A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation

Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research

Distribution of sedimentary rock types through time in a back-arc basin: A case study from the Jurassic of the Greater Caucasus (Northern Neotethys)

Abstract The evolution of sedimentary basins can be explored by analyzing the changes in their lithologies and lithofacies (i.e. predominant lithologies). The Greater Caucasus Basin, which was located at the northern margin of the Neotethys Ocean, represents a complete Sinemurian-Tithonian succession. A quantitative analysis of compiled datasets suggests that principal lithologies and lithofacies are represented by siliciclastics, shale and carbonates. The relative abundance of siliciclastics and shale decreased throughout the Jurassic, whereas that of carbonates increased. Evaporites are known from the Upper Jurassic, while volcaniclastics and volcanics, as well as coals, are known only in the Lower to Middle Jurassic. Siliceous rocks are extremely rare. Lithology and lithofacies proportions change accordingly. The Sinemurian-Bathonian sedimentary complex is siliciclastic-and-shale-dominated, whereas the Callovian-Tithonian sedimentary complex is carbonate-dominated. A major change in the character of sedimentation occurred during the Aalenian-Callovian time interval. Regional transgressions and regressions were more important controls of changes in the sedimentary rock proportions than average basin depth. Landward shoreline shifts were especially favorable for carbonate accumulation, whereas siliciclastics and shale were deposited preferentially in regressive settings. An extended area of the marine basin, its lower average depth, and a sharp bathymetric gradient favored a higher diversity of sedimentation. An orogeny at the Triassic-Jurassic transition was responsible for a large proportion of siliciclastics and extensive conglomerate deposition. An arcarc collision in the Middle Jurassic also enhanced the siliciclastic deposition. Both phases of tectonic activity were linked with an increase in volcanics and volcaniclastics. Volcanism itself might have been an important control on sedimentation. A transition to carbonate-dominated sedimentation occurred in the Late Jurassic, reflecting a tectonically calm period

Pediatric inflammatory bowel disease clinical innovations meeting of the Crohn's and colitis foundation: Charting the future of pediatric IBD

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Study of CP violation in Dalitz-plot analyses of B0 --> K+K-KS, B+ --> K+K-K+, and B+ --> KSKSK+

We perform amplitude analyses of the decays $B^0 \to K^+K^-K^0_S$, $B^+ \rightarrow K^+K^-K^+$, and $B^+ \to K^0_S K^0_S K^+$, and measure CP-violating parameters and partial branching fractions. The results are based on a data sample of approximately $470\times 10^6$ $B\bar{B}$ decays, collected with the BABAR detector at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory. For $B^+ \to K^+K^-K^+$, we find a direct CP asymmetry in $B^+ \to \phi(1020)K^+$ of $A_{CP}= (12.8\pm 4.4 \pm 1.3)$, which differs from zero by $2.8 \sigma$. For $B^0 \to K^+K^-K^0_S$, we measure the CP-violating phase $\beta_{\rm eff} (\phi(1020)K^0_S) = (21\pm 6 \pm 2)^\circ$. For $B^+ \to K^0_S K^0_S K^+$, we measure an overall direct CP asymmetry of $A_{CP} = (4 ^{+4}_{-5} \pm 2)$. We also perform an angular-moment analysis of the three channels, and determine that the $f_X(1500)$ state can be described well by the sum of the resonances $f_0(1500)$, $f_2^{\prime}(1525)$, and $f_0(1710)$.Comment: 35 pages, 68 postscript figures. v3 - minor modifications to agree with published versio

Dioctahedral mixed K-Na-micas and paragonite in diagenetic to low-temperature metamorphic terrains: bulk rock chemical, thermodynamic and textural constraints

Abstract Metamorphic mineral assemblages in low-temperature metaclastic rocks often contain paragonite and/or its precursor metastable phase (mixed K-Na-white mica). Relationships between the bulk rock major element chemistries and the formation of paragonite at seven localities from Central and SE-Europe were studied, comparing the bulk chemical characteristics with mineral assemblage, mineral chemical and metamorphic petrological data. Considerable overlaps between the projection fields of bulk chemistries of the Pg-free and Pg-bearing metaclastic rocks indicate significant differences between the actual (as analyzed) and effective bulk chemical compositions. Where inherited, clastic, inert phases/constituents were excluded, it was found that a decrease in Na/(Na+Al*) and in K/(K+Al*) ratios of rocks favors the formation and occurrence of Pg and its precursor phases (Al* denotes here the atomic quantity of aluminum in feldspars, white micas and “pure” hydrous or anhydrous aluminosilicates). In contrast to earlier suggestions, enrichment in Na and/or an increase in Na/K ratio by themselves do not lead to formation of paragonite. Bulk rock chemistries favorable to formation of paragonite and its precursor phases are characterized by enrichment in Al and depletion in Na, K, Ca (and also, Mg and Fe2+). Such bulk rock chemistries are characteristic of chemically “mature” (strongly weathered) source rocks of the pelites and may also be formed by synand post-sedimentary magmatism-related hydrothermal (leaching) activity. What part of the whole rock is active in determining the effective bulk chemistry was investigated by textural examination of diagenetic and anchizone-grade samples. It is hypothesized that although solid phases act as local sources and sinks, transport of elements such as Na through the grain boundaries have much larger communication distances. Sodium-rich white micas nucleate heterogeneously using existing phyllosilicates as templates and are distributed widely on the thin section scale. The results of modeling by THERMOCALC suggest that paragonite preferably forms at higher pressures in low-T metapelites. The stability fields of Pg-bearing assemblages increase, the Pg-in reaction line is shifted towards lower pressures, while the stability field of the Chl-Ms-Ab-Qtz assemblage decreases and is shifted towards higher temperatures with increasing Al* content and decreasing Na/(Na+Al*) and K/(K+Al*) ratios

Sacituzumab govitecan in metastatic triple-negative breast cancer

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan

Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK

Objective Symptoms and clinical course during inflammatory bowel disease (IBD) vary among individuals. Personalised care is therefore essential to effective management, delivered by a strong patient-centred multidisciplinary team, working within a well-designed service. This study aimed to fully rewrite the UK Standards for the healthcare of adults and children with IBD, and to develop an IBD Service Benchmarking Tool to support current and future personalised care models. Design Led by IBD UK, a national multidisciplinary alliance of patients and nominated representatives from all major stakeholders in IBD care, Standards requirements were defined by survey data collated from 689 patients and 151 healthcare professionals. Standards were drafted and refined over three rounds of modified electronic-Delphi. Results Consensus was achieved for 59 Standards covering seven clinical domains; (1) design and delivery of the multidisciplinary IBD service; (2) prediagnostic referral pathways, protocols and timeframes; (3) holistic care of the newly diagnosed patient; (4) flare management to support patient empowerment, self-management and access to specialists where required; (5) surgery including appropriate expertise, preoperative information, psychological support and postoperative care; (6) inpatient medical care delivery (7) and ongoing long-term care in the outpatient department and primary care setting including shared care. Using these patient-centred Standards and informed by the IBD Quality Improvement Project (IBDQIP), this paper presents a national benchmarking framework. Conclusions The Standards and Benchmarking Tool provide a framework for healthcare providers and patients to rate the quality of their service. This will recognise excellent care, and promote quality improvement, audit and service development in IBD