Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Outcomes of elective liver surgery worldwide: a global, prospective, multicenter, cross-sectional study

Background: The outcomes of liver surgery worldwide remain unknown. The true population-based outcomes are likely different to those vastly reported that reflect the activity of highly specialized academic centers. The aim of this study was to measure the true worldwide practice of liver surgery and associated outcomes by recruiting from centers across the globe. The geographic distribution of liver surgery activity and complexity was also evaluated to further understand variations in outcomes. Methods: LiverGroup.org was an international, prospective, multicenter, cross-sectional study following the Global Surgery Collaborative Snapshot Research approach with a 3-month prospective, consecutive patient enrollment within January–December 2019. Each patient was followed up for 90 days postoperatively. All patients undergoing liver surgery at their respective centers were eligible for study inclusion. Basic demographics, patient and operation characteristics were collected. Morbidity was recorded according to the Clavien–Dindo Classification of Surgical Complications. Country-based and hospital-based data were collected, including the Human Development Index (HDI). (NCT03768141). Results: A total of 2159 patients were included from six continents. Surgery was performed for cancer in 1785 (83%) patients. Of all patients, 912 (42%) experienced a postoperative complication of any severity, while the major complication rate was 16% (341/2159). The overall 90-day mortality rate after liver surgery was 3.8% (82/2,159). The overall failure to rescue rate was 11% (82/ 722) ranging from 5 to 35% among the higher and lower HDI groups, respectively. Conclusions: This is the first to our knowledge global surgery study specifically designed and conducted for specialized liver surgery. The authors identified failure to rescue as a significant potentially modifiable factor for mortality after liver surgery, mostly related to lower Human Development Index countries. Members of the LiverGroup.org network could now work together to develop quality improvement collaboratives

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Single-Operation Deracemization of 3H-Indolines and Tetrahydroquinolines Enabled by Phase Separation

The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields

Isolation and Reactivity of Trifluoromethyl Iodonium Salts.

The strategic incorporation of the trifluoromethyl (CF3) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF3 moiety onto an array of molecular architectures, and, in particular, CF3 λ(3)-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF3 iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF3 iodoniums is paramount for the development of new trifluoromethylative strategies involving λ(3)-iodanes. Here, we demonstrate that CF3 iodonium salts are readily prepared from common λ(3)-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF3 iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF3 iodonium intermediates in trifluoromethylative processes mediated by λ(3)-iodanes. The isolation of CF3 iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes

Arterial supply to the colon

The strategic incorporation of the trifluoromethyl (CF₃) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF₃ moiety onto an array of molecular architectures, and, in particular, CF₃ λ³-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF₃ iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF₃ iodoniums is paramount for the development of new trifluoromethylative strategies involving λ³-iodanes. Here, we demonstrate that CF₃ iodonium salts are readily prepared from common λ³-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF₃ iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF₃ iodonium intermediates in trifluoromethylative processes mediated by λ³-iodanes. The isolation of CF₃ iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes

Single-Operation Deracemization of 3H-Indolines and Tetrahydroquinolines Enabled by Phase Separation

The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients with Hepatocellular Carcinoma

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. METHODS: We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). RESULTS: Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete responses to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and \u3e1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. CONCLUSION: Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population

Single-Operation Deracemization of 3H-Indolines and Tetrahydroquinolines Enabled by Phase Separation

The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation, and resulted in the isolation of highly enantioenriched starting materials in high yields