Colonic irrigation for defecation disorders after dynamic graciloplasty

AB - BACKGROUND AND AIMS: Dynamic graciloplasty (DGP) improves anal continence and quality of life for most patients. However, in some patients, DGP fails and fecal incontinence is unsolved or only partially improved. Constipation is also a significant problem after DGP, occurring in 13-90%. Colonic irrigation can be considered as an additional or salvage treatment for defecation disorders after unsuccessful or partially successful DGP. In this study, the effectiveness of colonic irrigation for the treatment of persistent fecal incontinence and/or constipation after DGP is investigated. MATERIALS AND METHODS: Patients with defecation disorders after DGP visiting the outpatient clinic of the University Hospital Maastricht were selected for colonic irrigation as additional therapy or salvage therapy in the period between January 1999 and June 2003. The Biotrol(R) Irrimatic pump or the irrigation bag was used for colonic irrigation. Relevant physical and medical history was collected. The patients were asked to fill out a detailed questionnaire about colonic irrigation. RESULTS: Forty-six patients were included in the study with a mean age of 59.3 +/- 12.4 years (80% female). On average, the patients started the irrigation 21.39 +/- 38.77 months after the DGP. Eight patients started irrigation before the DGP. Fifty-two percent of the patients used the irrigation as additional therapy for fecal incontinence, 24% for constipation, and 24% for both. Irrigation was usually performed in the morning. The mean frequency of irrigation was 0.90 +/- 0.40 times per day. The mean amount of water used for the irrigation was 2.27 +/- 1.75 l with a mean duration of 39 +/- 23 min. Four patients performed antegrade irrigation through a colostomy or appendicostomy, with good results. Overall, 81% of the patients were satisfied with the irrigation. Thirty-seven percent of the patients with fecal incontinence reached (pseudo-)continence, and in 30% of the patients, the constipation completely resolved. Side effects of the irrigation were reported in 61% of the patients: leakage of water after irrigation, abdominal cramps, and distended abdomen. Seven (16%) patients stopped the rectal irrigation. CONCLUSION: Colonic irrigation is an effective alternative for the treatment of persistent fecal incontinence after DGP and/or recurrent or onset constipation additional to unsuccessful or (partially) successful DG

Stochastic ionization through noble tori: Renormalization results

We find that chaos in the stochastic ionization problem develops through the break-up of a sequence of noble tori. In addition to being very accurate, our method of choice, the renormalization map, is ideally suited for analyzing properties at criticality. Our computations of chaos thresholds agree closely with the widely used empirical Chirikov criterion

Early Planet Formation in Embedded Disks (eDisk). II. Limited Dust Settling and Prominent Snow Surfaces in the Edge-on Class I Disk IRAS 04302+2247

While dust disks around optically visible, Class II protostars are found to be vertically thin, when and how dust settles to the midplane are unclear. As part of the Atacama Large Millimeter/submillimeter Array (ALMA) large program, Early Planet Formation in Embedded Disks, we analyze the edge-on, embedded, Class I protostar IRAS 04302+2247, also nicknamed the ``Butterfly Star." With a resolution of 0.05" (8~au), the 1.3 mm continuum shows an asymmetry along the minor axis which is evidence of an optically thick and geometrically thick disk viewed nearly edge-on. There is no evidence of rings and gaps, which could be due to the lack of radial substructure or the highly inclined and optically thick view. With 0.1" (16~au) resolution, we resolve the 2D snow surfaces, i.e., the boundary region between freeze-out and sublimation, for $^{12}$CO $J$=2--1, $^{13}$CO $J$=2--1, C$^{18}$O $J$=2--1, $H_{2}$CO $J$=$3_{0,3}$--$2_{0,2}$, and SO $J$=$6_{5}$--$5_{4}$, and constrain the CO midplane snow line to $\sim 130$ au. We find Keplerian rotation around a protostar of $1.6 \pm 0.4 M_{\odot}$ using C$^{18}$O. Through forward ray-tracing using RADMC-3D, we find that the dust scale height is $\sim 6$ au at a radius of 100~au from the central star and is comparable to the gas pressure scale height. The results suggest that the dust of this Class~I source has yet to vertically settle significantly.Comment: 33 pages, 21 figures. Accepted for publication in ApJ as one of the first-look papers of the eDisk ALMA Large Progra

Early Planet Formation in Embedded Disks (eDisk) III: A first high-resolution view of sub-mm continuum and molecular line emission toward the Class 0 protostar L1527 IRS

Studying the physical and chemical conditions of young embedded disks is crucial to constrain the initial conditions for planet formation. Here, we present Atacama Large Millimeter/submillimeter Array (ALMA) observations of dust continuum at $\sim$0.06" (8 au) resolution and molecular line emission at $\sim$0.17" (24 au) resolution toward the Class 0 protostar L1527 IRS from the Large Program eDisk (Early Planet Formation in Embedded Disks). The continuum emission is smooth without substructures, but asymmetric along both the major and minor axes of the disk as previously observed. The detected lines of $^{12}$CO, $^{13}$CO, C$^{18}$O, H$_2$CO, c-C$_3$H$_2$, SO, SiO, and DCN trace different components of the protostellar system, with a disk wind potentially visible in $^{12}$CO. The $^{13}$CO brightness temperature and the H$_2$CO line ratio confirm that the disk is too warm for CO freeze out, with the snowline located at $\sim$350 au in the envelope. Both molecules show potential evidence of a temperature increase around the disk-envelope interface. SO seems to originate predominantly in UV-irradiated regions such as the disk surface and the outflow cavity walls rather than at the disk-envelope interface as previously suggested. Finally, the continuum asymmetry along the minor axis is consistent with the inclination derived from the large-scale (100" or 14,000 au) outflow, but opposite to that based on the molecular jet and envelope emission, suggesting a misalignment in the system. Overall, these results highlight the importance of observing multiple molecular species in multiple transitions to characterize the physical and chemical environment of young disks.Comment: 27 pages, 16 figures, 2 tables, 10 pages appendix with 12 figures. Accepted for publication in ApJ as one of the first-look papers of the eDisk ALMA Large Progra

Early Planet Formation in Embedded Disks (eDisk). VII. Keplerian Disk, Disk Substructure, and Accretion Streamers in the Class 0 Protostar IRAS 16544-1604 in CB 68

We present observations of the Class 0 protostar IRAS 16544-1604 in CB 68 from the ''Early Planet Formation in Embedded Disks (eDisk)'' ALMA Large program. The ALMA observations target continuum and lines at 1.3-mm with an angular resolution of $\sim$5 au. The continuum image reveals a dusty protostellar disk with a radius of $\sim$30 au seen close to edge-on, and asymmetric structures both along the major and minor axes. While the asymmetry along the minor axis can be interpreted as the effect of the dust flaring, the asymmetry along the major axis comes from a real non-axisymmetric structure. The C$^{18}$O image cubes clearly show the gas in the disk that follows a Keplerian rotation pattern around a $\sim$0.14 $M_{\odot}$ central protostar. Furthermore, there are $\sim$1500 au-scale streamer-like features of gas connecting from North-East, North-North-West, and North-West to the disk, as well as the bending outflow as seen in the $^{12}$CO (2-1) emission. At the apparent landing point of NE streamer, there are SO (6$_5$-5$_4$) and SiO (5-4) emission detected. The spatial and velocity structure of NE streamer can be interpreted as a free-falling gas with a conserved specific angular momentum, and the detection of the SO and SiO emission at the tip of the streamer implies presence of accretion shocks. Our eDisk observations have unveiled that the Class 0 protostar in CB 68 has a Keplerian rotating disk with flaring and non-axisymmetric structure associated with accretion streamers and outflows.Comment: 30 pages, 24 figures, accepted for publication in The Astrophysical Journal as one of the first-look papers of the eDisk ALMA Large Progra

Early Planet Formation in Embedded Disks (eDisk). I. Overview of the Program and First Results

We present an overview of the Large Program, ``Early Planet Formation in Embedded Disks (eDisk)'', conducted with the Atacama Large Millimeter/submillimeter Array (ALMA). The ubiquitous detections of substructures, particularly rings and gaps, in protoplanetary disks around T Tauri stars raise the possibility that at least some planet formation may have already started during the embedded stages of star formation. In order to address exactly how and when planet formation is initiated, the program focuses on searching for substructures in disks around 12 Class 0 and 7 Class I protostars in nearby ($<$200 pc) star-forming regions through 1.3 mm continuum observations at a resolution of $\sim7$ au (0.04"). The initial results show that the continuum emission, mostly arising from dust disks around the sample protostars, has relatively few distinctive substructures, such as rings and spirals, in marked contrast to Class II disks. The dramatic difference may suggest that substructures quickly develop in disks when the systems evolve from protostars to Class II sources or alternatively that high optical depth of the continuum emission could obscure internal structures. Kinematic information obtained through CO isotopologue lines and other lines reveals the presence of Keplerian disks around protostars, providing us with crucial physical parameters, in particular, the dynamical mass of the central protostars. We describe the background of the eDisk program, the sample selection and their ALMA observations, the data reduction, and also highlight representative first-look results.Comment: This is a publication of a series of eDisk ALMA large program first-look paper

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells

Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are purported to be responsible for tumor initiation, maintenance, metastases, and disease recurrence. Interleukin-8 (IL-8) is upregulated in breast cancer compared with normal breast tissue and is associated with poor prognosis. IL-8 is reported to promote breast cancer progression by increasing cell invasion, angiogenesis, and metastases and is upregulated in HER2-positive cancers. Recently, we and others have established that IL-8 via its cognate receptors, CXCR1 and CXCR2, is also involved in regulating breast CSC activity. Our work demonstrates that in metastatic breast CSCs, CXCR1/2 signals via transactivation of HER2. Given the importance of HER2 in breast cancer and in regulating CSC activity, a pathway driving the activation of these receptors would have important biological and clinical consequences, especially in tumors that express high levels of IL-8 and other CXCR1/2-activating ligands. Here, we review the IL-8 signaling pathway and the role of HER2 in maintaining an IL-8 inflammatory loop and discuss the potential of combining CXCR1/2 inhibitors with other treatments such as HER2-targeted therapy as a novel approach to eliminate CSCs and improve patient survival

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation