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Abstract Skin diseases affect one-third of the global population, posing a major healthcare burden. Deep learning may optimise healthcare workflows through processing skin images via neural networks to make predictions. A focus of deep learning research is skin lesion triage to detect cancer, but this may not translate to the wider scope of >2000 other skin diseases. We searched for studies applying deep learning to skin images, excluding benign/malignant lesions (1/1/2000-23/6/2022, PROSPERO CRD42022309935). The primary outcome was accuracy of deep learning algorithms in disease diagnosis or severity assessment. We modified QUADAS-2 for quality assessment. Of 13,857 references identified, 64 were included. The most studied diseases were acne, psoriasis, eczema, rosacea, vitiligo, urticaria. Deep learning algorithms had high specificity and variable sensitivity in diagnosing these conditions. Accuracy of algorithms in diagnosing acne (median 94%, IQR 86–98; n = 11), rosacea (94%, 90–97; n = 4), eczema (93%, 90–99; n = 9) and psoriasis (89%, 78–92; n = 8) was high. Accuracy for grading severity was highest for psoriasis (range 93–100%, n = 2), eczema (88%, n = 1), and acne (67–86%, n = 4). However, 59 (92%) studies had high risk-of-bias judgements and 62 (97%) had high-level applicability concerns. Only 12 (19%) reported participant ethnicity/skin type. Twenty-four (37.5%) evaluated the algorithm in an independent dataset, clinical setting or prospectively. These data indicate potential of deep learning image analysis in diagnosing and monitoring common skin diseases. Current research has important methodological/reporting limitations. Real-world, prospectively-acquired image datasets with external validation/testing will advance deep learning beyond the current experimental phase towards clinically-useful tools to mitigate rising health and cost impacts of skin disease.

A utilização de pregão eletrônico nas aquisições de medicamentos em hospitais públicos é um processo que impacta todas as demais atividades e sua reformulação deve ser constantemente estimulada com o desenvolvimento de novas técnicas. Logo, o trabalho tem por objetivo abordar as dimensões da transação, sob os aspectos da Teoria dos Custos de Transação (TCT), nos processos de pregão eletrônico para aquisição de medicamentos de um Hospital Público Federal. Trata-se de uma pesquisa exploratória com abordagem qualitativa na modalidade de um estudo de caso, com aplicação de entrevistas, observação in loco e pesquisa documental. Os resultados apontaram que as dimensões interagem entre si e influenciam os resultados dos processos licitatórios de pregão eletrônico do hospital público federal gerando impactos de superdimensionamento das previsões de medicamentos e excessivo número de cancelamentos de itens, sugerindo que uma demanda especial na abordagem desse tipo de aquisição pode minimizar a influência dos custos de transação e, consequentemente, reduzir custos.

Plastic environmental pollution is threatening water resources, aquatic ecosystems, and human wellbeing but is still highly uncertain with global fluxes to sea of 0.4–13 Mt\yr, and up to 517 Mt of mismanaged plastics on land. Catchment modelling tools are required to challenge current knowledge, simulate impacts of management initiatives, and complement global and observation-based studies. Here we present the first spatiotemporally explicit model for mismanaged plastic mobilization and transport from land to sea from the INtegrated CAtchment (INCA) family. INCA-Macroplastics encompasses all components of the catchment, is driven by available data (weather, population, solid waste) and enables calibration and validation against diverse observations (river monitoring, household surveys). INCA-Macroplastics was applied to the Imus River, Philippines, one of World’s most polluted rivers. Given large uncertainties on catchment plastic retention, two calibrations and two emission scenarios were developed to describe catchment plastic fluxes, residence time and stocks over 1990–2020. Plastic fluxes to the sea are highly variable over years and seasons (55–75% exported during the wet season) and have increased exponentially over 1990–2020 from 5–100 to 2000–15000 tons\yr. INCA-Macroplastics is the first model handling plastic accumulation on land and highlights the importance of extreme flooding events in mobilizing and transporting legacy plastics. Model outputs explicitly show that current land plastic pollution can impact fluxes to the ocean for up to 30 years into the future. INCA-Macroplastics is useful to provide tailored recommendations for local monitoring, testing waste management scenarios and pointing towards future research avenues.

