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Abstract To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

BackgroundChildren with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase.Methods and findingsIn a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite.ConclusionsEmpirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM.Trial registrationClinicalTrials.gov NCT02246296.

Background: A preceding exploratory study (J. Clin. Pathol. 57(2004), 1201–1207) had shown that a karyometric assessment of nuclei from papillary urothelial neoplasms of low malignant potential (PUNLMP) revealed subtle differences in phenotype which correlated with recurrence of disease. Aim of the Study: To validate the results from the exploratory study on a larger sample size. Materials: 93 karyometric features were analyzed on haematoxylin and eosin-stained sections from 85 cases of PUNLMP. 45 cases were from patients who had a solitary PUNLMP lesion and were disease-free during a follow-up period of at least 8 years. The other 40 were from patients with a unifocal PUNLMP, with one or more recurrences in the follow-up. A combination of the previously defined classification functions together with a new P-index derived classification method was used in an attempt to classify cases and identify a biomarker of recurrence in PUNLMP lesions. Results: Validation was pursued by a number of separate approaches. First, the exact procedure from the exploratory study was applied to the large validation set. Second, since the discriminant function 2 of the exploratory study had been based on a small sample size, a new discriminant function was derived. The case classification showed a correct classification of 61% for non-recurrent and 74% for recurrent cases, respectively. Greater success was obtained by applying unsupervised learning technologies to take advantage of phenotypical composition (correct classification of 92%). This approach was validated by dividing the data into training and test sets with 2/3 of the cases assigned to the training sets, and 1/3 to the test sets, on a rotating basis, and validation of the classification rate was thus tested on three separate data sets by a leave-k-out process. The average correct classification was 92.8% (training set) and 84.6% (test set). Conclusions: Our validation study detected subvisual differences in chromatin organization state between non-recurrent and recurrent PUNLMP, thus allowing a very stable method of predicting recurrence of papillary urothelial neoplasms of low malignant potential by karyometry.

Zusammenfassung  Nach großen viszeralchirurgischen Eingriffen ist mit postoperativen Komplikationen in 10% der Fälle zu rechnen. Davon sind >80% „chirurgische“ Komplikationen, >70% septische Komplikationen und >60% Folgen einer Anastomoseninsuffizienz, die weiterhin die häufigste Ursache für die postoperative Mortalität ist. Der Schlüssel für ein erfolgreiches Management liegt in der frühzeitigen Diagnostik bei ersten Anzeichen einer Störung im postoperativen Verlauf. Primäre Behandlungsziele sind grundsätzlich die suffiziente Drainage der Leckage nach außen und die Verhinderung einer weiteren Kontamination durch Ableitung des Gastrointestinalinhalts aus dem Bereich der Insuffizienz. In Abhängigkeit von der klinischen Klassifikation und der Lokalisation der Insuffizienz im Gastrointestinaltrakt ist das Spektrum der Therapieoptionen aber durchaus unterschiedlich. Bei der chirurgischen Peritonitisbehandlung sind die frühzeitige Diagnostik einer persistierenden Sepsis und neu aufgetretener intraabdomineller Komplikationen sowie die effektive antibiotische Initialtherapie prognosebestimmend. [ABSTRACT FROM AUTHOR]

Zusammenfassung  Die Mediastinitis auf dem Boden einer Anastomoseninsuffizienz ist heute der führende Morbiditäts- und Mortalitätsfaktor bei der operativen Therapie des Ösophaguskarzinoms. Das Krankheitsbild ist gekennzeichnet durch ein lokales intrathorakales Geschehen (Mediastinitis) und extrathorakale Allgemeinreaktionen (Sepsis). Damit sind die Therapiekonzepte klar definiert. Der Schlüssel für ein erfolgreiches Management ist die frühzeitige Diagnostik bei den ersten Anzeichen einer Störung im postoperativen Verlauf. Dabei kommt der Endoskopie zur Beurteilung der Durchblutungsverhältnisse und Größe der Leckage entscheidende Bedeutung zu. In Abhängigkeit von der Lokalisation und klinischen Klassifikation der Insuffizienz reicht das Spektrum der Therapieoptionen von der einfachen Drainageableitung über endoskopische Interventionen und Stentplatzierung bis zur Reoperation und Diskontinuitätsresektion. Dabei muss immer das Behandlungsziel die suffiziente Drainage nach außen und die Verhinderung einer weiteren Kontamination durch Ableitung von Gastrointestinalinhalt aus dem Bereich der Insuffizienz sein. Von gleich großer Bedeutung ist aber auch der frühzeitige Beginn einer systemischen Sepsistherapie zur Unterstützung bereits gestörter Organfunktionen. Beide Maßnahmen, aggressive lokale Interventionen und der Einsatz moderner Konzepte in der Sepsisbehandlung, sind heute die Voraussetzung für ein erfolgreiches Management. [ABSTRACT FROM AUTHOR]

Abstract  In previous work we introduced a construction to produce biorthogonal multiresolutions from given subdivisions. The approach involved estimating the solution to a least squares problem by means of a number of smaller least squares approximations on local portions of the data. In this work we use a result by Dahlquist, et al. on the method of averages to make observational comparisons between this local least squares estimation and full least squares approximation. We have explored examples in two problem domains: data reduction and data approximation. We observe that, particularly for design matrices with a repetitive pattern of column entries, the least squares solution is often well estimated by local least squares, that the estimation rapidly improves with the size of the local least squares problems, and that the quality of the estimate is largely independent of the size of the full problem. [ABSTRACT FROM AUTHOR]

Abstract The modified technique of abdomino-right-thoracic esophagectomy (the Lewis-Tanner approach) is increasingly being favoured as the surgical procedure of choice in patients with resectable adenocarcinoma of the distal esophagus, so-called Barretts cancer. The technical details of this procedure and the reconstruction of gastrointestinal continuity using a gastric tube with high intrathoracic anastomosis are illustrated, as they have proved useful in our own practice during recent years. [ABSTRACT FROM AUTHOR]

Abstract Tracheostomy has become the method of choice in managing patients requiring long-term mechanical ventilation. At present, there are several alternatives to conventional surgical tracheostomy such as percutaneous dilatational techniques according to Ciaglia, Frova, and Fantoni. The basic principle of these new techniques is percutaneous puncture of the trachea and subsequent dilatation of the puncture channel until the tracheal cannula can be inserted. The advantages are bedside performance in the intensive care unit and the use of minimal technical equipment. Nevertheless, dilatation tracheostomy is not always technically feasible and safe. Some significant complications and contraindications have been recognized recently. This should be taken into account when planning tracheostomy in long-term ventilated patients. Compared to conventional surgical tracheostomy, this new procedure retains its value and benefit only if these contraindications are carefully observed. [ABSTRACT FROM AUTHOR]

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