyperglycaemia over 26 weeks. ASPIRE-DNA was a pilot study. Participants were randomised into three arms to receive either (i) Control arm: standard care (NICE guidelines) (n = 51), (ii) Intervention arm: DNA-personalised dietary advice (n = 50), or (iii) Exploratory arm: DNA-personalised dietary advice via a self-guided app and wearable device (n = 46). The primary outcome was the difference in fasting plasma glucose (FPG) between the Control and Intervention arms after 6 weeks. 180 people were recruited, of whom 148 people were randomised, mean age of 59 years (SD = 11), 69% of whom were female. There was no significant difference in the FPG change between the Control and Intervention arms at 6 weeks (- 0.13 mmol/L (95% CI [- 0.37, 0.11]), p = 0.29), however, we found that a DNA-personalised dietary intervention led to a significant reduction of FPG at 26 weeks in the Intervention arm when compared to standard care (- 0.019 (SD = 0.008), p = 0.01), as did the Exploratory arm (- 0.021 (SD = 0.008), p = 0.006). HbA1c at 26 weeks was significantly reduced in the Intervention arm when compared to standard care (- 0.038 (SD = 0.018), p = 0.04). There was some evidence suggesting prevention of progression to T2DM across the groups that received a DNA-based intervention (p = 0.06). Personalisation of dietary advice based on DNA did not result in glucose changes within the first 6 weeks but was associated with significant reduction of FPG and HbA1c at 26 weeks when compared to standard care. The DNA-based diet was effective regardless of intervention type, though results should be interpreted with caution due to the low sample size. These findings suggest that DNA-based dietary guidance is an effective intervention compared to standard care, but there is still a minimum timeframe of adherence to the intervention before changes in clinical outcomes become apparent.Trial Registration: www.clinicaltrials.gov.uk Ref: NCT03702465.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency.

BACKGROUND: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK-cell and B-cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date. OBJECTIVES: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2. METHODS: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency. RESULTS: The investigators identified novel heterozygous variants in PLCG2 in 2 families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss of function due to haploinsufficiency with impaired NK-cell calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B-cell function remained intact. Plcg2+/- mice also displayed impaired NK-cell function with preserved B-cell function, phenocopying human disease. CONCLUSIONS: PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK-cell immunodeficiency with herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease.

A solution-processed radiative cooling glass.

Passive daytime radiative cooling materials could reduce the energy needed for building cooling up to 60% by reflecting sunlight and emitting long-wave infrared (LWIR) radiation into the cold Universe (~3 kelvin). However, developing passive cooling structures that are both practical to manufacture and apply while also displaying long-term environmental stability is challenging. We developed a randomized photonic composite consisting of a microporous glass framework that features selective LWIR emission along with relatively high solar reflectance and aluminum oxide particles that strongly scatter sunlight and prevent densification of the porous structure during manufacturing. This microporous glass coating enables a temperature drop of ~3.5° and 4°C even under high-humidity conditions (up to 80%) during midday and nighttime, respectively. This radiative "cooling glass" coating maintains high solar reflectance even when exposed to harsh conditions, including water, ultraviolet radiation, soiling, and high temperatures.

Equity, diversity, and inclusion at the Global Alliance for Genomics and Health.

A lack of diversity in genomics for health continues to hinder equitable leadership and access to precision medicine approaches for underrepresented populations. To avoid perpetuating biases within the genomics workforce and genomic data collection practices, equity, diversity, and inclusion (EDI) must be addressed. This paper documents the journey taken by the Global Alliance for Genomics and Health (a genomics-based standard-setting and policy-framing organization) to create a more equitable, diverse, and inclusive environment for its standards and members. Initial steps include the creation of two groups: the Equity, Diversity, and Inclusion Advisory Group and the Regulatory and Ethics Diversity Group. Following a framework that we call "Reflected in our Teams, Reflected in our Standards," both groups address EDI at different stages in their policy development process.

Therapeutic Potential of Targeting Prokineticin Receptors in Diseases.