Abstract Background The ubiquity of pedigrees in many scientific areas calls for versatile and user-friendly software. Previously published online pedigree tools have limited support for complex pedigrees and do not provide analysis of relatedness between pedigree members. Results We introduce QuickPed, a web application for interactive pedigree creation and analysis. It supports complex inbreeding and comes with a rich built-in library of common and interesting pedigrees. The program calculates all standard coefficients of relatedness, including inbreeding, kinship and identity coefficients, and offers specialised plots for visualising relatedness. It also implements a novel algorithm for describing pairwise relationships in words. Conclusion QuickPed is a user-friendly pedigree tool aimed at researchers, case workers and teachers. It contains a number of features not found in other similar tools, and represents a significant addition to the body of pedigree software by making advanced relatedness analyses available for non-bioinformaticians.

Abstract Background While representing a significant improvement, the introduction of next‐generation sequencing in genetic diagnosis also prompted new challenges. Despite widely recognized consensus guidelines for the interpretation of sequence variants, many variants remain unclassified or are discordantly interpreted. In heritable thoracic aortic aneurysms with dissection (HTAAD), most cases are caused by a heterozygous, private missense mutation, possibly contributing to the relatively common reports of variants with uncertain significance in this group. Segregation analysis necessitates advanced likelihood‐based methods typically inaccessible to non‐experts and is hampered by reduced penetrance, possible phenocopies, and non‐availability of DNA from deceased relatives. Methods In this report, challenges in variant interpretation and the use of segregation analyses were illustrated in two families with a suspected HTAAD disorder. The R package segregatr, a novel implementation of full‐likelihood Bayes factor (FLB), was performed to explore the cosegregation of the variants in these families. Conclusion Using the R package segregatr, cosegregation in the reported families concluded with strong and supporting evidence for pathogenicity. Surveillance of families in a multidisciplinary team enabling systematic phenotype description for standardized segregation analysis with a robust calculation method may be imperative for reliable variant interpretation in HTAAD.

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular steno-occlusive disease of largely unknown etiology. Variants in the RNF213 gene are strongly associated with MMD in East-Asia. In MMD patients of Northern-European origin, no predominant susceptibility variants have been identified so far. Research question: Are there specific candidate genes associated with MMD of Northern-European origin, including the known RNF213 gene? Can we establish a hypothesis for MMD phenotype and associated genetic variants identified for further research? Material and methods: Adult patients of Northern-European origin, treated surgically for MMD at Oslo University Hospital between October 2018 to January 2019 were asked to participate. WES was performed, with subsequent bioinformatic analysis and variant filtering. The selected candidate genes were either previously reported in MMD or known to be involved in angiogenesis. The variant filtering was based on variant type, location, population frequency, and predicted impact on protein function. Results: Analysis of WES data revealed nine variants of interest in eight genes. Five of those encode proteins involved in nitric oxide (NO) metabolism: NOS3, NR4A3, ITGAV, GRB7 and AGXT2. In the AGXT2 gene, a de novo variant was detected, not previously described in MMD. None harboured the p.R4810K missense variant in the RNF213 gene known to be associated with MMD in East-Asian patients. Discussion and conclusion: Our findings suggest a role for NO regulation pathways in Northern-European MMD and introduce AGXT2 as a new susceptibility gene. This pilot study warrants replication in larger patient cohorts and further functional investigations.

Abstract We address computational and statistical aspects of DNA-based identification of victims in the aftermath of disasters. Current methods and software for such identification typically consider each victim individually, leading to suboptimal power of identification and potential inconsistencies in the statistical summary of the evidence. We resolve these problems by performing joint identification of all victims, using the complete genetic data set. Individual identification probabilities, conditional on all available information, are derived from the joint solution in the form of posterior pairing probabilities. A closed formula is obtained for the a priori number of possible joint solutions to a given DVI problem. This number increases quickly with the number of victims and missing persons, posing computational challenges for brute force approaches. We address this complexity with a preparatory sequential step aiming to reduce the search space. The examples show that realistic cases are handled efficiently. User-friendly implementations of all methods are provided in the R package dvir, freely available on all platforms.

Abstract We use 20 years of continuous magnetic field measurements from the Ørsted, CHAMP and Swarm satellite missions, supplemented by calibrated platform magnetometer data from the CryoSat-2 satellite, to study time variations of the Earth’s core field at satellite altitude and at the core–mantle boundary (CMB). From the satellite data we derive composite time series of the core field secular variation (SV) with 4-month cadence, at 300 globally distributed Geomagnetic Virtual Observatories (GVO). A previous gap in the GVO series between 2010 and 2014 is successfully filled using CryoSat-2, and sub-decadal variations are identified during this period. Tests showed that similar sub-decadal SV patterns were obtained from the CryoSat-2 data regardless of whether IGRF-13 or CHAOS-6x9 was used in their calibration. Cryosat-2 radial field SV series at non-polar latitudes have a mean standard deviation level compared to smoothing spline fits of 3.5 nT/yr compared to 1.8 nT/yr for CHAMP and 0.9 nT/yr for Swarm. GVO radial SV series display regional fluctuations with 5–10 years duration and amplitudes reaching 20 nT/yr, most notably at low latitudes over Indonesia (2014), over South America and the South Atlantic (2007, 2011 and 2014), and over the central Pacific (2017). Applying the Subtractive Optimally Localized Averages (SOLA) method, we also map the radial SV at the CMB as a collection of locally averaged SV estimates. We demonstrate that using 2-year windows of CryoSat-2 data, it is possible to reliably estimate the SV and its time derivative, the secular acceleration (SA), at the CMB, with a spatial resolution, corresponding to spherical harmonic degree 10. Along the CMB geographic equator, we find strong SA features with amplitude $$\pm 2.5\mu \mathrm{T}/\mathrm{yr}^2$$ ± 2.5 μ T / yr 2 under Indonesia from 2011–2014, under central America from 2015 to 2019, and sequences of SA with alternating sign under the Atlantic during 2004–2019. We find that platform magnetometer data from CryoSat-2 make a valuable contribution to the emerging picture of sub-decadal core field variations. Using 1-year windows of data from the Swarm satellites, we show that it is possible to study SA changes at low latitudes on timescales down to 1 year, with spatial resolution corresponding to spherical harmonic degree 10. We find strong positive and negative SA features appearing side-by-side in the Pacific in 2017, and thereafter drift westward.

Abstract We present geomagnetic main field and secular variation time series, at 300 equal-area distributed locations and at 490 km altitude, derived from magnetic field measurements collected by the three Swarm satellites. These Geomagnetic Virtual Observatory (GVO) series provide a convenient means to globally monitor and analyze long-term variations of the geomagnetic field from low-Earth orbit. The series are obtained by robust fits of local Cartesian potential field models to along-track and East–West sums and differences of Swarm satellite data collected within a radius of 700 km of the GVO locations during either 1-monthly or 4-monthly time windows. We describe two GVO data products: (1) ‘Observed Field’ GVO time series, where all observed sources contribute to the estimated values, without any data selection or correction, and (2) ‘Core Field’ GVO time series, where additional data selection is carried out, then de-noising schemes and epoch-by-epoch spherical harmonic analysis are applied to reduce contamination by magnetospheric and ionospheric signals. Secular variation series are provided as annual differences of the Core Field GVOs. We present examples of the resulting Swarm GVO series, assessing their quality through comparisons with ground observatories and geomagnetic field models. In benchmark comparisons with six high-quality mid-to-low latitude ground observatories we find the secular variation of the Core Field GVO field intensities, calculated using annual differences, agrees to an rms of 1.8 nT/yr and 1.2 nT/yr for the 1-monthly and 4-monthly versions, respectively. Regular sampling in space and time, and the availability of data error estimates, makes the GVO series well suited for users wishing to perform data assimilation studies of core dynamics, or to study long-period magnetospheric and ionospheric signals and their induced counterparts. The Swarm GVO time series will be regularly updated, approximately every four months, allowing ready access to the latest secular variation data from the Swarm satellites.

