Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.Peer reviewe

FinnGen provides genetic insights from a well-phenotyped isolated population

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.publishedVersionPeer reviewe

Partitioning of the milk fat globule membrane between buttermilk and butter serum is determined by the thermal behaviour of the fat globules

Isolation of the industrially interesting milk fat globule membrane (MFGM) components from dairy streams is challenging, and a full exploitation of their benefits can be gained by better understanding of the behaviour of the fat globule membrane fraction during milk fat processing. In this study, microfiltration of the cream before churning and the comprehensive compositional analysis of the process streams revealed new insights on MFGM partitioning during the phase inversion in butter making. After removal of the smallest fat globules by microfiltration, a reduced phospholipid content was reflected in the buttermilk, but not in the butter serum. Regardless of the cream washing, buttermilk and butter serum lipids were different in PL-to-fat ratio, phospholipid composition, degree of unsaturation and melting behaviour. We suggest that partitioning of the MFGM fraction between butter and buttermilk is a direct result of the physico-chemical properties of the fat globules, partly related to the globule size.Peer reviewe

FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals

Fibroblast growth factors (FGFs) are signaling molecules of the isthmic organizer, which regulates development of the midbrain and cerebellum. Tissue-specific inactivation of one of the FGF receptor (FGFR) genes, Fgfr1, in the midbrain and rhombomere 1 of the hindbrain of mouse embryos results in deletion of the inferior colliculi in the posterior midbrain and vermis of the cerebellum. Analyses of both midbrain–hindbrain and midbrain-specific Fgfr1 mutants suggest that after establishment of the isthmic organizer, FGFR1 is needed for continued response to the isthmic signals, and that it has direct functions on both sides of the organizer. In addition, FGFR1 appears to modify cell adhesion properties critical for maintaining a coherent organizing center. This may be achieved by regulating expression of specific cell-adhesion molecules at the midbrain–hindbrain border

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients

Identification of a dipole band above the Iπ = 31/2- isomeric state in 189Pb

A dipole band of six transitions built upon a firmly established I π = 31/2− isomeric state has been identified in 189Pb using recoil-isomer tagging. This is the lightest odd-mass Pb nucleus in which a dipole band is known. The dipole nature of the new transitions has been confirmed through angular-intensity arguments. The evolution of the excitation energy and the aligned-angular momentum of the states in the new dipole band are compared with those of dipole bands in heavier, odd-mass lead isotopes. This comparison suggests that the new band in 189Pb is based upon a π[s−2 1/2h9/2i13/2]11− ⊗ ν[i −1 13/2+ ]13/2+ configuration. However, the increased aligned-angular momentum in 189Pb may suggest evidence for a reduced repulsive proton/neutron-hole interaction compared to dipole bands in the heavier mass isotopes.peerReviewe

Spectroscopy of proton-rich 66Se up toJ=6+ J = 6^+: Isospin-breaking effect in the A = 66 isobaric triplet

Candidates for three excited states in the 66Se have been identified using the recoil-β tagging method together with a veto detector for charged-particle evaporation channels. These results allow a comparison of mirror and triplet energy differences between analog states across the A = 66 triplet as a function of angular momentum. The extracted triplet energy differences follow the negative trend observed in the f7/2 shell. Shell-model calculations indicate that the strength of the Coulomb isotensor part alone is not sufficient to account for this trend in the case of the A = 66 triplet.peerReviewe

Fine structure in the α decay of high-spin isomers in 155Lu and 156Hf

Fine structure in the α decay of high-spin isomers in 155Lu(25/2−) and 156Hf (8+) has been studied for the first time using αγ -coincidence analysis. Three new α decays from 155Lu(25/2−) and two from 156Hf (8+) have been identified, populating seniority s > 1 states in the N = 82 nuclei 151Tm and 152Yb, respectively. The reduced hindrance factors of the α decays support the previous configuration assignments of the populated states. This is the first observation of states with excitation energy greater than 1.5 MeV being populated following α decay in nuclei outside of the 208Pb region.peerReviewe

Spectroscopy on the proton drip-line : Probing the structure dependence of isospin nonconserving interactions

The recoil-β tagging technique was used to identify transitions associated with the decay of the 2+ and, tentatively, the 4+ excited states in 74Sr. Combining these results with published data for the A = 74 isobars, triplet energy differences (TEDs) have been extracted, the heaviest case for which these values have been evaluated. State-of-the-art shell-model calculations using the JUN45 interaction and incorporating a J = 0 isospin nonconserving (INC) interaction with an isotensor strength of 100 keV can reproduce the trend in the TED data, with particularly good agreement for the 2+ state. This agreement for the TED data taken together with the fact that agreement has also been shown between shell-model calculations with the same strength of INC interaction in the f7/2 shell and recently for A = 66 strongly suggests that such an interaction exists throughout the nuclear chart and cannot have a strong dependence on details of nuclear structure such as which nuclear orbitals are occupied. It also supports the hypothesis that only a J = 0 component of the INC interaction need be included to explain the observed TEDs.peerReviewe