Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled ...haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.
GM-CSF together with IL-1 beta and TNF-alpha has been shown to play a key role in the maturation of LC in vitro. To investigate the presence of GM-CSF, IL-1 beta and TNF-alpha in human skin-derived ...lymph, we cannulated microsurgically a superficial lymph vessel on the lower leg of six healthy volunteers. Messenger RNA levels were estimated by a reverse transcriptase polymerase chain reaction (RT-PCR) method. From a total of 20 different samples, each consisting of 10(6) lymph cells, total RNA was extracted, reverse transcribed to cDNA and amplified using specific primers for the target gene. Amplified products were sized by electrophoresis and visualized by ethidium bromide. Specific transcripts for GM-CSF were detected in all lymph samples, indicating that circulating human skin-derived lymph cells express GM-CSF mRNA. A mean level of 11.5 +/- 2.1 pg/ml GM-CSF was detected in the lymph samples examined, as determined by a sensitive ELISA. In contrast to GM-CSF, occasional weak mRNA signals together with a mean level of 2.7 +/- 2.2 pg/ml were found for IL-1 beta, and neither specific transcripts nor protein were detected for TNF-alpha. Thus, our results demonstrate that afferent skin lymph cells constitutively express GM-CSF.
Background. Gambling and gaming disorders have been included as “disorders due to addictive behaviors” in the International Classification of Diseases (ICD-11). Other problematic behaviors may be ...considered as “other specified disorders due to addictive behaviors (6C5Y).” Methods. Narrative review, experts' opinions. Results. We suggest the following meta-level criteria for considering potential addictive behaviors as fulfilling the category of “other specified disorders due to addictive behaviors”: 1. Clinical relevance: Empirical evidence from multiple scientific studies demonstrates that the specific potential addictive behavior is clinically relevant and individuals experience negative consequences and functional impairments in daily life due to the problematic and potentially addictive behavior. 2. Theoretical embedding: Current theories and theoretical models belonging to the field of research on addictive behaviors describe and explain most appropriately the candidate phenomenon of a potential addictive behavior. 3. Empirical evidence: Data based on self-reports, clinical interviews, surveys, behavioral experiments, and, if available, biological investigations (neural, physiological, genetic) suggest that psychological (and neurobiological) mechanisms involved in other addictive behaviors are also valid for the candidate phenomenon. Varying degrees of support for problematic forms of pornography use, buying and shopping, and use of social networks are available. These conditions may fit the category of “other specified disorders due to addictive behaviors”. Conclusion. It is important not to over-pathologize everyday-life behavior while concurrently not trivializing conditions that are of clinical importance and that deserve public health considerations. The proposed meta-level-criteria may help guide both research efforts and clinical practice.
Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated ...stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.
PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0–2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1–2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.
Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference −1·9 percentage points, 95% CI −6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference −4·2 percentage points, 95% CI −10·0 to 1·7; p=0·16). No treatment-related deaths occurred.
Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.
Accuray and National Institute of Health Research.
ABSTRACT
This paper reports observations of a 22 GHz water maser ‘superburst’ in the G25.65+1.05 massive star-forming region, conducted in response to an alert from the Maser Monitoring Organisation ...(M2O). Very long baseline interferometry (VLBI) observations using the European VLBI Network (EVN) recorded a maser flux density of 1.2 × 104 Jy. The superburst was investipgated in the spectral, structural, and temporal domains and its cause was determined to be an increase in maser path length generated by the superposition of multiple maser emitting regions aligning in the line of sight to the observer. This conclusion was based on the location of the bursting maser in the context of the star-forming region, its complex structure, and its rapid onset and decay.
This study investigated multiple (di-, tri- and tetra-)incorporation of selected minor and trace elements (Al3+, Cr3+, V3–5+, Zn2+, Mo6+ and As5+) into hematite. The purpose was to improve ...understanding of how hematite may control trace element mobility in the environment, and how physical and chemical properties of hematite are impacted by multi-element incorporation at x/Fe molar ratios of up to 10%. Simultaneous structural incorporation of Al±Cr±V±Zn into hematite was achieved, with both synergistic and antagonistic effects occurring between certain element combinations. Cr+Al had synergistic effects on their co-incorporation, while V negatively affected Al incorporation, and both V and Zn negatively affected Cr incorporation. In contrast, Mo was minimally associated with hematite, and As prevented hematite formation completely. X-ray diffraction indicated contraction and expansion of the hematite unit-cell upon substitution was related to the ionic radius of the substituting element in single-element samples, while V predominantly controlled the direction of deviation in multi-element samples. X-ray absorption near-edge structure spectroscopy indicated V was present as a mixture of V3+-V5+, with a higher average V oxidation state associated with multi-element samples. Results provide new insights into trace element geochemistry within hematite, and highlight the importance of multi-element studies to better understand natural and anthropogenic systems.
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•Trace element combinations influenced hematite versus goethite formation from precursor ferrihydrite.•Chromium and V had synergistic effects on co-incorporation of Al, while Zn acted to lower Al incorporation in hematite.•Vanadium and Zn acted antagonistically to lower co-incorporation of Cr in hematite.•Vanadium’s oxidation state was influenced by co-incorporation of other trace elements.•Vanadium exhibited a major control on unit-cell deviations in multi-element samples.
Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter ...treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT.
PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0–2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1–2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258.
We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% 95% CI –1·3 to 4·0; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference –1·3% 95% CI –3·9 to 1·1; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe.
In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited.
Accuray.
The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates ...immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression--as observed in inflammatory bowel disease--may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Lactic acidosis (LA) is a marker for mortality in severe malaria, but the mechanisms that lead to LA in the different types of severe malaria and the extent to which LA-associated mortality differs ...by type of severe malaria are not well described. We assessed the frequency of LA in children admitted to Mulago Hospital, Kampala, Uganda with cerebral malaria (CM, n = 193) or severe malarial anemia (SMA, n = 216). LA was compared to mortality and measures of parasite biomass and sequestration (P. falciparum histidine-rich protein-2 (PfHRP2) concentration, platelet count), and to a measure of systemic tissue oxygen delivery (hemoglobin level). LA was more frequent in children with SMA than CM (SMA, 47.7%, CM, 34.2%, P = 0.006), but mortality was higher in children with CM (13.0%) than SMA (0.5%, P<0.0001). In CM, LA was associated with increased PfHRP2 concentration and decreased platelet count but was not associated with hemoglobin level. In contrast, in SMA, LA was associated with a decreased hemoglobin level, but was not associated with PfHRP2 concentration or platelet count. LA was related to mortality only in CM. In multivariable regression analysis of the effect PfHRP2 and hemoglobin levels on LA and DB, only PfHRP2 level increased risk of LA and DB in CM, while in SMA, elevated hemoglobin strongly decreased risk of LA and DB, and PfHRP2 level modestly increased risk of LA. The study findings suggest that LA in CM is due primarily to parasite sequestration, which currently has no effective adjunctive therapy, while LA in SMA is due primarily to anemia, which is rapidly corrected with blood transfusion. Differing etiologies of LA in CM and SMA may explain why LA is associated with mortality in CM but not SMA.
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