Abstract We present the CHAOS-7 model of the time-dependent near-Earth geomagnetic field between 1999 and 2020 based on magnetic field observations collected by the low-Earth orbit satellites Swarm, CryoSat-2, CHAMP, SAC-C and Ørsted, and on annual differences of monthly means of ground observatory measurements. The CHAOS-7 model consists of a time-dependent internal field up to spherical harmonic degree 20, a static internal field which merges to the LCS-1 lithospheric field model above degree 25, a model of the magnetospheric field and its induced counterpart, estimates of Euler angles describing the alignment of satellite vector magnetometers, and magnetometer calibration parameters for CryoSat-2. Only data from dark regions satisfying strict geomagnetic quiet-time criteria (including conditions on IMF $$B_z$$ B z and $$B_y$$ B y at all latitudes) were used in the field estimation. Model parameters were estimated using an iteratively reweighted regularized least-squares procedure; regularization of the time-dependent internal field was relaxed at high spherical harmonic degree compared with previous versions of the CHAOS model. We use CHAOS-7 to investigate recent changes in the geomagnetic field, studying the evolution of the South Atlantic weak field anomaly and rapid field changes in the Pacific region since 2014. At Earth’s surface a secondary minimum of the South Atlantic Anomaly is now evident to the south west of Africa. Green’s functions relating the core–mantle boundary radial field to the surface intensity show this feature is connected with the movement and evolution of a reversed flux feature under South Africa. The continuing growth in size and weakening of the main anomaly is linked to the westward motion and gathering of reversed flux under South America. In the Pacific region at Earth’s surface between 2015 and 2018 a sign change has occurred in the second time derivative (acceleration) of the radial component of the field. This acceleration change took the form of a localized, east–west oriented, dipole. It was clearly recorded on ground, for example at the magnetic observatory at Honolulu, and was seen in Swarm observations over an extended region in the central and western Pacific. Downward continuing to the core–mantle boundary, we find this event originated in field acceleration changes at low latitudes beneath the central and western Pacific in 2017.

Abstract We present the geomagnetic field model COV-OBS.x2 that covers the period 1840–2020. It is primarily constrained by observatory series, satellite data, plus older surveys. Over the past two decades, we consider annual differences of 4-monthly means at ground-based stations (since 1996), and virtual observatory series derived from magnetic data of the satellite missions CHAMP (over 2001–2010) and Swarm (since 2013). A priori information is needed to complement the constraints carried by geomagnetic records and solve the ill-posed geomagnetic inverse problem. We use for this purpose temporal cross-covariances associated with auto-regressive stochastic processes of order 2, whose parameters are chosen so as to mimic the temporal power spectral density observed in paleomagnetic and observatory series. We aim this way to obtain as far as possible realistic posterior model uncertainties. These can be used to infer for instance the core dynamics through data assimilation algorithms, or an envelope for short-term magnetic field forecasts. We show that because of the projection onto splines, one needs to inflate the formal model error variances at the most recent epochs, in order to account for unmodeled high frequency core field changes. As a by-product of the core field model, we co-estimate the external magnetospheric dipole evolution on periods longer than 2 years. It is efficiently summarized as the sum of a damped oscillator (of period 10.5 years and decay rate 55 years), plus a short-memory (6 years) damped random walk.

Background and Aims: Morphological changes in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) are well-characterized. Yet, it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression and DNA methylation in the ipsilateral hippocampus (ILH) using the intracortical kainate mouse model of mTLE-HS. In order to explore the effects of epileptic activity alone and also to further disentangle what triggers morphological alterations, we investigated glial and neuronal changes in gene expression and DNA methylation in the contralateral hippocampus (CLH).Methods: The intracortical kainic acid mouse model of mTLE-HS was used to elicit status epilepticus. Hippocampi contralateral to the injection site from eight kainate-injected and eight sham mice were extracted and shock frozen at 24 h post-injection. Glial and neuronal nuclei were sorted by flow cytometry. Alterations in gene expression and DNA methylation were assessed using reduced representation bisulfite sequencing and RNA sequencing. The R package edgeR was used for statistical analysis.Results: The CLH featured substantial, mostly cell-specific changes in both gene expression and DNA methylation in glia and neurons. While changes in gene expression overlapped to a great degree between CLH and ILH, alterations in DNA methylation did not. In the CLH, we found a significantly lower number of glial genes up- and downregulated compared to previous results from the ILH. Furthermore, several genes and pathways potentially involved in anti-epileptogenic effects were upregulated in the CLH. By comparing gene expression data from the CLH to previous results from the ILH (featuring hippocampal sclerosis), we derive potential upstream targets for epileptogenesis, including glial Cox2 and Cxcl10.Conclusion: Despite the absence of morphological changes, the CLH displays substantial changes in gene expression and DNA methylation. We find that gene expression changes related to potential anti-epileptogenic effects seem to dominate compared to the pro-epileptogenic effects in the CLH and speculate whether this imbalance contributes to prevent morphological alterations like neuronal death and reactive gliosis.

