Separating positional noise from neutral alignment in multicomponent statistical shape models

Given sufficient training samples, statistical shape models can provide detailed population representations for use in anthropological and computational genetic studies, injury biomechanics, musculoskeletal disease models or implant design optimization. While the technique has become extremely popular for the description of isolated anatomical structures, it suffers from positional interference when applied to coupled or articulated input data. In the present manuscript we describe and validate a novel approach to extract positional noise from such coupled data. The technique was first validated and then implemented in a multicomponent model of the lower limb. The impact of noise on the model itself as well as on the description of sexual dimorphism was evaluated. The novelty of our methodology lies in the fact that no rigid transformations are calculated or imposed on the data by means of idealized joint definitions and by extension the models obtained from them

A mosaic variant in CTNNB1/β-catenin as a novel cause for osteopathia striata with cranial sclerosis

Context: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of beta-catenin via AXIN stabilization, acting as a negative regulator of the WNT/beta-catenin signaling pathway, a central pathway in bone formation.Objective: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1.Results: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for beta-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the beta-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the beta-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn beta-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn beta-catenin.Conclusion: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.Metabolic health: pathophysiological trajectories and therap

Identification of compound heterozygous variants in LRP4 D\demonstrates that a pathogenic variant outside the third beta-propeller domain can cause sclerosteosis

Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third beta-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first beta-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first beta-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.Diabetes mellitus: pathophysiological changes and therap

Respiratory Syncytial Virus Disease Burden in Community-Dwelling and Long-Term Care Facility Older Adults in Europe and the United States: A Prospective Study

Background. Data on respiratory syncytial virus (RSV) disease burden in adults remain scarce. We assessed the burden of confirmed RSV-acute respiratory infections (cRSV-ARIs) in community-dwelling (CD) adults and those in long-term care facilities (LTCFs).Methods. In this prospective cohort study covering 2 RSV seasons (October 2019-March 2020 and October 2020-June 2021), RSVARIs were identified through active surveillance, in medically stable CD-adults =50 years (Europe) or adults =65 years in LTCFs (Europe and the United States). RSV infection was confirmed by polymerase chain reaction from combined nasal and throat swabs.Results. Of 1981 adults enrolled, 1251 adults in CD and 664 LTCFs (season 1) and 1223 adults in CD and 494 LTCFs (season 2) were included in the analyses. During season 1, overall incidence rates ([IRs] cases/1000 person-years) and attack rates (ARs) for cRSVARIs were 37.25 (95% confidence interval [CI], 22.62-61.35) and 1.84% in adults in CD and 47.85 (CI, 22.58-101.4) and 2.26% in adults in LTCFs. Complications occurred for 17.4% (CD) and 13.3% (LTCFs) of cRSV-ARIs. One cRSV-ARI occurred in season 2 (IR = 2.91 [CI, 0.40-20.97]; AR = 0.20%), without complications. No cRSV-ARIs led to hospitalization or death. Viral pathogens were codetected in =17.4% of cRSV-ARIs.Conclusions. RSV is an important cause of disease burden in adults in CD and LTCFs. Despite the observed low severity of cRSVARI, our results support the need for RSV prevention strategies among adults =50 years old

Biocontrol Potential of Forest Tree Endophytes

Peer reviewe

Genotype-stratified treatment for monogenic insulin resistance: a systematic review

This is the final version. Available from Nature Research via the DOI in this record. Data availability: All data used in this review is available from publicly available and herein referenced sources. A list of included studies is provided in Supplementary Data 1. All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data for the figures are available as Supplementary Data 2.BACKGROUND: Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology. METHODS: Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy. RESULTS: 10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions. CONCLUSIONS: The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.Wellcome TrustWellcome Trus

Predicting creditworthiness in retail banking with limited scoring data

The preoccupation with modelling credit scoring systems including their relevance to predicting and decision making in the financial sector has been with developed countries, whilst developing countries have been largely neglected. The focus of our investigation is on the Cameroonian banking sector with implications for fellow members of the Banque des Etats de L'Afrique Centrale (BEAC) family which apply the same system. We apply logistic regression (LR), Classification and Regression Tree (CART) and Cascade Correlation Neural Network (CCNN) in building our knowledge-based scoring models. To compare various models’ performances, we use ROC curves and Gini coefficients as evaluation criteria and the Kolmogorov-Smirnov curve as a robustness test. The results demonstrate that an improvement in terms of predicting power from 15.69% default cases under the current system, to 7.68% based on the best scoring model, namely CCNN can be achieved. The predictive capabilities of all models are rated as at least very good using the Gini coefficient; and rated excellent using the ROC curve for CCNN. Our robustness test confirmed these results. It should be emphasised that in terms of prediction rate, CCNN is superior to the other techniques investigated in this paper. Also, a sensitivity analysis of the variables identifies previous occupation, borrower's account functioning, guarantees, other loans and monthly expenses as key variables in the forecasting and decision making processes which are at the heart of overall credit policy