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Despite international consensus on the harmful effects of valproate during pregnancy, women should not be denied the human right to make their own decisions after fully informed discussion, say Heather Angus-Leppan and Rebecca Liu

There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Royal Free London NHS Foundation Trust.

Using a combination of Hubble Space Telescope (HST), JWST, and Atacama Large Millimeter/submillimeter Array (ALMA) data, we perform spatially resolved spectral energy distributions (SED) fitting of fourteen 4 < z < 6 ultraviolet (UV)-selected main-sequence galaxies targeted by the ALMA Large Program [C ii] Resolved ISM in Star-forming Galaxies. We consistently model the emission from stars and dust in ∼0.5–1 kpc spatial bins to obtain maps of their physical properties. We find no offsets between the stellar masses (M *) and star formation rates (SFRs) derived from their global emission and those from adding up the values in our spatial bins, suggesting there is no bias of outshining by young stars on the derived global properties. We show that ALMA observations are important to derive robust parameter maps because they reduce the uncertainties in L dust (hence, AV and SFR). Using these maps, we explore the resolved star-forming main sequence for z ∼ 5 galaxies, finding that this relation persists in typical star-forming galaxies in the early Universe. We find less obscured star formation where the M * (and SFR) surface densities are highest, typically in the central regions, contrary to the global relation between these parameters. We speculate this could be caused by feedback driving gas and dust out of these regions. However, more observations of IR luminosities with ALMA are needed to verify this. Finally, we test empirical SFR prescriptions based on the UV+IR and [C ii] line luminosity, finding they work well at the scales probed (approximately kiloparsec). Our work demonstrates the usefulness of joint HST-, JWST-, and ALMA-resolved SED modeling analyses at high redshift.

Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with FLT3 mutations led to a median overall survival of 9.3 months (vs. 5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).

The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10(-6) and P = 2.7 × 10(-8), respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10(-17)), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.

IntroductionFedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate).MethodsIn this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin.ResultsPlasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated.ConclusionsThese results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs.Trial registrationClinicaltrials.gov NCT04231435 on January 18, 2020.

In a pragmatic trial, more than 30,000 patients requiring blood transfusion were randomly assigned to receive blood after short-term storage or long-term storage. In-hospital mortality did not differ significantly between the two groups. Red-cell transfusion is one of the most common medical interventions. 1 Blood is stored for up to 42 days before transfusion. Biochemical, structural, and functional changes during storage may reduce oxygen delivery to tissues, and the release of extracellular vesicles and cell-free DNA during storage may cause a hypercoagulable state. 2 Observational studies have suggested that prolonged blood storage is associated with an increased risk of cardiovascular events. 3 Randomized, controlled trials have not shown harm in transfusing red-cell units with a longer duration versus a shorter duration of storage. However, most of these trials have been restricted to high-risk populations and have . . .

The need to combat widespread degradation of grassland ecosystem services makes grassland restoration a global sustainability priority. However, simultaneously enhancing multiple ecosystem services (i.e. ecosystem service multifunctionality) is a major challenge for grassland restoration due to trade-offs among services. We use a long-term multifactor grassland restoration experiment established in 1989 on agriculturally improved, species-poor grassland in northern England, to assess how increasing the number of restoration treatments, including addition of manure, inorganic fertiliser, a seed mixture, and promotion of a nitrogen-fixing legume ( Trifolium pratense ), affects ecosystem service multifunctionality, based on 26 ecosystem service indicators measured between 2011 and 2014. We find that single interventions usually lead to trade-offs among services and thus have few positive effects on ecosystem service multifunctionality. However, ecosystem service multifunctionality increases with the number of restoration interventions, as trade-offs are reduced. Our findings highlight the significant potential for combined use of multiple targeted interventions to aid the restoration of ecosystem service multifunctionality in degraded grasslands, and potentially, other ecosystems. Widespread grassland degradation poses major societal and environmental challenges. Here, the authors propose multiple targeted interventions as a crucial strategy for simultaneously enhancing grassland ecosystem services and improving their equitability.

As the master regulator in utero , the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P < 2.5 × 10 − 6 , we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A , both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course. The impact of placental transcriptomics on fetal traits throughout development is not well understood. Here, the authors apply distal-SNP-enriched transcriptome-wide association studies to detect genetic contributions, mediated through fetal placental genomics, to developmental programming of complex traits across the life course.

The evolution of reproductive barriers is the first step in the formation of new species and can help us understand the diversification of life on Earth. These reproductive barriers often take the form of hybrid incompatibilities, in which alleles derived from two different species no longer interact properly in hybrids 1 – 3 . Theory predicts that hybrid incompatibilities may be more likely to arise at rapidly evolving genes 4 – 6 and that incompatibilities involving multiple genes should be common 7 , 8 , but there has been sparse empirical data to evaluate these predictions. Here we describe a mitonuclear incompatibility involving three genes whose protein products are in physical contact within respiratory complex I of naturally hybridizing swordtail fish species. Individuals homozygous for mismatched protein combinations do not complete embryonic development or die as juveniles, whereas those heterozygous for the incompatibility have reduced complex I function and unbalanced representation of parental alleles in the mitochondrial proteome. We find that the effects of different genetic interactions on survival are non-additive, highlighting subtle complexity in the genetic architecture of hybrid incompatibilities. Finally, we document the evolutionary history of the genes involved, showing signals of accelerated evolution and evidence that an incompatibility has been transferred between species via hybridization. Analysis of naturally hybridizing swordtail fish species reveals a mitonuclear genetic incompatibility among three genes that encode components of mitochondrial respiratory complex I, providing insights into the emergence of hybrid incompatibilities and reproductive barriers.