Covering Points by Disjoint Boxes with Outliers

For a set of n points in the plane, we consider the axis--aligned (p,k)-Box Covering problem: Find p axis-aligned, pairwise-disjoint boxes that together contain n-k points. In this paper, we consider the boxes to be either squares or rectangles, and we want to minimize the area of the largest box. For general p we show that the problem is NP-hard for both squares and rectangles. For a small, fixed number p, we give algorithms that find the solution in the following running times: For squares we have O(n+k log k) time for p=1, and O(n log n+k^p log^p k time for p = 2,3. For rectangles we get O(n + k^3) for p = 1 and O(n log n+k^{2+p} log^{p-1} k) time for p = 2,3. In all cases, our algorithms use O(n) space.Comment: updated version: - changed problem from 'cover exactly n-k points' to 'cover at least n-k points' to avoid having non-feasible solutions. Results are unchanged. - added Proof to Lemma 11, clarified some sections - corrected typos and small errors - updated affiliations of two author

Incidence and diagnostic yield of repeat urine culture in hospitalized patients: An opportunity for diagnostic stewardship

There is limited knowledge on the incidence, diagnostic yield, and cost associated with inappropriate repeat urine cultures. The factors that affect repeat urine culturing practices are not well understood. We conducted a retrospective study of adult inpatients who had ≥1 urine culture performed during their hospitalization between January 2015 and February 2018. We analyzed the proportion of inappropriate repeat urine cultures performed \u3c48 h after the index culture. We defined an inappropriate repeat urine culture to be a repeat urine culture performed following a negative index culture or a repeat urine specimen obtained from the same urinary catheter. Overall, 28,141 urine cultures were performed on 21,306 patients. There were 2,060 (7.3%) urine cultures repeated in \u3c48 h. Of these, 1,120 (54.4%) urine cultures were inappropriate. Predictors for inappropriate repeat urine cultures included collection of the initial urine sample for culture in the emergency department (adjusted odds ratio [aOR], 5.65; 95% confidence interval [CI], 4.70 to 6.78), male gender (aOR, 1.61; 95% CI, 1.42 to 1.84), congestive heart failure (aOR, 1.20; 95% CI, 1.03 to 1.38), and a longer hospital stay (aOR, 1.01 per day; 95% CI, 1.00 to 1.01). A patient with an index urine culture obtained from an indwelling catheter (aOR, 0.65; 95% CI, 0.53 to 0.80) was less likely to have an inappropriate repeat culture. Among 1,120 negative index urine cultures, only 4.7% of repeat cultures were positive for bacteriuria. The estimated laboratory charges for inappropriate repeat urine cultures were $16,800 over the study period. Among inpatients, over half of all urine cultures repeated in \u3c48 h were inappropriate. This offers an opportunity for diagnostic stewardship and optimization of antimicrobial use

Three-dimensional structure of Schistosoma japonicum glutathione S-transferase fused with a six-amino acid conserved neutralizing epitope of gp41 from HIV

The 3-dimensional crystal structure of glutathione S-transferase (GST) of Schistosoma japonicum (Sj) fused with a conserved neutralizing epitope on gp41 (glycoprotein, 41 kDa) of human immunodeficiency virus type 1 (HIV-1) was determined at 2.5 A resolution. The structure of the 3-3 isozyme rat GST of the mu gene class was used as a molecular replacement model. The structure consists of a 4-stranded beta-sheet and 3 alpha-helices in domain 1 and 5 alpha-helices in domain 2. The space group of the Sj GST crystal is P4(sub 3)2(sub 1)2 with unit cell dimensions of a = b = 94.7 A, and c = 58.1 A. The crystal has 1 GST monomer per asymmetric unit, and 2 monomers that form an active dimer are related by crystallographic 2-fold symmetry. In the binding site, the ordered structure of reduced glutathione is observed. The gp41 peptide (Glu-Leu-Asp-Lys-Trp-Ala) fused to the C-terminus of Sj GST forms a loop stabilized by symmetry-related GSTs. The Sj GST structure is compared with previously determined GST structures of mammalian gene classes mu, alpha, and pi. Conserved amino acid residues among the 4 GSTs that are important for hydrophobic and hydrophilic interactions for dimer association and glutathione binding are discussed

Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40highB cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

\u3cem\u3eBorrelia burgdorferi\u3c/em\u3e EbfC Defines a Newly-Identified, Widespread Family of Bacterial DNA-Binding Proteins

The Lyme disease spirochete, Borrelia burgdorferi, encodes a novel type of DNA-binding protein named EbfC. Orthologs of EbfC are encoded by a wide range of bacterial species, so characterization of the borrelial protein has implications that span the eubacterial kingdom. The present work defines the DNA sequence required for high-affinity binding by EbfC to be the 4 bp broken palindrome GTnAC, where ‘n’ can be any nucleotide. Two high-affinity EbfC-binding sites are located immediately 5′ of B. burgdorferi erp transcriptional promoters, and binding of EbfC was found to alter the conformation of erp promoter DNA. Consensus EbfC-binding sites are abundantly distributed throughout the B. burgdorferi genome, occurring approximately once every 1 kb. These and other features of EbfC suggest that this small protein and its orthologs may represent a distinctive type of bacterial nucleoid-associated protein. EbfC was shown to bind DNA as a homodimer, and site-directed mutagenesis studies indicated that EbfC and its orthologs appear to bind DNA via a novel α-helical ‘tweezer’-like structure

Application of a target array Comparative Genomic Hybridization to prenatal diagnosis

<p>Abstract</p> <p>Background</p> <p>While conventional G-banded karyotyping still remains a gold standard in prenatal genetic diagnoses, the widespread adoption of array Comparative Genomic Hybridization (array CGH) technology for postnatal genetic diagnoses has led to increasing interest in the use of this same technology for prenatal diagnosis. We have investigated the value of our own designed DNA chip as a prenatal diagnostic tool for detecting submicroscopic deletions/duplications and chromosome aneuploidies.</p> <p>Methods</p> <p>We designed a target bacterial artificial chromosome (BAC)-based aCGH platform (MacArray™ M-chip), which specifically targets submicroscopic deletions/duplications for 26 known genetic syndromes of medical significance observed prenatally. To validate the DNA chip, we obtained genomic DNA from 132 reference materials generated from patients with 22 genetic diseases and 94 clinical amniocentesis samples obtained for karyotyping.</p> <p>Results</p> <p>In the 132 reference materials, all known genomic alterations were successfully identified. In the 94 clinical samples that were also subjected to conventional karyotyping, three cases of balanced chromosomal aberrations were not detected by aCGH. However, we identified eight cases of microdeletions in the Yq11.23 chromosomal region that were not found by conventional karyotyping. This region harbors the DAZ gene, and deletions may lead to non-obstructive spermatogenesis.</p> <p>Conclusions</p> <p>We have successfully designed and applied a BAC-based aCGH platform for prenatal diagnosis. This platform can be used in conjunction with conventional karyotyping and will provide rapid and accurate diagnoses for the targeted genomic regions while eliminating the need to interpret clinically-uncertain genomic regions.</p

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations.This study was supported by NCI K08 CA1939915, Alex's Lemonade Stand Foundation for Childhood Cancer, and St. Baldrick's Foundation (to J.M. Kalish); European Research Council Advanced Researcher Award (to E.R. Maher); and NCI 5P30CA054174-21 (to G.E. Tomlinson)