Generating automated kidney transplant biopsy reports combining molecular measurements with ensembles of machine learning classifiers

We previously reported a system for assessing rejection in kidney transplant biopsies using microarray‐based gene expression data, the Molecular Microscope^® Diagnostic System (MMDx). The present study was designed to optimize the accuracy and stability of MMDx diagnoses by replacing single machine learning classifiers with ensembles of diverse classifier methods. We also examined the use of automated report sign‐outs and the agreement between multiple human interpreters of the molecular results. Ensembles generated diagnoses that were both more accurate than the best individual classifiers, and nearly as stable as the best, consistent with expectations from the machine learning literature. Human experts had ≈93% agreement (balanced accuracy) signing out the reports, and random forest‐based automated sign‐outs showed similar levels of agreement with the human experts (92% and 94% for predicting the expert MMDx sign‐outs for T cell–mediated (TCMR) and antibody‐mediated rejection (ABMR), respectively). In most cases disagreements, whether between experts or between experts and automated sign‐outs, were in biopsies near diagnostic thresholds. Considerable disagreement with histology persisted. The balanced accuracies of MMDx sign‐outs for histology diagnoses of TCMR and ABMR were 73% and 78%, respectively. Disagreement with histology is largely due to the known noise in histology assessments (ClinicalTrials.gov NCT01299168).     

Rapid Selection of Plasmodium falciparum Chloroquine Resistance Transporter Gene and Multidrug Resistance Gene-1 Haplotypes Associated with Past Chloroquine and Present Artemether-Lumefantrine Use in Inhambane District,Southern Mozambique

Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P ≤ 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246 haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased use of CQ and large-scale use of AL. In the absence of a clear AL-resistance marker and the (almost) continent-wide use of AL in sub-Saharan Africa, and when considering CQ reintroduction, continued monitoring of these markers is needed.     

Genetic variation associated with chromosomal aberration frequency: A genome-wide association study

Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples. To have a broad look at the genetic susceptibility associated with CA frequency, the sample sets composed of individuals either differentially exposed to smoking, occupational/environmental hazards, or they were untreated cancer patients. Phenotypes were divided into chromosome- and chromatid-type aberrations (CSAs and CTAs, respectively) and total chromosomal aberrations (CAtot). The arbitrary cutoff point between individuals with high and low CA frequency was 2% for CAtot and 1% for CSA and CTA. The data were analyzed using age, sex, occupation/cancer and smoking history as covariates. Altogether 11 loci reached the P-value of 10⁻⁵ in the GWAS. Replication 1 supported the association of rs1383997 (8q13.3) and rs2824215 (21q21.1) in CAtot and rs983889 (5p15.1) in CTA analysis. These loci were found to be associated with genes involved in mitosis, response to environmental and chemical factors and genes involved in syndromes linked to chromosomal abnormalities. Identification of new genetic variants for the frequency of CAs offers prediction tools for cancer risk in future. Environ. Mol. Mutagen. 60:17–28, 2019. © 2018 Wiley Periodicals, Inc.     

How to use a nasopharyngeal prong in Pierre Robin sequence

Pierre Robin sequence (PRS) describes a small mandible with retrognathia, an elevated and posteriorly positioned tongue, and an associated U-shaped cleft palate. The retracted tongue may obstruct the airway leading to respiratory failure, with failure to thrive and adverse neurodevelopmental outcomes if not addressed. If the airway obstruction cannot be overcome with conservative measures, there are non-surgical and surgical options. A nasopharyngeal prong (NPP) is a non-surgical, temporary treatment that avoids the complications inherent in an operation, especially given the natural history of mandibular growth and improved airway obstruction in PRS. Although the use of a prong requires training, support, and follow up, it effectively bypasses the obstruction in the majority of children with PRS, and allows the child to outgrow the airway obstruction until the prong is no longer required. On average, the prong can be removed between 6 and 12 months of age.     

WEILBY-BURTON ARTHROPLASTY OF THE TRAPEZIOMETACARPAL JOINT OF THE THUMB

Twenty-three patients (25 thumbs) were treated by tendon interposition arthroplasty for trapeziometacarpal arthrosis as described by Weilby and modified slightly as described by Burton and Pellegrini. There was good (4/25, 16%) or complete (19/25, 76%) pain relief in 23 (92%) of the cases. Activities of daily living were generally easier. Mobility and strength of the thumb were satisfactory. One patient had signs of instability during a stress test. We conclude that our technique produces a stable and pain-free thumb joint. However, careful selection of the patients for this procedure is essential, and the patient must be given comprehensive information about all stages.