Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project

Background: Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication ‘single autosomal recessive mutation in rare disease’. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic ‘second-hit’ variants. Methods: To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. Results: Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2–6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. Conclusion: Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Reversible thermal behaviour of layered double hydroxides: A thermogravimetric study

Layered double hydroxides (LDHs) of Mg with trivalent cations such as Al, Cr and Fe show two mass loss steps on heating; the low-temperature (25-250°C) loss is due to dehydration and the high-temperature (250-450°C) loss is due to decomposition. Both steps are reversible and the oxide residues obtained after calcination at 700°C reconstruct back to the hydroxide phase. On the other hand the LDHs of Ca and Ni dehydrate reversibly but their decomposition reaction is irreversible. The LDHs of Zn and Co lose mass continuously up to 700°C without any well resolved steps and the loss is irreversible. These results have implications on the synthesis of selective catalysts by calcination of LDHs

Effectiveness of Reproductive Health Education Among Rural Adolescent Girls: A School Based Intervention Study in Udupi Taluk, Karnataka

Background :Adolescence is the most important and sensitive period of one′s life [1] . According to the World Health Organization (WHO) Expert Committee, adolescence is defined as the period between 10 and 19 years, the second decade of life. Objective :To determine the effectiveness of an educational intervention program on knowledge of reproductive health among adolescent girls. Settings and Design :This educational intervention study was carried out over a period of one year. A total of 791 rural girls in the age group 16-19 years were randomly selected from coastal villages in Udupi District, Karnataka. Materials and Methods :Adolescent girls were educated regarding reproductive health and their awareness levels were evaluated immediately following intervention. Statistical Analysis :Data was tabulated and analyzed using SPSS version 11.0 for Windows. Findings were described in terms of proportions and percentages. Chi square test was used to test the effect of the intervention. Results :A significant increase in overall knowledge after the intervention (from 14.4 to 68%, P < 0.01) was observed regarding contraception. Knowledge regarding ovulation, first sign of pregnancy and fertilization improved by 37.2% (95% CI = (35.2, 39.2), P < 0.001). Knowledge regarding the importance of diet during pregnancy improved from 66 to 95% following the intervention. Conclusion : This study clearly showed that an educational intervention program can bring about a desirable change in knowledge among adolescent girls regarding reproductive health

Investigations on structural and radiation shielding properties of Er 3+ doped zinc bismuth borate glasses

Novel optical glasses 10ZnO-5Na 2 CO 3 -10Bi 2 O 3 -(75-x)B 2 O 3 -xEr 2 O 3 with x = (0, 0.1, 0.3, 0.5, 0.7, 1.0) mol%, were synthesized by melt quench technique and characterized through XRD, EDAX, optical and luminescent properties, before and after irradiating them with high energy (1.3 MeV) gamma rays. Moreover, the gamma photons attenuation characterizations for the samples under study were studied. The mass attenuation coefficients for the selected glasses were affected with the addition of Er 2 O 3 . Based on the findings from the mass attenuation coefficients, ZNBBEr-5 has better photon attenuation features in comparison with the other samples. Also, arising the Er 2 O 3 content in the glasses, led to increase the effective atomic number. The mean free path for the prepared samples were compared with some shieling glasses. Shielding performance of the present glass samples against gamma radiation reveals pair production is prominent at 1.3 MeV. UV-VIS–NIR absorption edge was red shifted after gamma irradiation indicating the formation of electron/absorption centers in the glass matrix. Thermally stimulated Luminescence (TL) spectroscopy technique showed five electron trap centers at 445K, 491K, 545K, 590K, 620K with acceptable FOM [&lt; 5%] values. The number of overlapping peaks and their trapping parameters like kinetic order, activation energy, peak temperature, frequency factor and half life were determined using the Computerized Glow Curve Deconvolution (CGCD). Linear behaviour obtained through the dose response of the glass (5 kGy–50 kGy) proved their suitability for dosimetric application in the food irradiation zones and in red LEDs (&lt;50 kGy)