Training Big Random Forests with Little Resources

Without access to large compute clusters, building random forests on large datasets is still a challenging problem. This is, in particular, the case if fully-grown trees are desired. We propose a simple yet effective framework that allows to efficiently construct ensembles of huge trees for hundreds of millions or even billions of training instances using a cheap desktop computer with commodity hardware. The basic idea is to consider a multi-level construction scheme, which builds top trees for small random subsets of the available data and which subsequently distributes all training instances to the top trees' leaves for further processing. While being conceptually simple, the overall efficiency crucially depends on the particular implementation of the different phases. The practical merits of our approach are demonstrated using dense datasets with hundreds of millions of training instances.Comment: 9 pages, 9 Figure

The β-cell/EC axis: how do islet cells talk to each other?

Author version made available in accordance with the publisher's policy.Within the pancreatic islet, the beta cell represents the ultimate biosensor. Its central function is to accurately sense glucose levels in the blood, and consequently release appropriate amounts of insulin. As the only cell type capable of insulin production, the beta cell must balance this crucial workload with self-preservation and, when required, regeneration. Evidence suggests that the beta cell has an important ally in intra-islet endothelial cells. As well as providing a conduit for delivery of the primary input stimulus (glucose) and dissemination of its most important effector (insulin), intra-islet blood vessels deliver oxygen to these dense clusters of metabolically active cells. Furthermore, it appears that endothelial cells directly impact insulin gene expression, secretion and beta cell survival. This review discusses the molecules and pathways involved in the crosstalk between beta cells and intra-islet endothelial cells. The evidence supporting the intra-islet endothelial cell as an important partner for beta cell function is examined to highlight the relevance of this axis in the context of type 1 and type 2 diabetes. Recent work which has established the potential of endothelial cells or their progenitors to enhance the reestablishment of glycaemic control following pancreatic islet transplantation in animal models is discussed

COVID and the Kidney:An Update

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has led to a global pandemic that continues to be responsible for ongoing health issues for people worldwide. Immunocompromised individuals such as kidney transplant recipients and dialysis patients have been and continue to be among the most affected, with poorer outcomes after infection, impaired response to COVID-19 vaccines, and protracted infection. The pandemic also has had a significant impact on patients with underlying chronic kidney disease (CKD), with CKD increasing susceptibility to COVID-19, risk of hospital admission, and mortality. COVID-19 also has been shown to lead to acute kidney injury (AKI) through both direct and indirect mechanisms. The incidence of COVID-19 AKI has been decreasing as the pandemic has evolved, but continues to be associated with adverse patient outcomes correlating with the severity of AKI. There is also increasing evidence examining the longer-term effect of COVID-19 on the kidney demonstrating continued decline in kidney function several months after infection. This review summarizes the current evidence examining the impact of COVID-19 on the kidney, covering both the impact on patients with CKD, including patients receiving kidney replacement therapy, in addition to discussing COVID-19 AKI.<br/

COVID and the Kidney:An Update

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has led to a global pandemic that continues to be responsible for ongoing health issues for people worldwide. Immunocompromised individuals such as kidney transplant recipients and dialysis patients have been and continue to be among the most affected, with poorer outcomes after infection, impaired response to COVID-19 vaccines, and protracted infection. The pandemic also has had a significant impact on patients with underlying chronic kidney disease (CKD), with CKD increasing susceptibility to COVID-19, risk of hospital admission, and mortality. COVID-19 also has been shown to lead to acute kidney injury (AKI) through both direct and indirect mechanisms. The incidence of COVID-19 AKI has been decreasing as the pandemic has evolved, but continues to be associated with adverse patient outcomes correlating with the severity of AKI. There is also increasing evidence examining the longer-term effect of COVID-19 on the kidney demonstrating continued decline in kidney function several months after infection. This review summarizes the current evidence examining the impact of COVID-19 on the kidney, covering both the impact on patients with CKD, including patients receiving kidney replacement therapy, in addition to discussing COVID-19 AKI.<br/

Implementation of an Ultraviolet Phototherapy Service at a National Referral Hospital in Western Kenya: Reflections on Challenges and Lessons Learned.

IntroductionIn order to manage skin conditions at a national referral hospital level in Kenya, specialized dermatology services, such as dermatologic surgery, dermatopathology, phototherapy, and sub-specialty care, should be offered, as is typically available in referral hospitals around the world. A Kenyan patient with prurigo nodularis, whose severe itch remitted after phototherapy treatment at the University of California, San Francisco (UCSF), inspired the development of a phototherapy service at Academic Model Providing Access to Healthcare (AMPATH), a partnership in Western Kenya between Moi Teaching and Referral Hospital, Moi University College of Health Sciences, and a consortium of North American academic medical centers.MethodsInitial project funds were raised through a crowdfunding campaign and fundraising events. A new narrowband ultraviolet B phototherapy unit and replacement bulbs were donated and air shipped to Eldoret, Kenya. A team of dermatologists and phototherapy nurses from UCSF conducted a 2-day training session. US-based dermatologists affiliated with AMPATH provide ongoing support through regular communication and on-site visits.ResultsEarly in implementation, challenges faced included training clinical staff with limited experience in phototherapy and improving communication between nurses and clinicians. More recent challenges include frequent rotation of specialty clinic nurses in the dermatology clinic, adaptation of phototherapy guidelines to balance patient volume with service delivery capacity, and training assessment of disease activity in darkly pigmented skin.ConclusionStrategies that have been helpful in addressing implementation challenges include: increasing on-site and remote training opportunities for clinicians and nurses, developing a tiered payment schema, educating patients to combat misconceptions about phototherapy, dynamic phototherapy referral guidelines to accommodate service delivery capacity, and prioritizing the engagement of a multidisciplinary team

