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Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling. PREGCARE is a new strategy for families who had a child with a pathogenic de novo mutation, that efficiently identifies couples at higher recurrence risk due to parental mosaicism, while reassuring many others that their recurrence risk is negligible. [ABSTRACT FROM AUTHOR]

Innovative testing approaches and care pathways are required to meet HIV, hepatitis B (HBV) and hepatitis C (HCV) elimination goals. Routine testing for blood-borne viruses (BBVs) within emergency departments (EDs) is suggested by the European Centre for Disease Prevention and Control but there is a paucity of supporting evidence. We evaluated the introduction of routine BBV testing in EDs at a large teaching hospital in northern England. In October 2018, we modified the electronic laboratory ordering system to reflex opt-out HIV, HBV and HCV testing for all ED attendees aged 16–65 years who had a routine blood test for urea and electrolytes (U&Es). Linkage to care (LTC) was attempted for newly diagnosed patients, those never referred and those who had previously disengaged from care. The project operated for 18 months, here we present evaluation of the initial nine months (2 October 2018–1 July 2019). We analysed testing uptake, BBV seropositivity, LTC and treatment initiation within six months post-diagnosis. Over 9 months, 17,026/28,178 (60.4%) ED attendees who had U&Es performed were tested for ≥ 1 BBV. 299 active BBV infections were identified: 70 HIV Ab/Ag-positive (0.4% seroprevalence), 73 HBsAg-positive (0.4%) and 156 HCV RNA-positive (1.0%). Only 24.3% (17/70) HIV Ab/Ag-positive individuals required LTC, compared to 94.9% (148/156) HCV RNA-positive and 53.4% (39/73) HBsAg-positive individuals. LTC was successful in 94.1% (16/17) HIV Ab/Ag-positive and 69.3% (27/39) HBsAg-positive individuals. However, at 6 months LTC was just 39.2% (58/148) for HCV RNA-positive individuals, with 64% (37/58) of these commencing treatment. Universal opt-out ED BBV testing proved feasible and effective in identifying active BBV infections, especially among marginalised populations with reduced healthcare access. Our integrated approach achieved good LTC rates although further service development is necessary, particularly for HCV RNA-positive people who inject drugs. [ABSTRACT FROM AUTHOR]

Mosaic loss of the Y chromosome (LOY) is the most frequent chromosomal aberration in aging men and is strongly correlated with mortality and disease. To date, studies of LOY have only been performed in humans, and so it is unclear whether LOY is a natural consequence of our relatively long lifespan or due to exposure to human-specific external stressors. Here, we explored whether LOY could be detected in rats. We applied a locus-specific PCR and target sequencing approach that we used as a proxy to estimate LOY in 339 samples covering eleven tissues from young and old individuals. We detected LOY in four tissues of older rats. To confirm the results from the PCR screening, we re-sequenced 60 full genomes from old rats, which revealed that the Y chromosome is the sole chromosome with low copy numbers. Finally, our results suggest that LOY is associated with other structural aberrations on the Y chromosome and possibly linked to the mosaic loss of the X chromosome. This is the first report, to our knowledge, demonstrating that the patterns of LOY observed in aging men are also present in a rodent, and conclude that LOY may be a natural process in placental mammals. Alberto Orta et al. demonstrate that frequent mosaic loss of chromosome Y (LOY) observed in aging men might also be present in rats. They show that, like in humans, LOY in rats is associated with aging, but is not dependent on environmental stressors, and may be a natural process in placental mammals. [ABSTRACT FROM AUTHOR]

Campylobacter is the leading cause of bacterial foodborne gastroenteritis worldwide. Handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. One potential control strategy is to select poultry with increased resistance to Campylobacter. We associated high-density genome-wide genotypes (600K single nucleotide polymorphisms) of 3000 commercial broilers with Campylobacter load in their caeca. Trait heritability was modest but significant (h2 = 0.11 ± 0.03). Results confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified in inbred chicken lines, and detected two additional QTLs on chromosomes 19 and 26. RNA-Seq analysis of broilers at the extremes of colonisation phenotype identified differentially transcribed genes within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We identified strong cis-QTLs located within MHC suggesting the presence of cis-acting variation in MHC class I and II and BG genes. Pathway and network analyses implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin–angiotensin signalling. While co-selection for enhanced resistance and other breeding goals is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influenced Campylobacter colonisation. [ABSTRACT FROM AUTHOR]

Genomic analysis of paired tumor–normal samples and clinical data can be used to match patients to cancer therapies or clinical trials. We analyzed 500 patient samples across diverse tumor types using the Tempus xT platform by DNA-seq, RNA-seq and immunological biomarkers. The use of a tumor and germline dataset led to substantial improvements in mutation identification and a reduction in false-positive rates. RNA-seq enhanced gene fusion detection and cancer type classifications. With DNA-seq alone, 29.6% of patients matched to precision therapies supported by high levels of evidence or by well-powered studies. This proportion increased to 43.4% with the addition of RNA-seq and immunotherapy biomarker results. Combining these data with clinical criteria, 76.8% of patients were matched to at least one relevant clinical trial on the basis of biomarkers measured by the xT assay. These results indicate that extensive molecular profiling combined with clinical data identifies personalized therapies and clinical trials for a large proportion of patients with cancer and that paired tumor–normal plus transcriptome sequencing outperforms tumor-only DNA panel testing. Genomic profiling of cancer samples yields more therapeutic options by including germline, RNA-seq and immunotherapy biomarkers. [ABSTRACT FROM AUTHOR]

Purpose: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance.Methods: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization.Results: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01).Conclusion: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity. Methods: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA. Results: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC values ranging from 0.2 to 1.4 μm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC (mean IC reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 ( P = 0.014). Conclusion: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents. [ABSTRACT FROM AUTHOR]

A safe and reliable in vivo nanoscale communication network will be of great benefit for medical diagnosis and monitoring as well as medical implant communication. This review article provides a brief introduction to nanoscale and molecular networking in general and provides opinions on the role of active networking for in vivo nanoscale information transport. While there are many in vivo communication mechanisms that can be leveraged, for example, forms of cell signaling, gap junctions, calcium and ion signaling, and circulatory borne communication, this review examines two in particular: molecular motor transport and neuronal information communication. Molecular motors transport molecules representing information and neural coding operates by means of the action potential; these mechanisms are reviewed within the theoretical framework of an active network. This review suggests that an active networking paradigm is necessary at the nanoscale along with a new communication constraint, namely, minimizing the communication impact upon the living environment. The goal is to assemble efficient nanoscale and molecular communication channels while minimizing disruption to the host organism. [ABSTRACT FROM AUTHOR]

This paper describes an approach to detecting distributed denial of service (DDoS) attacks that is based on fundamentals of Information Theory, specifically Kolmogorov Complexity. A theorem derived using principles of Kolmogorov Complexity states that the joint complexity measure of random strings is lower than the sum of the complexities of the individual strings when the strings exhibit some correlation. Furthermore, the joint complexity measure varies inversely with the amount of correlation. We propose a distributed active network-based algorithm that exploits this property to correlate arbitrary traffic flows in the network to detect possible denial-of-service attacks. One of the strengths of this algorithm is that it does not require special filtering rules and hence it can be used to detect any type of DDoS attack. We implement and investigate the performance of the algorithm in an active network. Our results show that DDoS attacks can be detected in a manner that is not sensitive to legitimate background traffic. [ABSTRACT FROM AUTHOR]

We present a simple distributed concept that appears to insinuate SWARM behavior in a collection of mobile platforms. The control is based on the inter-mobile platform communication links' signal-to-noise ratio. This double use of communications is a natural linkage for SWARM behavior. [ABSTRACT FROM AUTHOR]

This article discusses trends in communication and networking. Active and programmable networking have always been stimulating. Active networking is becoming important in sensor and power-limited mobile ad hoc networks because of its efficiency. The author observes that no rigorous definition of complexity has yet been devised that shows a clear relationship between complexity and communication efficiency. Computation, complexity, and communication are coupled directly within algorithmic information theory.

