SIV Infection Is Associated with Transient Acute-Phase Steatosis in Hepatocytes In Vivo.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a major cause of morbidity and mortality in HIV-infected individuals, even those receiving optimal antiretroviral therapy. Here, we utilized the SIV rhesus macaque model and advanced laparoscopic techniques for longitudinal collection of liver tissue to elucidate the timing of pathologic changes. The livers of both SIV-infected (N = 9) and SIV-naïve uninfected (N = 8) macaques were biopsied and evaluated at four time points (weeks -4, 2, 6, and 16-20 post-infection) and at necropsy (week 32). SIV DNA within the macaques' livers varied by over 4 logs at necropsy, and liver SIV DNA significantly correlated with SIV RNA in the plasma throughout the study. Acute phase liver pathology (2 weeks post-infection) was characterized by evidence for fat accumulation (microvesicular steatosis), a transient elevation in both AST and cholesterol levels within the serum, and increased hepatic expression of the PPARA gene associated with cholesterol metabolism and beta oxidation. By contrast, the chronic phase of the SIV infection (32 weeks post-infection) was associated with sinusoidal dilatation, while steatosis resolved and concentrations of AST and cholesterol remained similar to those in uninfected macaques. These findings suggest differential liver pathologies associated with the acute and chronic phases of infection and the possibility that therapeutic interventions targeting metabolic function may benefit liver health in people newly diagnosed with HIV.

Expanding the Landscape of Noncanonical Amino Acids in RiPP Biosynthesis.

Advancements in DNA sequencing technologies and bioinformatics have enabled the discovery of new metabolic reactions from overlooked microbial species and metagenomic sequences. Using a bioinformatic co-occurrence strategy, we previously generated a network of ∼600 uncharacterized quorum-sensing-regulated biosynthetic gene clusters that code for ribosomally synthesized and post-translationally modified peptide (RiPP) natural products and are tailored by radical S-adenosylmethionine (RaS) enzymes in streptococci. The most complex of these is the GRC subfamily, named after a conserved motif in the precursor peptide and found exclusively in Streptococcus pneumoniae, the causative agent of bacterial pneumonia. In this study, using both in vivo and in vitro approaches, we have elucidated the modifications installed by the grc biosynthetic enzymes, including a ThiF-like adenylyltransferase/cyclase that generates a C-terminal Glu-to-Cys thiolactone macrocycle, and two RaS enzymes, which selectively epimerize the ß-carbon of threonine and desaturate histidine to generate the first instances of l-allo-Thr and didehydrohistidine in RiPP biosynthesis. RaS-RiPPs that have been discovered thus far have stood out for their exotic macrocycles. The product of the grc cluster breaks this trend by generating two noncanonical residues rather than an unusual macrocycle in the peptide substrate. These modifications expand the landscape of nonproteinogenic amino acids in RiPP natural product biosynthesis and motivate downstream biocatalytic applications of the corresponding enzymes.

Sulfur cycling at natural hydrocarbon and sulfur seeps in Santa Paula Creek, CA.

Biogeochemical cycling of sulfur is relatively understudied in terrestrial environments compared to marine environments. However, the comparative ease of access, observation, and sampling of terrestrial settings can expand our understanding of organisms and processes important in the modern sulfur cycle. Furthermore, these sites may allow for the discovery of useful process analogs for ancient sulfur-metabolizing microbial communities at times in Earth's past when atmospheric O2 concentrations were lower and sulfide was more prevalent in Earth surface environments. We identified a new site at Santa Paula Creek (SPC) in Ventura County, CA-a remarkable freshwater, gravel-bedded mountain stream charged with a range of oxidized and reduced sulfur species and heavy hydrocarbons from the emergence of subsurface fluids within the underlying sulfur- and organic-rich Miocene-age Monterey Formation. SPC hosts a suite of morphologically distinct microbial biofacies that form in association with the naturally occurring hydrocarbon seeps and sulfur springs. We characterized the geology, stream geochemistry, and microbial facies and diversity of the Santa Paula Creek ecosystem. Using geochemical analyses and 16S rRNA gene sequencing, we found that SPC supports a dynamic sulfur cycle that is largely driven by sulfide-oxidizing microbial taxa, with contributions from smaller populations of sulfate-reducing and sulfur-disproportionating taxa. This preliminary characterization of SPC revealed an intriguing site in which to study geological and geochemical controls on microbial community composition and to expand our understanding of sulfur cycling in terrestrial environments.

Pharmacologic Mydriasis Secondary to Topical Glycopyrronium Tosylate Cloths: Clinical Characterization From a Multicenter Analysis.