Partial nephrectomy for renal cell carcinoma in an allograft kidney with limited functional reserve

Abstract The increased risk of malignancies is a well-recognized complication of organ transplantation. When renal cell carcinoma (RCC) occurs in kidney transplant recipients, less than 10% of it affects the allograft. Recent experience suggests that partial allograft nephrectomy for tumours less than 4 cm may be considered the treatment of choice. We report a case of a 3.3 cm RCC discovered in a renal allograft. Limited allograft function was due to segmental infarction after transplant surgery and chronic allograft nephropathy. She underwent successful partial allograft nephrectomy. At 36 months post-surgery, there is no evidence of RCC recurrence and she remains free of renal replacement therapy

Endothelial Progenitor Cells Enhance Islet Engraftment, Influence b-Cell Function, and Modulate Islet Connexin 36 Expression

This article has been made available by the publisher under a Creative Commons Attribution Non-Commercial (CC BY NC) license. https://www.cognizantcommunication.com/general-subscription-policies/open-access-policy Accessed 10/2/15The success of pancreatic islet transplantation is limited by delayed engraftment and suboptimal function in the longer term. Endothelial progenitor cells (EPCs) represent a potential cellular therapy that may improve the engraftment of transplanted pancreatic islets. In addition, EPCs may directly affect the function of pancreatic β-cells. The objective of this study was to examine the ability of EPCs to enhance pancreatic islet transplantation in a murine syngeneic marginal mass transplant model and to examine the mechanisms through which this occurs. We found that cotransplanted EPCs improved the cure rate and initial glycemic control of transplanted islets. Gene expression data indicate that EPCs, or their soluble products, modulate the expression of the β-cell surface molecule connexin 36 and affect glucose-stimulated insulin release in vitro. In conclusion, EPCs are a promising candidate for improving outcomes in islet transplantation, and their mechanisms of action warrant further study

Insulin-like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation

BackgroundThe early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life.MethodsWe used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed.ResultsAd-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (PConclusionsAntiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F.; Drogemuller, Chris J.; Coates, P. Toby H

Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials

Background A diet rich in fruit, vegetables and dietary fibre and low in fat is associated with reduced risk of chronic disease. This review aimed to estimate the effectiveness of interventions to promote healthy diet for primary prevention among participants attending primary care.&lt;p&gt;&lt;/p&gt; Methods A systematic review of trials using individual or cluster randomisation of interventions delivered in primary care to promote dietary change over 12 months in healthy participants free from chronic disease or defined high risk states. Outcomes were change in fruit and vegetable intake, consumption of total fat and fibre and changes in serum cholesterol concentration.&lt;p&gt;&lt;/p&gt; Results Ten studies were included with 12,414 participants. The design and delivery of interventions were diverse with respect to grounding in behavioural theory and intervention intensity. A meta-analysis of three studies showed an increase in fruit consumption of 0.25 (0.01 to 0.49) servings per day, with an increase in vegetable consumption of 0.25 (0.06 to 0.44) serving per day. A further three studies that reported on fruit and vegetable consumption together showed a pooled increment of 0.50 (0.13 to 0.87) servings per day. The pooled effect on consumption of dietary fibre, from four studies, was estimated to be 1.97 (0.43 to 3.52) gm fibre per day. Data from five studies showed a mean decrease in total fat intake of 5.2% of total energy (1.5 to 8.8%). Data from three studies showed a mean decrease in serum cholesterol of 0.10 (-0.19 to 0.00) mmol/L.&lt;p&gt;&lt;/p&gt; Conclusion Presently-reported interventions to promote healthy diet for primary prevention in primary care, which illustrate a diverse range of intervention methods, may yield small beneficial changes in consumption of fruit, vegetables, fibre and fat over 12 months. The present results do not exclude the possibility that more effective intervention strategies might be developed.&lt;p&gt;&lt;/p&gt

Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135–145)1,2,3,4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3135–145-specific T cells expand in patients with Goodpasture disease and, in α3135–145-immunized HLA-DR15 transgenic mice, α3135–145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135–145 epitope in different binding registers. HLA-DR15-α3135–145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135–145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135–145-specific T-cell antigen receptor usage, HLA-DR15-α3135–145 tetramer+ Foxp3− Tconv and HLA-DR1-α3135–145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135–145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity