DNA Unicorn: An N-of-1 Community Advocacy Resource

With the wider use of genetic testing, an increasing number of people are receiving molecular diagnoses of ultra-rare or N-of-1 diseases. The medical and psychosocial challenges of these individuals are compounded by a lack of support and advice from disease-specific communities. A website ( www.dnaunicorn.org) was developed to help N-of-1 families connect with caregivers, researchers, and patients with the same or related medical conditions. The site provides directions and links to resources to facilitate data-sharing through access to databases, and aids in the construction of social media campaigns to connect genotypically- or phenotypically-related patients and families to each other. Furthermore, the website provides step-by-step instructions and templates for users to optimize their use of Twitter, Facebook, GenomeConnect, MyGene2 and other potential avenues to find and build a community. Fourteen genetic counselors provided feedback by answering seven questions on the usefulness of an early version of the web-based tool kit. Free text responses were also elicited. Five themes emerged in qualitative analysis of their responses: aesthetics, language, resource choice, how-to guide utility, and overall clinical utility. Aesthetics was mentioned most frequently, with eight genetic counselors commenting on font size and text placement. Responses to the website were overwhelmingly positive; 100% of participants agreed that it would be useful in clinical practice and would refer patients to the website. Counselors also described a need for more resources for families with N-of-1 or ultra-rare molecular diagnoses, which our site attempts to address

Adapting the Quality Maternal and Newborn Care (QMNC) Framework to evaluate models of antenatal care:A pilot study

<div><p>Background</p><p>Recent evidence indicates that continuity models of maternity care result in improved clinical and psychosocial outcomes, but their causal mechanisms are poorly understood. The recent Lancet Series on Midwifery’s Quality Maternal and Newborn Care Framework describes five components of quality care and their associated characteristics. As an initial step in developing this Framework into an evaluation toolkit, we transformed its components and characteristics into a topic guide to assess stakeholder perceptions and experiences of care provided and received. The main purpose of this study was to assess the feasibility of this process.</p><p>Methods</p><p>We conducted twelve focus groups in two Scottish health board areas with 13 pregnant women, 18 new mothers, 26 midwives and 12 obstetricians who had experience of a range of different models of maternity care. Transcripts were analysed using a six-phase approach of thematic analysis. We mapped the identified themes and sub-themes back to the Framework.</p><p>Results</p><p>The emerging themes and sub-themes demonstrated the feasibility of using the QMNC framework as a data collection tool, and as a lens for analysing the data. Of the four emerging themes, only Organisation Culture / Work Structure’ mapped directly to a single Framework component. The others—‘Relationships’; ‘Information and support’; and ‘Uncertainty’–mapped to between two and five components, illustrating the interconnectedness of the Framework’s components. Some negative sub-themes mirrored positive Framework characteristics of care. Some re-phrasing and re-ordering of the topic guides in later focus groups ensured we could cover all aspects of the Framework adequately.</p><p>Conclusion</p><p>Adapting the Quality Maternal and Newborn Care Framework enabled us to focus on aspects of care which worked well and which didn’t work well for these key stakeholders. Identifying ‘what works for whom and why’ in different models of care is a necessary step in reinforcing and replicating the most effective models of care.</p></div

Using the Quality Maternal and Newborn Care Framework to evaluate women's experiences of different models of care:A qualitative study

© 2019 Elsevier Ltd Objective: There is evidence that continuity of care - increasingly a focus of maternity care policy in the UK - contributes to improved outcomes. However, uncertainty remains about which models of care are most effective in which circumstances, and why this is. A plausible explanation is grounded in the idea that the continuity elements of care contribute to and reinforce best quality care. The Quality Maternal and Newborn Care Framework describes the components and characteristics of quality care. As a first step in developing a maternity care evaluation toolkit, we adapted this Framework to see if it could be used to evaluate perceptions and experiences of different models of care. Design: A qualitative comparative enquiry using focus groups. From a six-phase thematic analysis, we first derived then compared the principal sub-themes from the focus groups and mapped these to the original Framework. Setting: Two health boards in Scotland. Participants: Pregnant women, new mothers, midwives and obstetricians who had experience of various models of maternity care. This paper reports findings from the pregnant women and new mothers. Results: These are presented in two parts: the seven focus groups with pregnant women and new mothers are reported in this paper; the five focus groups with midwives and obstetricians in our accompanying paper. Those using the maternity services had experience of caseloading midwifery, ‘modified universal provision’ and ‘high risk’ models of maternity care. While women from all groups shared certain perspectives, those with experience of caseloading midwifery were consistently positive, reporting positive relationships, tailored care and effective communication. Women experiencing other models of care, especially the modified universal provision model, tended to report more negative relational experiences: lack of information, lack of tailored care, and anxiety and confusion. Timing of the focus group (i.e. during pregnancy or after the birth) appeared to make little difference to responses. Mapping responses to the Framework's characteristics of care was straightforward; mapping also showed how the Framework's components of care are interlinked. Key conclusions: Our adaptation of the Quality Maternal and Newborn Care Framework as a data collection tool allowed us to compare women with experience of different models of care, and relational factors were identifiable in many responses. Positive responses were found in all models but were most emphasised in the caseloading midwifery model, suggesting that the experience of caseloading continuity and its relational elements is highly valued. While further work is required to identify if this can be linked to improved clinical outcomes, we have established that the Quality Maternal and Newborn Care Framework can be adapted as an exploratory tool for assessing perceptions and experiences of maternity care

