The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Synthesis of hydroazafullerene C59HN, the parent hydroheterofuIlerene

The electronic and geometric properties of C60 can be perturbed by replacing one or more carbon atoms of the fullerene skeleton with an atom of a different element. Exchange of one carbon atom with nitrogen, a trivalent atom with a lone pair of electrons, produces the azafullerene radical C59N·, which is isoelectronic with the C60 radical anion. The process is slightly similar to doping silicon with phosphorus. We have previously described the synthesis of the azafullerene dimer; here we report the bulk preparation of the simplest azafullerene, C59HN. The electronic, vibrational and 13C NMR spectroscopic features of C59HN are similar to those of the dimer, except for the signature of the sp3 (C-H) carbon. C59HN should open the door to a new chemistry of heterofullerenes.

Synthesis of hydroazafullerene C59HN, the parent hydroheterofullerene

THE electronic and geometric properties of C-60 can be perturbed by replacing one or more carbon atoms of the fullerene skeleton with an atom of a different element. Exchange of one carbon atom with nitrogen, a trivalent atom with a lone pair of electrons, produces the azafullerene radical C59N; which is isoelectronic with the C-60 radical anion. The process is slightly similar to doping silicon with phosphorus(1). We have previously described the synthesis of the azafullerene dimer(2); here we report the bulk preparation of the simplest azafullerene, C59HN. The electronic, vibrational and C-13 NMR spectroscopic features of C59HN are similar to those of the dimer(2), except for the signature of the sp(3) (C-H) carbon. C59HN should open the door to a new chemistry of heterofullerenes

How is recovery from low back pain measured? A systematic review of the literature

Recovery is commonly used as an outcome measure in low back pain (LBP) research. There is, however, no accepted definition of what recovery involves or guidance as to how it should be measured. The objective of the study was designed to appraise the LBP literature from the last 10 years to review the methods used to measure recovery. The research design includes electronic searches of Medline, EMBASE, CINAHL, Cochrane database of clinical trials and PEDro from the beginning of 1999 to December 2008. All prospective studies of subjects with non-specific LBP that measured recovery as an outcome were included. The way in which recovery was measured was extracted and categorised according to the domain used to assess recovery. Eighty-two included studies used 66 different measures of recovery. Fifty-nine of the measures did not appear in more than one study. Seventeen measures used pain as a proxy for recovery, seven used disability or function and seventeen were based on a combination of two or more constructs. There were nine single-item recovery rating scales. Eleven studies used a global change scale that included an anchor of ‘completely recovered’. Three measures used return to work as the recovery criterion, two used time to insurance claim closure and six used physical performance. In conclusion, almost every study that measured recovery from LBP in the last 10 years did so differently. This lack of consistency makes interpretation and comparison of the LBP literature problematic. It is likely that the failure to use a standardised measure of recovery is due to the absence of an established definition, and highlights the need for such a definition in back pain research

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes