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Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes. Prediabetes has been associated with diabetes complications, but these relationships may be confounded. Here the authors show, using genetic data in causal inference analyses, that prediabetes raises risk of coronary heart disease, but not other diabetes complications.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20663-6

RNA polymerase (pol) III transcription is a major determinant of biosynthetic capacity, providing essential products such as tRNA and 5S rRNA. It is controlled directly by the tumour suppressors RB and p53. High-risk types of human papillomavirus (HPV), such as HPV16, express the oncoproteins E6 and E7 that can inactivate p53 and RB, respectively. Accordingly, both E6 and E7 stimulate pol III transcription in cultured cells. HPV16-positive cervical biopsies express elevated levels of tRNA and 5S rRNA when compared to biopsies that test negative for HPV or are infected with the lower risk HPV11. Integration of viral DNA into the host cell genome stimulates expression of E6 and E7 and correlates with induction of tRNA and 5S rRNA. Expression of mRNA encoding the pol III-specific transcription factor Brf1 also correlates with the presence of integrated HPV16. Brf1 levels are limiting for tRNA and 5S rRNA synthesis in cervical cells. Furthermore, pol III-transcribed genes that do not use Brf1 are not induced in HPV16-positive biopsies. Three complementary mechanisms may therefore allow high-risk HPV to stimulate production of tRNA and 5S rRNA: E6-mediated removal of p53; E7-mediated neutralization of RB; and induction of Brf1. The resultant increase in biosynthetic capacity may contribute to deregulated cell growth.

Cyclotides are diverse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express Oa AEP1 b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, Oa AEP1 b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant Oa AEP1 b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired. Cyclotides are plant backbone-cyclised peptides with potential as pharmaceutical scaffolds. Here the authors report on the efficient backbone cyclization of cyclotides and unrelated peptides by a newly identified asparaginyl endopeptidase from Oldenlandia affinis .

Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

Independent validation is essential to justify use of models of breast cancer risk prediction and inform decisions about prevention options and screening. Few independent validations had been done using cohorts for common breast cancer risk prediction models, and those that have been done had small sample sizes and short follow-up periods, and used earlier versions of the prediction tools. We aimed to validate the relative performance of four commonly used models of breast cancer risk and assess the effect of limited data input on each one's performance. In this validation study, we used the Breast Cancer Prospective Family Study Cohort (ProF-SC), which includes 18 856 women from Australia, Canada, and the USA who did not have breast cancer at recruitment, between March 17, 1992, and June 29, 2011. We selected women from the cohort who were 20–70 years old and had no previous history of bilateral prophylactic mastectomy or ovarian cancer, at least 2 months of follow-up data, and information available about family history of breast cancer. We used this selected cohort to calculate 10-year risk scores and compare four models of breast cancer risk prediction: the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model (BOADICEA), BRCAPRO, the Breast Cancer Risk Assessment Tool (BCRAT), and the International Breast Cancer Intervention Study model (IBIS). We compared model calibration based on the ratio of the expected number of breast cancer cases to the observed number of breast cancer cases in the cohort, and on the basis of their discriminatory ability to separate those who will and will not have breast cancer diagnosed within 10 years as measured with the concordance statistic (C-statistic). We did subgroup analyses to compare the performance of the models at 10 years in BRCA1 or BRCA2 mutation carriers (ie, BRCA-positive women), tested non-carriers and untested participants (ie, BRCA-negative women), and participants younger than 50 years at recruitment. We also assessed the effect that limited data input (eg, restriction of the amount of family history and non-genetic information included) had on the models' performance. After median follow-up of 11·1 years (IQR 6·0–14·4), 619 (4%) of 15 732 women selected from the ProF-SC cohort study were prospectively diagnosed with breast cancer after recruitment, of whom 519 (84%) had histologically confirmed disease. BOADICEA and IBIS were well calibrated in the overall validation cohort, whereas BRCAPRO and BCRAT underpredicted risk (ratio of expected cases to observed cases 1·05 [95% CI 0·97–1·14] for BOADICEA, 1·03 [0·96–1·12] for IBIS, 0·59 [0·55–0·64] for BRCAPRO, and 0·79 [0·73–0·85] for BRCAT). The estimated C-statistics for the complete validation cohort were 0·70 (95% CI 0·68–0·72) for BOADICEA, 0·71 (0·69–0·73) for IBIS, 0·68 (0·65–0·70) for BRCAPRO, and 0·60 (0·58–0·62) for BCRAT. In subgroup analyses by BRCA mutation status, the ratio of expected to observed cases for BRCA-negative women was 1·02 (95% CI 0·93–1·12) for BOADICEA, 1·00 (0·92–1·10) for IBIS, 0·53 (0·49–0·58) for BRCAPRO, and 0·97 (0·89–1·06) for BCRAT. For BRCA-positive participants, BOADICEA and IBIS were well calibrated, but BRCAPRO underpredicted risk (ratio of expected to observed cases 1·17 [95% CI 0·99–1·38] for BOADICEA, 1·14 [0·96–1·35] for IBIS, and 0·80 [0·68–0·95] for BRCAPRO). We noted similar patterns of calibration for women younger than 50 years at recruitment. Finally, BOADICEA and IBIS predictive scores were not appreciably affected by limiting input data to family history for first-degree and second-degree relatives. Our results suggest that models that include multigenerational family history, such as BOADICEA and IBIS, have better ability to predict breast cancer risk, even for women at average or below-average risk of breast cancer. Although BOADICEA and IBIS performed similarly, further improvements in the accuracy of predictions could be possible with hybrid models that incorporate the polygenic risk component of BOADICEA and the non-family-history risk factors included in IBIS. US National Institutes of Health, National Cancer Institute, Breast Cancer Research Foundation, Australian National Health and Medical Research Council, Victorian Health Promotion Foundation, Victorian Breast Cancer Research Consortium, Cancer Australia, National Breast Cancer Foundation, Queensland Cancer Fund, Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and Cancer Foundation of Western Australia.