BACKGROUND: Topical glycopyrronium tosylate (GT) is an anticholinergic medication for treatment of axillary hyperhidrosis. Pharmacologic mydriasis and anisocoria from topical GT has been reported and may be underrecognized. This study aims to clinically characterize patients presenting with pharmacologic mydriasis from exposure to this medication. METHODS: This study is a retrospective observational case series. A multicenter chart review of 16 patients diagnosed with pharmacologic mydriasis secondary to topical GT was performed. RESULTS: Eight patients (50.0%) were age 18 years and younger, and 14 patients (87.5%) were female. Unilateral mydriasis (anisocoria) occurred in 14 patients (87.5%). Fourteen patients (87.5%) did not initially volunteer topical GT as a "medication," and the history of topical GT exposure needed to be elicited with further questioning. Hand hygiene details were known for 12 patients, and all reported that they did not wash their hands after GT application. Six patients (37.5%) were soft contact lens users. One patient had possible exposure through a family member's use of the medication. Ocular symptoms were common (blurry vision [11 patients, 68.8%] and eye dryness [7 patients, 43.8%]), but systemic anticholinergic symptoms were uncommon (such as constipation [1 patient, 6.3%] and urinary symptoms [3 patients, 18.8%]). CONCLUSIONS: Mydriasis associated with topical GT seems to be a consequence of local exposure rather than systemic toxicity. Because patients may not volunteer topical GT as a medication, eliciting a history of exposure often requires further specific questioning. Soft contact lens wear and poor postapplication hand hygiene seem to be associated with mydriasis in GT use.

The Sense of Self Over Time: Assessing Diachronicity in Dissociative Identity Disorder, Psychosis and Healthy Comparison Groups.

Dissociative experiences have been associated with diachronic disunity. Yet, this work is in its infancy. Dissociative identity disorder (DID) is characterized by different identity states reporting their own relatively continuous sense of self. The degree to which patients in dissociative identity states experience diachronic unity (i.e., sense of self over time) has not been empirically explored. This study examined the degree to which patients in dissociative identity states experienced diachronic unity. Participants were DID adults (n=14) assessed in adult and child identity states, adults with a psychotic illness (n=19), adults from the general population (n=55), children from the general population (n=26) and adults imagining themselves as children (n=23). They completed the Diachronic Disunity Scale (DDS), the Dissociative Experiences Scale (DES), and the Self-Concept Clarity Scale (SCCS). Diachronic disunity was not limited to psychiatric groups, but evident to some degree in all adult and child samples. The DID adult sample experienced more dissociation and self-confusion than the psychosis and adult comparison groups, but did not differ on the diachronic measure. DID patients in their child identity states and child comparisons showed disunity and were significantly different from child simulators, who showed relatively more unity. Results suggest that DID patients in either adult or child dissociative identity states, like those in other samples, do not universally experience themselves as having a consistent sense of self over time.

Optic neuropathy and diplopia from thyroid eye disease: update on pathophysiology and treatment.

PURPOSE OF REVIEW: Thyroid eye disease (TED) is a disfiguring disease that can lead to neuro-ophthalmic manifestations including diplopia and optic neuropathy. The aim of this review is to shed light on the diagnosis of TED based on clinical examination findings and diagnostic imaging. We will also discuss gold standard as well as newly emerging therapies for TED. RECENT FINDINGS: We discussed diagnostic criteria for TED and differentiating TED from other causes of binocular diplopia. We also reviewed the pathophysiology and differential diagnoses for dysthyroid optic neuropathy as well as recent developments on controversial causes. New imaging techniques are available for evaluation and prognosis of TED comorbidities. Most of the recent developments in TED have been focused on new treatment modalities that have thus far had promising results. We reviewed recently approved and novel potential therapies that are helpful in treating both diplopia and dysthyroid optic neuropathy. SUMMARY: TED is a complicated disorder with many clinical manifestations as well as treatment modalities. Our aim of this review was to outline new developments in the diagnosis and management of TED.

Aryl hydrocarbon receptor-induced activation of the human IGH hs1.2 enhancer: Mutational analysis of putative regulatory binding motifs.