There is a trend toward the use of predictivesystems in communications networks. At the systems andnetwork management level predictive capabilities arefocused on anticipating network faults and performance degradation. Simultaneously, mobilecommunication networks are being developed withpredictive location and tracking mechanisms. Theinteractions and synergies between these systems presenta new set of problems. A new predictive network managementframework is developed and examined. The interactionbetween a predictive mobile network and the proposednetwork management system is discussed. The Rapidly Deployable Radio Network (RDRN) is used as aspecific example to illustrate theseinteractions. [ABSTRACT FROM AUTHOR]

This paper extends a stochastic theory for buffer fill distribution for multiple 'on' and 'off' sources to a mobile environment. Queue fill distribution is described by a set of differential equations assuming sources alternate asynchronously between exponentially distributed periods in 'on' and 'off' states. This paper includes the probabilities that mobile sources have links to a given queue. The sources represent mobile user nodes, and the queue represents the capacity of a switch. This paper presents a method of analysis which uses mobile parameters such as speed, call rates per unit area, cell area, and call duration and determines queue fill distribution at the ATM cell level. The analytic results are compared with simulation results. [ABSTRACT FROM AUTHOR]

This paper describes the design of a control and management network (orderwire) for a mobile wireless Asynchronous Transfer Mode (ATM) network. This mobile wireless ATM network is part of the Rapidly Deployable Radio Network (RDRN). The orderwire system consists of a packet radio network which overlays the mobile wireless ATM network. Each network element in this network uses Global Positioning System (GPS) information to control a beamforming antenna subsystem which provides for spatial reuse. This paper also proposes a novel Virtual Network Configuration (VNC) algorithm for predictive network configuration. A mobile ATM Private Network–Network Interface (PNNI) based on VNC is also discussed. Finally, as a prelude to the system implementation, results of a Maisie simulation of the orderwire system are discussed. [ABSTRACT FROM AUTHOR]

There are several articles in the literature reporting laparoscopic surgery in patients with ventriculoperitoneal shunts (VPSs). Although the majority of these conclude that a pneumoperitoneum in these patients is safe, there are other reports indicating possible complications of the insufflation. This is the first known report of a robotic-assisted hysterectomy performed on a patient with a VPS and the management of the shunt during the procedure. [ABSTRACT FROM AUTHOR]

The European honey bee (Apis mellifera) plays a major role in pollination and food production. Honey bee health is a complex product of the environment, host genetics and associated microbes (commensal, opportunistic and pathogenic). Improved understanding of these factors will help manage modern challenges to bee health. Here we used DNA sequencing to characterise the genomes and metagenomes of 19 honey bee colonies from across Britain. Low heterozygosity was observed in many Scottish colonies which had high similarity to the native dark bee. Colonies exhibited high diversity in composition and relative abundance of individual microbiome taxa. Most non-bee sequences were derived from known honey bee commensal bacteria or pathogens. However, DNA was also detected from additional fungal, protozoan and metazoan species. To classify cobionts lacking genomic information, we developed a novel network analysis approach for clustering orphan DNA contigs. Our analyses shed light on microbial communities associated with honey bees and demonstrate the power of high-throughput, directed metagenomics for identifying novel biological threats in agroecosystems. Numerous microbial symbionts, both commensal and pathogenic, are associated with honey bees. Here, the authors genomically characterize this ‘metagenome’ of the British honey bee, identifying a diversity of commensal microbes as well as known and putative pathogens [ABSTRACT FROM AUTHOR]