Background. On 8 October 2008, members of a tour group experienced diarrhea and vomiting throughout an airplane flight from Boston, Massachusetts, to Los Angeles, California, resulting in an emergency diversion 3 h after takeoff. An investigation was conducted to determine the cause of the outbreak, assess whether transmission occurred on the airplane, and describe risk factors for transmission. Methods. Passengers and crew were contacted to obtain information about demographics, symptoms, locations on the airplane, and possible risk factors for transmission. Case patients were defined as passengers with vomiting or diarrhea (⩾ loose stools in 24 h) and were asked to submit stool samples for norovirus testing by real-time reverse-transcription polymerase chain reaction. Results. Thirty-six (88%) of 41 tour group members were interviewed, and 15 (41%) met the case definition (peak date of illness onset, 8 October 2008). Of 106 passengers who were not tour group members, 85 (80%) were interviewed, and 7 (8%) met the case definition after the flight (peak date of illness onset, 10 October 2008). Multivariate logistic regression analysis showed that sitting in an aisle seat (adjusted relative risk, 11.0; 95% confidence interval, 1.4–84.9) and sitting near any tour group member (adjusted relative risk, 7.5; 95% confidence interval, 1.7–33.6) were associated with the development of illness. Norovirus genotype II was detected by reversetranscription polymerase chain reaction in stool samples from case patients in both groups. Conclusions. Despite the short duration, transmission of norovirus likely occurred during the flight.

Nutrition and physical activity interventions are important components of cancer care. With an increasing demand for services, there is a need to consider flexible, easily accessible, and tailored models of care while maintaining optimal outcomes. This systematic review describes and appraises the efficacy of technology-supported self-guided nutrition and physical activity interventions for people with cancer. A systematic search of multiple databases from 1973 to July 2018 was conducted for randomized and nonrandomized trials investigating technology-supported self-guided nutrition and physical activity interventions. Risk of bias was assessed using the Cochrane Risk of Bias tool. Outcomes included behavioural, health-related, clinical, health service, or financial measures. Sixteen randomized controlled trials representing 2684 participants were included. Most studies were web-based interventions (n=9) and had a 12-week follow-up duration (n=8). Seven studies assessed dietary behaviour, of which two reported a significant benefit on diet quality or fruit and vegetable intake. Fifteen studies measured physical activity behaviour, of which eight studies reported a significant improvement in muscle strength and moderate-to-vigorous physical activity. Four of the nine studies assessing the health-related quality of life (HRQoL) reported a significant improvement in global HRQoL or a domain subscale. A significant improvement in fatigue was found in four of six studies. Interpretation of findings was influenced by inadequate reporting of intervention description and compliance. This review identified short-term benefits of technology-supported self-guided interventions on the physical activity level and fatigue and some benefit on dietary behaviour and HRQoL in people with cancer. However, current literature demonstrates a lack of evidence for long-term benefit. PROSPERO CRD42017080346; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=80346.