Abstract Background The mechanism by which protein complexes interact to regulate the deposition of post-translational modifications of histones remains poorly understood. This is particularly important at regulatory regions, such as CpG islands (CGIs), which are known to recruit Trithorax (TrxG) and Polycomb group proteins. The CxxC zinc finger protein 1 (CFP1, also known as CGBP) is a subunit of the TrxG SET1 protein complex, a major catalyst of trimethylation of H3K4 (H3K4me3). Results Here, we used ChIP followed by high-throughput sequencing (ChIP-seq) to analyse genomic occupancy of CFP1 in two human haematopoietic cell types. We demonstrate that CFP1 occupies CGIs associated with active transcription start sites (TSSs), and is mutually exclusive with H3K27 trimethylation (H3K27me3), a marker of polycomb repressive complex 2. Strikingly, rather than being restricted to active CGI TSSs, CFP1 also occupies a substantial fraction of active non-CGI TSSs and enhancers of transcribed genes. However, relative to other TrxG subunits, CFP1 was specialised to TSSs. Finally, we found enrichment of CpG-containing DNA motifs in CFP1 peaks at CGI promoters. Conclusions We found that CFP1 is not solely recruited to CpG islands as it was originally defined, but also other regions including non-CpG island promoters and enhancers.

Background: Underlying causes of adrenal insufficiency include congenital adrenal hyperplasia (CAH) and autoimmune adrenocortical destruction leading to autoimmune Addison's disease (AAD). Here, we report a patient with a homozygous stop-gain mutation in 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2), in addition to impaired steroidogenesis due to AAD.Case Report: Whole exome sequencing revealed an extremely rare homozygous nonsense mutation in exon 2 of the HSD3B2 gene, leading to a premature stop codon (NM_000198.3: c.15C>A, p.Cys5Ter) in a patient with AAD and premature ovarian insufficiency. Scrutiny of old medical records revealed that the patient was initially diagnosed with CAH with hyperandrogenism and severe salt-wasting shortly after birth. However, the current steroid profile show complete adrenal insufficiency including low production of pregnenolone, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), without signs of overtreatment with steroids.Conclusion: To the best of our knowledge, this is the first description of autoimmune adrenalitis in a patient with 3βHSD2 deficiency and suggests a possible association between AAD and inborn errors of the steroidogenesis.

Autoimmune Addison's disease (AAD) is a classic organ-specific autoimmune disease characterized by an immune-mediated attack on the adrenal cortex. As most autoimmune diseases, AAD is believed to be caused by a combination of genetic and environmental factors, and probably interactions between the two. Persistent viral infections have been suggested to play a triggering role, by invoking inflammation and autoimmune destruction. The inability of clearing infections can be due to aberrations in innate immunity, including mutations in genes involved in the recognition of conserved microbial patterns. In a whole exome sequencing study of anonymized AAD patients, we discovered several rare variants predicted to be damaging in the gene encoding Toll-like receptor 3 (TLR3). TLR3 recognizes double stranded RNAs, and is therefore a major factor in antiviral defense. We here report the occurrence and functional characterization of five rare missense variants in TLR3 of patients with AAD. Most of these variants occurred together with a common TLR3 variant that has been associated with a wide range of immunopathologies. The biological implications of these variants on TLR3 function were evaluated in a cell-based assay, revealing a partial loss-of-function effect of three of the rare variants. In addition, rare mutations in other members of the TLR3-interferon (IFN) signaling pathway were detected in the AAD patients. Together, these findings indicate a potential role for TLR3 and downstream signaling proteins in the pathogenesis in a subset of AAD patients. Keywords: Autoimmunity, Addison's disease, Immunodeficiency, Innate immunity, Anti-viral immunity, Toll-like receptor 3