The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research. SIGNIFICANCE STATEMENT: This review provides an in-depth view of the prokineticin family and PK receptors that can be active without their endogenous ligand and exhibits "constitutive" activity in diseases. Their non- peptide ligands display promising effects in several preclinical disease models. PKs can be the diagnostic biomarker of several diseases. A thorough understanding of the role of prokineticin family and their receptor types in health and diseases is critical to develop novel therapeutic strategies with safety concerns.

The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the Tumor Microenvironment.

Background: Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. Design: We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAFWT/V600E-ATC-derived cells coimplanted with pericytes. Results: ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAFWT/V600E-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Conclusions and Implications: Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAFWT/V600E-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.

What is the best prophylaxis against venous thromboembolism in Asians following total knee arthroplasty? A systematic review and network meta-analysis.

PURPOSE: Asians have a low venous thromboembolism (VTE) incidence following total knee arthroplasty (TKA). This systematic review and network meta-analysis was conducted to evaluate the best prophylaxis against VTE in Asians following total knee arthroplasty in current literature. MATERIALS AND METHODS: A systematic search of PubMed, Embase and CINAHL was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Prophylaxis types were separated into low-molecular-weight heparin (LMWH), novel oral anti-coagulants (NOAC), mechanical-only prophylaxis (MOP) and no prophylaxis (NP). The primary outcome was VTE incidence, grouped according to diagnosis modality (ultrasound, venography, clinical). The secondary outcome was bleeding incidence, grouped into minor and major bleeding. RESULTS: Fourteen eligible articles, totalling 4259 patients, were pooled with the following significant results: NOACs had lower venography-diagnosed VTE incidence than LMWH (12.77%, p = 0.02) and NP (20.64, p < 0.001). MOP had lower venography-diagnosed VTE incidence than LMWH (23.72%, p < 0.001), NOACs (10.95%, p < 0.001) and NP (31.59%, p < 0.001) but, interestingly, a statistically higher ultrasound-diagnosed VTE incidence than LMWH (6.56%, p = 0.024) and NP (4.88%, p = 0.026). No significant differences were observed between prophylaxis types for symptomatic VTE, pulmonary embolism (PE) or death. LMWH and NOACs had a higher minor bleeding incidence than NP (11.71%, p < 0.001 and 6.33%, p < 0.02, respectively). No significant differences were observed between prophylaxis types for major bleeding incidence. CONCLUSION: NOACs are a superior form of chemoprophylaxis, compared with LMWH, in reducing venography-diagnosed VTE incidence with no added bleeding incidence. However, routine chemoprophylaxis may not be required as LMWH and NOACs do not appear to reduce symptomatic VTE incidence compared with MOP and NP with an increased minor bleeding incidence. Mechanical prophylaxis in the form of graduated compression stockings or intermittent pneumatic compression should be routinely considered with significantly lower rates of venography-diagnosed VTE compared with NP. On the basis of current evidence, we recommend an individualised approach to select the most appropriate prophylaxis type.

Increasing risk of mortality across the spectrum of aortic stenosis is independent of comorbidity & treatment: An international, parallel cohort study of 248,464 patients.

BACKGROUND: While large scientific and medical evidence has demonstrated the increased risk of death and cardiovascular mortality in patients with severe AS, the independent contribution of moderate AS to an increased risk of death remains uncertain. METHODS AND FINDINGS: We conducted a multicenter study including a cohort of 30,865 US patients and another cohort of 217,599 Australian patients with equivalent echocardiographic and aortic valve profiling over the same period (2003-2017). During a median 5.2 years (US) and 4.4 years (Australian) follow-up, the risk of death (hazard ratio) of patients with moderate AS as compared to those without AS was 1.66 (95%CI 1.52-1.80) and 1.37 (95%CI 1.34-1.41) in the US and Australian cohorts, even after adjusting this analysis for age and sex. This increased risk of death and cardiovascular mortality (odds ratio) in patients with moderate AS was consistent also across subgroups of left ventricular ejection fraction (LVEF) (subgroups of LVEF < 40%, 40-49%, 50-59%, and ≥ 60%: OR of moderate AS for CV mortality 2.0 [95%CI 1.4-2.7], 1.7 [95%CI 1.2-2.4], 1.5 [95%CI 1.1-1.9], and 1.4 [95%CI 1.2-1.6], respectively). CONCLUSIONS: The findings of this study suggest that patients with moderate AS have a potential increased risk of death and cardiovascular mortality, regardless of age, sex, and LVEF. Hence, these data suggest the need to develop specific strategies to detect and treat individuals with moderate AS.

Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse.

Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/-) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/- mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/- mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis.

Reported definitions of intraoperative hypotension in adults undergoing non-cardiac surgery under general anaesthesia: a review.

BACKGROUND: Intraoperative hypotension (IOH) during non-cardiac surgery is common and associated with major adverse kidney, neurological and cardiac events and even death. Given that IOH is a modifiable risk factor for the mitigation of postoperative complications, it is imperative to generate a precise definition for IOH to facilitate strategies for avoiding or treating its occurrence. Moreover, a universal and consensus definition of IOH may also facilitate the application of novel and emerging therapeutic interventions in treating IOH. We conducted a review to systematically record the reported definitions of intraoperative hypotension in adults undergoing non-cardiac surgery under general anaesthesia. METHODS: In accordance with Cochrane guidelines, we searched three online databases (OVID [Medline], Embase and Cochrane Library) for all studies published from 1 January 2000 to 6 September 2020. We evaluated the number of studies that reported the absolute or relative threshold values for defining blood pressure. Secondary aims included evaluation of the threshold values for defining IOH, the methodology for accounting for the severity of hypotension, whether the type of surgical procedure influenced the definition of IOH, and whether a study whose definition of IOH aligned with the Perioperative Quality Initiative-3 workgroup (POQI) consensus statement for defining was more likely to be associated with determining an adverse postoperative outcome. RESULTS: A total of 318 studies were included in the final qualitative synthesis. Most studies (n = 249; 78.3%) used an absolute threshold to define hypotension; 150 (60.5%) reported SBP, 117 (47.2%) reported MAP, and 12 (4.8%) reported diastolic blood pressure (DBP). 126 (39.6%) used a relative threshold to define hypotension. Of the included studies, 153 (48.1%) did not include any duration variable in their definition of hypotension. Among the selected 318 studies 148 (46.5%) studies defined IOH according to the POQI statement. When studies used a "relative blood pressure change" to define IOH, there was a weaker association in detecting adverse postoperative outcomes compared to studies who reported "absolute blood pressure change" (χ2(2) = 10.508, P = 0.005, Cramér's V = 0.182). When studies used the POQI statement definition of hypotension or defined IOH by values higher than the POQI statement definition there were statistical differences observed between IOH and adverse postoperative outcomes (χ2(1) = 6.581, P = 0.037, Cramér's V = 0.144). When both the duration of IOH or the numbers of hypotensive epochs were evaluated, we observed a significantly stronger relationship between the definition of IOH use the development of adverse postoperative outcomes. (χ2(1) = 4.860, P = 0.027, Cramér's V = 0.124). CONCLUSIONS: Most studies defined IOH by absolute or relative changes from baseline values. There are substantial inconsistencies in how IOH was reported. Further, definitions differed across different surgical specialities. Our findings further suggest that IOH should be defined using the absolute values stated in the POQI statement i.e., MAP < 60-70 mmHg or SBP < 100 mmHg. Finally, the number of hypotensive epochs or time-weighted duration of IOH should also be reported.

GA4GH Passport standard for digital identity and access permissions.

The Global Alliance for Genomics and Health (GA4GH) supports international standards that enable a federated data sharing model for the research community while respecting data security, ethical and regulatory frameworks, and data authorization and access processes for sensitive data. The GA4GH Passport standard (Passport) defines a machine-readable digital identity that conveys roles and data access permissions (called "visas") for individual users. Visas are issued by data stewards, including data access committees (DACs) working with public databases, the entities responsible for the quality, integrity, and access arrangements for the datasets in the management of human biomedical data. Passports streamline management of data access rights across data systems by using visas that present a data user's digital identity and permissions across organizations, tools, environments, and services. We describe real-world implementations of the GA4GH Passport standard in use cases from ELIXIR Europe, National Institutes of Health, and the Autism Sharing Initiative. These implementations demonstrate that the Passport standard has provided transparent mechanisms for establishing permissions and authorizing data access across platforms.

Lenvatinib Targets PDGFR-ß Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights.

CONTEXT: Pericyte populations abundantly express tyrosine kinases (eg, platelet-derived growth factor receptor-ß [PDGFR-ß]) and impact therapeutic response. Lenvatinib is a clinically available tyrosine kinase inhibitor that also targets PDGFR-ß. Duration of therapeutic response was shorter in patients with greater disease burden and metastasis. Patients may develop drug resistance and tumor progression. OBJECTIVES: Develop a gene signature of pericyte abundance to assess with tumor aggressiveness and determine both the response of thyroid-derived pericytes to lenvatinib and their synergies with thyroid carcinoma-derived cells. DESIGN: Using a new gene signature, we estimated the relative abundance of pericytes in papillary thyroid carcinoma (PTC) and normal thyroid (NT) TCGA samples. We also cocultured CD90+;PAX8- thyroid-derived pericytes and BRAFWT/V600E-PTC-derived cells to determine effects of coculture on paracrine communications and lenvatinib response. RESULTS: Pericyte abundance is significantly higher in BRAFV600E-PTC with hTERT mutations and copy number alterations compared with NT or BRAFWT-PTC samples, even when data are corrected for clinical-pathologic confounders. We have identified upregulated pathways important for tumor survival, immunomodulation, RNA transcription, cell-cycle regulation, and cholesterol metabolism. Pericyte growth is significantly increased by platelet-derived growth factor-BB, which activates phospho(p)-PDGFR-ß, pERK1/2, and pAKT. Lenvatinib strongly inhibits pericyte viability by down-regulating MAPK, pAKT, and p-p70S6-kinase downstream PDGFR-ß. Critically, lenvatinib significantly induces higher BRAFWT/V600E-PTC cell death when cocultured with pericytes, as a result of pericyte targeting via PDGFR-ß. CONCLUSIONS: This is the first thyroid-specific model of lenvatinib therapeutic efficacy against pericyte viability, which disadvantages BRAFWT/V600E-PTC growth. Assessing pericyte abundance in patients with PTC could be essential to selection rationales for appropriate targeted therapy with lenvatinib.

Implementing Electronic Patient-Reported Outcomes for Patients With New Oral Chemotherapy Prescriptions at an Academic Site and a Community Site.

PURPOSE: Oral chemotherapy challenges providers' abilities to safely monitor patients' symptoms, adherence, and financial toxicity. COVID-19 has increased the urgency of caring for patients remotely. Collection of electronic patient-reported outcomes (ePROs) has demonstrated efficacy for patients on intravenous chemotherapy, but limited data support their use in oral chemotherapy. We undertook a pilot project to assess the feasibility of implementing an ePRO system for patients starting oral chemotherapy at our cancer center, which includes both an academic site and a community site. METHODS: Patients initiating oral chemotherapy were asked to participate. A five-question tool was built in REDCap. Concerning responses triggered outreach within one business day. The primary outcome was time to first symptom assessment. For comparison, we used a historical cohort of patients who had been prescribed oral chemotherapies by providers in the same disease groups at the cancer center. RESULTS: Twenty-five of 62 (40%) patients completed ePRO assessments. Fifty historical charts were reviewed. Time to first symptom assessment was 7 days (IQR, 4-14 days) in the historical group compared with 3 days (IQR, 2-4 days) in the ePRO group. Time to clinical action was 14 days (7-35 days) in the historical group compared with 8 days (4-19 days) in the ePRO group. No statistically significant differences were detected in 30-day emergency department visit or hospitalization (12% for both groups) or 90-day emergency department visit or hospitalization rates (historical 28% and ePRO 20%). CONCLUSION: An ePRO tool monitoring patient concerns about adherence, cost, and toxicities for patients with new oral chemotherapy regimens is feasible and improves time to symptom assessment. Further investigation is needed to improve patient engagement with ePROs and evaluate the long-term impacts for patients on oral chemotherapy.

Pleiotropic effects of prokineticin 2 in the control of energy metabolism.

Prokineticins are family of small proteins involved in many important biological processes including food intake and control of energy balance. The prokineticin 2 (PROK2) is expressed in several peripheral tissues and areas in the central nervous system. PROK2 activates G protein-coupled receptors, namely, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Preclinical models exhibiting disturbances of the PROK2 pathway (at the level of PROK2 or its receptors) are characterized by changes in food intake, feeding behavior and insulin sensitivity related to a dysfunction of the energy balance control. In Humans, mutations of PROK2 and PROKR2 genes are associated to the Kallmann syndrome (KS) that affects both the hormonal reproductive axis and the sense of smell and may also lead to obesity. Moreover, plasma PROK2 concentration has been correlated with various cardiometabolic risk factors and type 2 diabetes (T2D). The present review summarizes knowledge on PROK2 structure, signaling and function focusing on its role in control of food intake and energy homeostasis.

The GA4GH Variation Representation Specification: A computational framework for variation representation and federated identification.

Maximizing the personal, public, research, and clinical value of genomic information will require the reliable exchange of genetic variation data. We report here the Variation Representation Specification (VRS, pronounced "verse"), an extensible framework for the computable representation of variation that complements contemporary human-readable and flat file standards for genomic variation representation. VRS provides semantically precise representations of variation and leverages this design to enable federated identification of biomolecular variation with globally consistent and unique computed identifiers. The VRS framework includes a terminology and information model, machine-readable schema, data sharing conventions, and a reference implementation, each of which is intended to be broadly useful and freely available for community use. VRS was developed by a partnership among national information resource providers, public initiatives, and diagnostic testing laboratories under the auspices of the Global Alliance for Genomics and Health (GA4GH).

Retrospective evaluation of echocardiographic variables for prediction of heart failure hospitalization in heart failure with preserved versus reduced ejection fraction: A single center experience.

BACKGROUND: Limited data exist on the differential ability of variables on transthoracic echocardiogram (TTE) to predict heart failure (HF) readmission across the spectrum of left ventricular (LV) systolic function. METHODS: We linked 15 years of TTE report data (1/6/2003-5/3/2018) at Beth Israel Deaconess Medical Center to complete Medicare claims. In those with recent HF, we evaluated the relationship between variables on baseline TTE and HF readmission, stratified by LVEF. RESULTS: After excluding TTEs with uninterpretable diastology, 5,900 individuals (mean age: 76.9 years; 49.1% female) were included, of which 2545 individuals (41.6%) were admitted for HF. Diastolic variables augmented prediction compared to demographics, comorbidities, and echocardiographic structural variables (p < 0.001), though discrimination was modest (c-statistic = 0.63). LV dimensions and eccentric hypertrophy predicted HF in HF with reduced (HFrEF) but not preserved (HFpEF) systolic function, whereas LV wall thickness, NT-proBNP, pulmonary vein D- and Ar-wave velocities, and atrial dimensions predicted HF in HFpEF but not HFrEF (all interaction p < 0.10). Prediction of HF readmission was not different in HFpEF and HFrEF (p = 0.93). CONCLUSIONS: In this single-center echocardiographic study linked to Medicare claims, left ventricular dimensions and eccentric hypertrophy predicted HF readmission in HFrEF but not HFpEF and left ventricular wall thickness predicted HF readmission in HFpEF but not HFrEF. Regardless of LVEF, diastolic variables augmented prediction of HF readmission compared to echocardiographic structural variables, demographics, and comorbidities alone. The additional role of medication adherence, readmission history, and functional status in differential prediction of HF readmission by LVEF category should be considered for future study.