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ObjectiveTo explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data.MethodsTwelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIBO]) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire.ResultsOne thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs.ConclusionUsing a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.

Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by inflammatory colitis and is associated with systemic inflammation. Herein, we aimed to investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation.We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients' colons and conducted compositional and functional pathway prediction analyses.The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha-diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilization were enriched in patients with colitis and correlated positively with fecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by fecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance is associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into "high" and "low" systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta-diversity analyses.The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

BACKGROUND: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. METHODS: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. FINDINGS:We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p

Multigrid solvers face multiple challenges on parallel computers. Two fundamental ones read as follows: Multiplicative solvers issue coarse grid solves which exhibit low concurrency and many multigrid implementations suffer from an expensive coarse grid identification phase plus adaptive mesh refinement overhead. We propose a new additive multigrid variant for spacetrees, that is, meshes as they are constructed from octrees and quadtrees: It is an additive scheme, that is, all multigrid resolution levels are updated concurrently. This ensures a high concurrency level, while the transfer operators between the mesh levels can still be constructed algebraically. The novel flavor of the additive scheme is an augmentation of the solver with an additive, auxiliary damping parameter per grid level per vertex that is in turn constructed through the next coarser level—an idea which utilizes smoothed aggregation principles or the motivation behind AFACx: Per level, we solve an additional equation whose purpose is to damp too aggressive solution updates per vertex which would otherwise, in combination with all the other levels, yield an overcorrection and, eventually, oscillations. This additional equation is constructed additively as well, that is, is once more solved concurrently to all other equations. This yields improved stability, closer to what is seen with multiplicative schemes, while pipelining techniques help us to write down the additive solver with single‐touch semantics for dynamically adaptive meshes.

The accurate assembly of the system matrix is an important step in any code that solves partial differential equations on a mesh. We either explicitly set up a matrix, or we work in a matrix‐free environment where we have to be able to quickly return matrix entries upon demand. Either way, the construction can become costly due to nontrivial material parameters entering the equations, multigrid codes requiring cascades of matrices that depend upon each other, or dynamic adaptive mesh refinement that necessitates the recomputation of matrix entries or the whole equation system throughout the solve. We propose that these constructions can be performed concurrently with the multigrid cycles. Initial geometric matrices and low accuracy integrations kickstart the multigrid iterations, while improved assembly data is fed to the solver as and when it becomes available. The time to solution is improved as we eliminate an expensive preparation phase traditionally delaying the actual computation. We eliminate algorithmic latency. Furthermore, we desynchronize the assembly from the solution process. This anarchic increase in the concurrency level improves the scalability. Assembly routines are notoriously memory‐ and bandwidth‐demanding. As we work with iteratively improving operator accuracies, we finally propose the use of a hierarchical, lossy compression scheme such that the memory footprint is brought down aggressively where the system matrix entries carry little information or are not yet available with high accuracy.

Multigrid algorithms are among the most efficient solvers for elliptic partial differential equations. However, we have to invest into an expensive matrix setup phase before we kick off the actual solve. This assembly effort is non-negligible; particularly if the fine grid stencil integration is laborious. Our manuscript proposes to start multigrid solves with very inaccurate, geometric fine grid stencils which are then updated and improved in parallel to the actual solve. This update can be realised greedily and adaptively. We furthermore propose that any operator update propagates at most one level at a time, which ensures that multiscale information propagation does not hold back the actual solve. The increased asynchronicity, i.e. the laziness improves the runtime without a loss of stability if we make the grid update sequence take into account that multiscale operator information propagates at finite speed.

Gastrointestinal (GI) disease is one of the major causes of morbidity in patients with systemic sclerosis (SSc). The most common manifestation of GI disease is oesophageal involvement affecting 70-90% of patients. Severe GI disease is uncommon, but results in symptoms such as early satiety, pseudo-obstruction, weight loss and malnutrition. The pathogenesis is relatively poorly understood, and management focuses on symptomatic control rather than immunomodulation.We describe two cases of patients with SSc myositis overlap syndrome with severe GI involvement who demonstrated improvements in swallowing, early satiety and diarrhoea following the administration of intravenous immunoglobulin (IVIg).Clinical data related to the two cases were collected by review of medical records.GI complications range from mild symptoms to debilitating and life threatening. We propose that IVIg may have an immunomodulatory effect in a subset of patients with SSc myositis overlap syndrome.

Systemic sclerosis is an autoimmune connective tissue disorder, which can be progressive with multisystem involvement. Guidance on the management of complications is based on a limited data set and practice amongst clinicians can vary. The UK Scleroderma study group set up several working groups to agree some consensus pathways for the management of specific complications. Approximately nine out of ten patients with systemic sclerosis will have involvement of the gastrointestinal system and in this review article we explore the management of these complications in a symptom-based approach. The algorithms are a useful tool for clinicians, which we hope, will be a point of reference and highlight the need for further research in these areas.

3 Mol p-Chlorbenzoylnitrit (III) reagieren mit der Hydrazonform (II) von l-Phenylazonaphthol-(2) (I) in Benzol bei Raumtemperatur zur N-Nitrosoverbindung (IV), die uber den Diazoather (V) in (VI) und (VII) zerfallt.

Reaction of N-nitroso[2′,4′,6′-2H3]acetanilide, formed in situ from [2′,4′,6′-2H3]acetanilide (99%[2H3]) and p-chlorobenzoyl nitrite, with tetraphenylcyclopentadienone and acetic acid in benzene gave biphenyl, from which no deuterium had been lost, and 1,2,3,4-tetraphenylnaphthalene which had lost one g atom of deuterium. Similar results were obtained from reaction of [2,4,6-2H3]benzenediazonium fluoroborate (99%[2H3]) with potassium acetate in benzene. The corresponding reaction using anthracene as a benzyne trap gave similar result. These results exclude the operation of a ‘pre-equilibrium’ type of E1cB mechanism in the formation of benzyne from the benzenediazonium acetate ion pair, but do not allow a distinction to be made between E1cB (irreversible) or concerted E2 mechanisms, particularly in view of the low (1·5–1·8) isotope effects observed with [2-2H]benzenediazonium salts.

The observations that 1,1-diphenylethylene and a series of related alkenes act as promoters for the formation of benzyne from benzenediazonium acetate even in the presence of furan, which otherwise promotes the competing radical reaction, leads also to an explanation of the hitherto puzzling promoting effect of tetraphenylcyclopentadienone.

Decomposition of benzenediazonium acetate, formed in situ in benzene from N-nitrosoacetanilide (NNA), in the presence of tetraphenylcyclopentadienone (tetracyclone) gives e.s.r. signals corresponding to new long lived radicals (4) formed by addition of a phenyl radical to position 2 of tetracyclone. Similar reactions of NNA with 2,3-diphenylindenone gave long lived signals corresponding to the 1-oxo-2,2,3-triphenylindenyl radical (5), an assignment supported by computer simulation. The use of dibenzoyl peroxide or pentyl nitrite–aniline as alternative sources of phenyl radicals also led to the formation of radical (5). The assignments of structures (4) and (5) were supported by analysis of the related signals obtained from reactions of NNA with 2-phenyl-3-(p-t-butylphenyl)- and 3-phenyl-2-(p-t-butylphenyl)-indenone, and by reactions of p-t-butyl-NNA with 2,3-diphenylindenone and with 2-phenyl-3-(p-t-butylphenyl)indenone. Related studies with 2-methyl-3,4,5-triphenyl-, 2,5-diethyl-3,4-diphenyl-, and 3,4-diphenyl-2,5-di-p-tolylcyclo-pentadienones were also carried out. These results with those described in the preceding paper lend support to the suggestion that benzyne promotion from NNA by tetracyclone and 2,3-diphenylindenone is explicable on the basis of inhibition of the competing NNA-derived radical chain phenylation of the solvent.

Benzenediazonium acetate, formed from N-nitrosoacetanilide in situ, in benzene in the presence of tetraphenylcyclopentadienone or 2,3-diarylindenones give e.s.r. signals corresponding to new long-lived radicals (2) and (3) formed by trapping of phenyl radicals by the dienones, thus providing evidence relating to the mechanism of benzyne promotion in these reactions.