The human hs1.2 enhancer within the Ig heavy chain gene (IGH) is polymorphic and associated with a number of autoimmune diseases. The polymorphic region is characterized by tandem repeats of an ∼53-bp invariant sequence containing possible binding sites for several transcription factors. Our previous studies suggest the human hs1.2 enhancer is sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant and high affinity ligand of the aryl hydrocarbon receptor (AhR). TCDD induced hs1.2 enhancer activity in an AhR-dependent manner and the number of invariant sequences influenced the magnitude of activity. To better understand the regulation of human hs1.2 enhancer activity, the objective of the current study was to utilize mutational analysis and luciferase reporter constructs to evaluate the contribution of putative transcription factor binding sites to overall hs1.2 enhancer activity and modulation by TCDD. Basal and LPS-induced activity of the hs1.2 enhancer appeared to be most affected by mutation of sites outside of the invariant sequence or deletion of the entire invariant sequence; whereas sites influencing the effect of TCDD were dependent on the cellular activation state (i.e. unstimulated vs. LPS stimulation) and relatively independent of the putative AhR binding site within the invariant sequence. These results suggest that AhR activation affects human hs1.2 activity through an as yet undetermined non-canonical pathway. A better understanding regarding the role of the hs1.2 enhancer in human Ig expression and how AhR ligands modulate its activity may lead to insights into overall Ig regulation and mechanisms of dysfunction.

Beyond Research Ethics: Novel Approaches of 3 Major Public Health Institutions to Provide Ethics Input on Public Health Practice Activities.

Public health institutions increasingly realize the importance of creating a culture in their organizations that values ethics. When developing strategies to strengthen ethics, institutions will have to take into account that while public health research projects typically undergo thorough ethics review, activities considered public health practice may not be subjected to similar oversight. This approach, based on a research-practice dichotomy, is increasingly being criticized as it does not adequately identify and manage ethically relevant risks to those affected by nonresearch activities. As a reaction, 3 major public health institutions (the World Health Organization, US Centers for Disease Control and Prevention, and Public Health Ontario) have implemented mechanisms for ethics review of public health practice activities. In this article, we describe and critically discuss the different modalities of the 3 approaches. We argue that although further evaluation is necessary to determine the effectiveness of the different approaches, public health institutions should strive to implement procedures to ensure that public health practice adheres to the highest ethical standards.

Global Abortion Policies Database: A descriptive analysis of the regulatory and policy environment related to abortion.

The World Health Organization (WHO) Safe abortion: technical and policy guidance for health systems states that regulatory, policy, and programmatic barriers that hinder access to and timely provision of safe abortion care should be removed. Although some regulatory requirements facilitate access, where they act as barriers, they can deter women from seeking safe abortion care. We use data available in the Global Abortion Policies Database as of February 2019 to review policies related to regulatory requirements identified as access barriers in the Safe abortion guidance. We include only countries where such policies apply, i.e., where abortion is lawful on the woman's request, with no requirement for justification and/or for one or more legal grounds. The results demonstrate the variation that exists in regulatory requirements, but little remains known about how they are implemented in practice and the implications on how women access and how providers offer safe abortion services.

Global Abortion Policies Database: a descriptive analysis of the legal categories of lawful abortion.

BACKGROUND: Texts and interpretations on the lawfulness of abortion and associated administrative requirements can be vague and confusing. It can also be difficult for a woman or provider to know exactly where to look for and how to interpret laws on abortion. To increase transparency, the Global Abortion Policies Database (GAPD), launched in 2017, facilitates the strengthening of knowledge and understanding of the complexities and nuances around lawful abortion as explicitly stated in laws and policies. METHODS: We report on data available in the GAPD as of May 2018. We reviewed the content and wording of laws, policies, standards and guidelines, judgments and other official statements for all countries where data is available in the GAPD. We analyzed data for 158 countries, where abortion is lawful on the woman's request with no requirement for justification and/or for at least one legal ground, including additional indications that are nonequivalent to a single common legal ground. We classified laws on the basis of the explicit wording of the text. The GAPD treats legal categories as the circumstances under which abortion is lawful, that is, allowed or not contrary to law, or explicitly permitted or specified by law. RESULTS: 32% of countries allow or permit abortion at the woman's request with no requirement for justification. Approximately 82% of countries allow or permit abortion to save the woman's life. 64% of countries specify health, physical health and/or mental (or psychological) health. 51% allow or permit abortion based on a fetal condition, 46% of countries allow or permit abortion where the pregnancy is the result of rape, and 10% specify an economic or social ground. Laws may also specify several additional indications that are nonequivalent to a single legal ground. CONCLUSIONS: The GAPD reflects details that exist within countries' laws and highlights the nuance within legal categories of abortion; no assumptions are made as to how laws are interpreted or applied in practice. By examining the text of the law, additional complexities related to the legal categories of abortion become more apparent.

Global Abortion Policies Database: a new approach to strengthening knowledge on laws, policies, and human rights standards.