Using a quality care framework to evaluate user and provider experiences of maternity care:A comparative study

© 2019 Objective: The Quality Maternal and Newborn Care Framework describes the components and characteristics of quality care and emphasises relational and continuity elements. Continuity of care is increasingly a focus of maternity care policy in the United Kingdom. While some outcomes have been shown to be improved, there is uncertainty about why certain models of care are more effective. Our overall objective is to develop a maternity care evaluation toolkit which incorporates this Framework along with other outcome evaluations. An initial step in developing this toolkit was to use the adapted Framework to evaluate perceptions and experiences of maternity care. Our specific objective in this study was to test this adapted Framework in a series of focus groups with key stakeholders, and to compare findings between different groups. Findings related to service users (pregnant women and new mothers) are reported in our accompanying paper; this paper presents findings from focus groups with service providers (midwives and obstetricians), and then compares user and provider perspectives. Design: A qualitative comparative enquiry involving three focus groups with 26 midwives (eight newly qualified; eight working in a community midwifery unit; and ten senior tertiary-based) and two focus groups with twelve obstetricians of all grades. We used a six-phase thematic analysis to derive then compare the focus groups’ principal sub-themes; we then mapped these to the original Quality Maternal and Newborn Care Framework and compared these service providers’ responses with those from the pregnant women and new mothers. Setting: Two health boards in Scotland. Participants: Midwives and obstetricians who had experience of various models of maternity care. Findings: There were significant areas of overlap in their perceptions of providing maternity care. All groups reported ‘limited resources and time’; the community midwifery unit and senior midwives and one group of obstetricians provided a critique of the system. Achieving tailored care was acknowledged as a problem by the senior midwives and one group of obstetricians. Only obstetricians discussed strategies for improvement. The newly qualified midwives were most positive in their responses. There was both overlap and contrast when comparing the views of service users and providers. We found most agreement when participants discussed some of the Framework's characteristics of care in negative terms, such as (in) accessible care, (lack of) adequate resources, and (absence of) tailored care. Key Conclusions: Being able firstly to map the participants’ responses to the Quality Maternal and Newborn Care Framework, and then to identify strengths and gaps in the provision of quality maternity care, suggests to us that the Framework, derived as it is from a comprehensive analysis of the global evidence on quality care, can indeed be used to inform an evaluation toolkit. While aware that we cannot generalise from this limited qualitative study, we are currently undertaking similar work in other countries by which we hope to confirm our findings and further develop the toolkit

Zoonotic Pathogens From Illegally Traded Wildlife Justify Adopting the One Health Perspective in Disease Response

Recent studies have described a direct relationship between the illegal wildlife trade (IWT) and the prevalence of zoonotic pathogens in human populations. In the Philippines, the Philippine Integrated Disease Surveillance and Response (PIDSR) framework outlines the monitoring, response, and management of disease outbreaks, but needs to be updated in the wake of zoonoses from IWT. Here, we identified zoonotic pathogens that may be introduced to human populations through the IWT, pinpointed potential outbreak hotspots, and provided recommendations on how to improve the Philippines’ public health response while considering One Health. Using seizure data from the Biodiversity Management Bureau (DENR-BMB) covering the period from 2010 to 2016, we found that birds (32.3% of volume) and reptiles (63.3% of volume) were the most frequently seized by law enforcement in terms of incidence and volume. About 54% of seized wildlife could potentially host zoonotic pathogens with bacteria (78.3%), protozoa (34.8%), and viruses (27.5%) being the most represented pathogen groups. Three cities in Metro Manila together accounted for 30% of all seizures in the country followed by Palawan province which accounted for about 28% of seizures. Of the twelve epidemic prone diseases identified in the PIDSR, five diseases were found to have causative agents that could potentially be hosted by the traded wildlife. These findings will not only enhance the approach to surveillance in the PIDSR but will also aid in identifying opportunities to improve policies on agriculture and food security, public health and disease surveillance, and biodiversity conservation

Phosphonate production by marine microbes: exploring new sources and potential function