Cognitive behavioural therapy for insomnia (CBT-I) is the recommended first-line treatment for insomnia. However, scaling this proven effective intervention to areas of high need remains a challenge, necessitating sensitive adaptation and evaluation. A randomised waitlist-controlled trial evaluated the efficacy of a hybrid digital CBT-I and emotion regulation (dCBT-I + ER) intervention delivered through workplaces. Participants with at least mild insomnia and depression or anxiety symptoms were randomised to the intervention or waitlist control groups. The intervention was delivered via a web-based platform and four video-conferencing therapy sessions. Participants tracked their sleep using actigraphy and a sleep diary that was used to pace the intervention delivered. Assessments occurred at baseline and 8 weeks post-randomisation, measuring insomnia, depression, anxiety, psychological well-being, quality of life, and work productivity. Of the 159 participants (mean age 43.6 ± 9.4 years, 76.7% female, 80.5% white), 80 received the intervention and 79 were in the control group. The intervention group showed significant improvements in insomnia (F1, 134 = 71.46, p < .0001); depression (F1, 134 = 35.67, p < .0001); and anxiety (F1, 134 = 17.63, p < .0001), with large effect sizes (d = 0.7-1.5). Sleep diary data supported these findings, whereas actigraphy data did not. Improvements in psychological well-being were significant (F1, 132.13 = 10.64, p < 0.001), whereas quality of life, work productivity, and satisfaction outcomes were not. This study suggests that a hybrid dCBT-I + ER intervention, delivered via workplaces, effectively improves insomnia, depression, and anxiety. It holds promise as a scalable solution, warranting further investigation into its long-term efficacy and economic impact.

Background The Australian Clinical Practice Guidelines for Pregnancy Care recommend that during the first and subsequent antenatal visits all pregnant women are weighed; advised of recommended gestational weight gain (GWG), dietary intake and physical activity; and offered referrals for additional support if needed. The extent to which these recommendations are implemented and women’s acceptability of recommended care is unknown. This study examines women’s reported receipt and acceptability of guideline care for GWG, and characteristics associated with receipt of such care and its acceptability. Methods From September 2018 to February 2019 a telephone survey was undertaken with women who had recently had a baby and received antenatal care from five public maternity services within a health district in Australia. Women self-reported their demographic characteristics, and receipt and acceptability of recommended GWG care. Receipt and acceptability of such care, and their association with the characteristics of women and the maternity service they attended, were examined using descriptive statistics and multivariable logistic regression analyses. Results Of 514 women, 13.1% (95%CI:10.3–16.5) reported that they received an assessment of weight at both their first and a subsequent antenatal visit, and less than one third (30.0%; 95%CI:26.0-33.9) received advice on their recommended GWG range, dietary intake and physical activity. Just 6.6% (95%CI:4.8–9.1) of women reported receiving all assessment and advice components of recommended antenatal care, and 9.9% (95%CI:7.6–12.8) of women reported being referred for extra support. Women who were younger (OR = 1.13;95%CI:1.05–1.21), identifying as Aboriginal and Torres Strait Islander (OR = 24.54;95%CI:4.98-120.94), had a higher pre-pregnancy BMI (OR = 1.13;95%CI:1.05–1.21), were experiencing their first pregnancy (OR = 3.36;95%CI:1.27–8.86), and lived in a least disadvantaged area (compared to mid-disadvantaged area (OR = 18.5;95%CI:2.6-130.5) and most disadvantaged area (OR = 13.1;95%CI:2.09–82.4)) were more likely to receive recommended assessment and advice. Most Aboriginal (92%) and non-Aboriginal (93%) women agreed that recommended GWG care is acceptable. Conclusion Most women perceive antenatal care for GWG as recommended by the Clinical Practice Guidelines as acceptable, but did not receive it. When provided, such care is not delivered consistently to all women regardless of their characteristics or those of the maternity service they attend. There is a need for service-wide practice change to increase routine GWG care in pregnancy for all women.