BACKGROUND AND AIMS:Mesial Temporal Lobe Epilepsy is characterized by progressive changes of both neurons and glia, also referred to as epileptogenesis. No curative treatment options, apart from surgery, are available. DNA methylation (DNAm) is a potential upstream mechanism in epileptogenesis and may serve as a novel therapeutic target. To our knowledge, this is the first study to investigate epilepsy-related DNAm, gene expression (GE) and their relationship, in neurons and glia. METHODS:We used the intracortical kainic acid injection model to elicit status epilepticus. At 24 hours post injection, hippocampi from eight kainic acid- (KA) and eight saline-injected (SH) mice were extracted and shock frozen. Separation into neurons and glial nuclei was performed by flow cytometry. Changes in DNAm and gene expression were measured with reduced representation bisulfite sequencing (RRBS) and mRNA-sequencing (mRNAseq). Statistical analyses were performed in R with the edgeR package. RESULTS:We observed fulminant DNAm- and GE changes in both neurons and glia at 24 hours after initiation of status epilepticus. The vast majority of these changes were specific for either neurons or glia. At several epilepsy-related genes, like HDAC11, SPP1, GAL, DRD1 and SV2C, significant differential methylation and differential gene expression coincided. CONCLUSION:We found neuron- and glia-specific changes in DNAm and gene expression in early epileptogenesis. We detected single genetic loci in several epilepsy-related genes, where DNAm and GE changes coincide, worth further investigation. Further, our results may serve as an information source for neuronal and glial alterations in both DNAm and GE in early epileptogenesis.

With widespread, long-term historical use of plastics and the presence of microplastics in a range of new and existing products, there is rising concern about their potential impacts on freshwater ecosystems. Understanding how microplastics are transported and distributed along river systems is key to assessing impacts. Modelling the main flow dynamics, mixing, sedimentation and resuspension processes is essential for an understanding of the transport processes. We use the new, processed based, dynamic, integrated catchments (INCA) microplastics model and apply this to the whole of the freshwater catchment of the River Thames, UK, to evaluate inputs, loads and concentrations along the river system. Recent data from UK water industry studies on microplastics in effluent discharges and sewage sludge disposal has been utilised to drive the INCA microplastics model. Predicted concentrations and microplastic loads moving along the river system are shown to be significant, with a build-up of concentrations along the river, with increasing deposition on the riverbed. The potential impacts on aquatic ecosystems are evaluated and a review of policy implications is explored.

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%-80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4(+) and CD8(+) cells using Illumina's HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4(+) cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease.

ObjectiveThe goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell-free fetal DNA or whole fetal cells.MethodIn collaboration with a National Institutes of Health-supported research ethics consultation committee together with feedback from an interdisciplinary group of clinicians, members of industry, legal experts, and genetic counselors, we developed a set of best practices for the provision of noninvasive prenatal genetic testing.ResultsPrincipal recommendations include the amendment of current informed consent procedures to include attention to the noninvasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not directly to consumers.ConclusionPrenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies, and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests.

Fibroblasts synthesize the extracellular matrix of connective tissue and play an essential role in maintaining the structural integrity of most tissues. Researchers have long suspected that fibroblasts exhibit functional specialization according to their organ of origin, body site, and spatial location. In recent years, a number of approaches have revealed the existence of fibroblast subtypes in mice. Here, we discuss fibroblast heterogeneity with a focus on the mammalian dermis, which has proven an accessible and tractable system for the dissection of these relationships. We begin by considering differences in fibroblast identity according to anatomical site of origin. Subsequently, we discuss new results relating to the existence of multiple fibroblast subtypes within the mouse dermis. We consider the developmental origin of fibroblasts and how this influences heterogeneity and lineage restriction. We discuss the mechanisms by which fibroblast heterogeneity arises, including intrinsic specification by transcriptional regulatory networks and epigenetic factors in combination with extrinsic effects of the spatial context within tissue. Finally, we discuss how fibroblast heterogeneity may provide insights into pathological states including wound healing, fibrotic diseases, and aging. Our evolving understanding suggests that ex vivo expansion or in vivo inhibition of specific fibroblast subtypes may have important therapeutic applications., Introduction A paradigm of the metazoan body plan is the combination of epithelial and mesenchymal elements into structured three-dimensional organs. Fibroblasts are cells that synthesize and integrate structural proteins such [...]