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Acker, M., Hogle, S. L., Berube, P. M., Hackl, T., Coe, A., Stepanauskas, R., Chisholm, S. W., & Repeta, D. J. Phosphonate production by marine microbes: exploring new sources and potential function. Proceedings of the National Academy of Sciences of the United States of America, 119(11), (2022): e2113386119, https://doi.org/10.1073/pnas.2113386119.Phosphonates are organophosphorus metabolites with a characteristic C-P bond. They are ubiquitous in the marine environment, their degradation broadly supports ecosystem productivity, and they are key components of the marine phosphorus (P) cycle. However, the microbial producers that sustain the large oceanic inventory of phosphonates as well as the physiological and ecological roles of phosphonates are enigmatic. Here, we show that phosphonate synthesis genes are rare but widely distributed among diverse bacteria and archaea, including Prochlorococcus and SAR11, the two major groups of bacteria in the ocean. In addition, we show that Prochlorococcus can allocate over 40% of its total cellular P-quota toward phosphonate production. However, we find no evidence that Prochlorococcus uses phosphonates for surplus P storage, and nearly all producer genomes lack the genes necessary to degrade and assimilate phosphonates. Instead, we postulate that phosphonates are associated with cell-surface glycoproteins, suggesting that phosphonates mediate ecological interactions between the cell and its surrounding environment. Our findings indicate that the oligotrophic surface ocean phosphonate pool is sustained by a relatively small fraction of the bacterioplankton cells allocating a significant portion of their P quotas toward secondary metabolism and away from growth and reproduction.This work was supported in part by grants from the NSF (OCE-1153588 and DBI-0424599 to S.W.C.; OCE-1335810 and OIA-1826734 to R.S.; and OCE-1634080 to D.J.R.), the Gordon and Betty Moore Foundation (no. 6000 to D.J.R.), and the Simons Foundation (Life Sciences Project Award IDs 337262 and 647135 to S.W.C.; 510023 to R.S.; and Simons Collaboration on Ocean Processes and Ecology [SCOPE] Award ID 329108 to S.W.C. and D.J.R.)

CD36 plays an important role in the clearance of oxLDL and associated age-dependent sub-retinal deposits

Age-related macular degeneration (AMD) represents the major cause of vision loss in industrialized nations. Laminar deposits in Bruch's membrane (BM) are among the first prominent histopathologic features, along with drusen formation, and have been found to contain oxidized lipids. Increases in concentrations of oxidized LDL (oxLDL) in plasma are observed with age and high fat high (HFHC) cholesterol diet. CD36 is the principal receptor implicated in uptake of oxLDL, and is expressed in the retinal pigment epithelium (RPE). We determined if CD36 participates in oxLDL uptake in RPE and correspondingly in clearance of sub-retinal deposits. Uptake of oxLDL by RPE in vitro and in vivo was CD36-dependent. CD36 deficiency in mice resulted in age-associated accumulation of oxLDL and sub-retinal BM thickening, despite fed a regular diet. Conversely, treatment of HFHC-fed ApoE null mice with a CD36 agonist, EP80317 (300 μg/kg/day), markedly diminished thickening of BM, and partially preserved (in part) photoreceptor function. In conclusion, our data uncover a new role for CD36 in the clearance of oxidized lipids from BM and in the prevention of age-dependent sub-retinal laminar deposits

People-selectivity, audiovisual integration and heteromodality in the superior temporal sulcus

The functional role of the superior temporal sulcus (STS) has been implicated in a number of studies, including those investigating face perception, voice perception, and face–voice integration. However, the nature of the STS preference for these ‘social stimuli’ remains unclear, as does the location within the STS for specific types of information processing. The aim of this study was to directly examine properties of the STS in terms of selective response to social stimuli. We used functional magnetic resonance imaging (fMRI) to scan participants whilst they were presented with auditory, visual, or audiovisual stimuli of people or objects, with the intention of localising areas preferring both faces and voices (i.e., ‘people-selective’ regions) and audiovisual regions designed to specifically integrate person-related information. Results highlighted a ‘people-selective, heteromodal’ region in the trunk of the right STS which was activated by both faces and voices, and a restricted portion of the right posterior STS (pSTS) with an integrative preference for information from people, as compared to objects. These results point towards the dedicated role of the STS as a ‘social-information processing’ centre

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor-positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observedwith PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PRmodulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored

Phosphonate production by marine microbes: Exploring new sources and potential function

Phosphonates are organophosphorus metabolites with a characteristic C-P bond. They are ubiquitous in the marine environment, their degradation broadly supports ecosystem productivity, and they are key components of the marine phosphorus (P) cycle. However, the microbial producers that sustain the large oceanic inventory of phosphonates as well as the physiological and ecological roles of phosphonates are enigmatic. Here, we show that phosphonate synthesis genes are rare but widely distributed among diverse bacteria and archaea, including Prochlorococcus and SAR11, the two major groups of bacteria in the ocean. In addition, we show that Prochlorococcus can allocate over 40% of its total cellular P-quota toward phosphonate production. However, we find no evidence that Prochlorococcus uses phosphonates for surplus P storage, and nearly all producer genomes lack the genes necessary to degrade and assimilate phosphonates. Instead, we postulate that phosphonates are associated with cell-surface glycoproteins, suggesting that phosphonates mediate ecological interactions between the cell and its surrounding environment. Our findings indicate that the oligotrophic surface ocean phosphonate pool is sustained by a relatively small fraction of the bacterioplankton cells allocating a significant portion of their P quotas toward secondary metabolism and away from growth and reproduction.</p