BACKGROUND: The Global Abortion Policies Database (GAPD), launched in June 2017, provides a verifiable, comprehensive, nuanced approach to information and data sources on abortion law and policy. Abortion laws, policies, and guidelines from United Nations (UN) and World Health Organization (WHO) Member States are juxtaposed to information and recommendations from WHO safe abortion guidance, national sexual and reproductive health indicators, and relevant UN human rights bodies' concluding observations to countries. MAIN BODY: The Global Abortion Policies Database aims to increase transparency of information and accountability of states for the protection of individuals' health and human rights. The database presents current information on abortion laws and policies that goes beyond categories of lawful abortion to include information on additional access requirements, service provision, conscientious objection, and penalties. Wide-ranging variations among countries' legal requirements and criminal penalties raise questions about the evidentiary and human rights basis for abortion laws and policies. Source documents found in the database highlight that in many jurisdictions legal and policy guidance is either non-existent, not clear, or conflicting. By juxtaposing a jurisdiction's abortion laws and policies to relevant WHO guidance and by facilitating comparisons of countries' sexual and reproductive health indicators, the database can enable deep policy analysis of states' obligations to meet the health needs and human rights of individuals in the context of abortion. Policy analysis in the context of authoritative guidance on human rights standards can enable health and rights advocates to hold governments accountable for respecting, protecting, and fulfilling individuals' human rights. CONCLUSION: The GAPD is a comprehensive tool that can be used to strengthen knowledge, inform law and policy research to generate evidence on the impact of laws and policies in practice, and facilitate greater awareness of the many challenges to creating enabling policy environments for safe abortion.

Harmonizing national abortion and pregnancy prevention laws and policies for sexual violence survivors with the Maputo Protocol: proceedings of a 2016 regional technical meeting in sub-Saharan Africa.

In April 2016, the Population Council, in partnership with the World Health Organization (WHO) and the International Consortium for Emergency Contraception, convened a regional meeting in Lusaka, Zambia, geared toward supporting countries in East and Southern Africa in meeting their obligations under the Maputo Protocol. These obligations include expanding access to women's reproductive health services - especially women survivors of sexual violence. Government and civil society representatives from six countries participated: Botswana, Ethiopia, Kenya, Malawi, Rwanda, and Zambia. Countries were selected based on to their being priority settings for the projects that sponsored the meeting, coupled with the fact that they were each far enough along in addressing post-rape care to be able to develop concrete policy, programming, and/or legal action plans by the end of the meeting. The meeting was the first activity in a joint project of technical assistance by the conveners, aimed at strengthening access to comprehensive post-rape care for survivors of sexual violence. It aimed to sensitize Member States to their obligations under the Maputo Protocol to expand women's access to emergency contraception (EC) and safe abortion services, and to inspire them to do so by providing information, research evidence, and a platform for discussion. The meeting deliberations fostered a better understanding of opportunities to broaden access to EC and safe abortion for survivors in the region. Discussions on EC in this regard centered on strengthening EC delivery in the clinical context, decentralizing EC services, increasing community awareness, and overcoming policy barriers. Safe abortion discussions focused primarily on legislation, policy, and integrating these services into existing services for sexual violence survivors. Country-specific action plans were developed to address gaps and weaknesses. The regional technical meeting concluded with a discussion of practical steps that participants could take to facilitate legal, policy, and program reform with respect to pregnancy prevention and safe abortion in their respective countries. The steps revolved around three mainly areas, namely: establishing an evidence base to inform action; creating forums for discussing the issues; and drafting action points to carry the momentum from the meeting forward. This paper details the proceedings from this regional technical meeting - proceedings that are of interest to the field of sexual and gender-based violence (and reproductive health, more broadly) as challenges faced by countries in implementing the Maputo Protocol are outlined, and evidence-informed and practice-based strategies for addressing these challenges are provided.

Correction to: Harmonizing national abortion and pregnancy prevention laws and policies for sexual violence survivors with the Maputo Protocol: proceedings of a 2016 regional technical meeting in sub-Saharan Africa.

[This corrects the article DOI: 10.1186/s12919-018-0101-5.].

Access to knowledge and the Global Abortion Policies Database.

Research shows that women, healthcare providers, and even policy makers worldwide have limited or inaccurate knowledge of the abortion law and policies in their country. These knowledge gaps sometimes stem from the vague and broad terms of the law, which breed uncertainty and even conflict when unaccompanied by accessible regulation or guidelines. Inconsistency across national law and policy further impedes safe and evidence-based practice. This lack of transparency creates a crisis of accountability. Those seeking care cannot know their legal entitlements, service providers cannot practice with legal protection, and governments can escape legal responsibility for the adverse effects of their laws. This is the context for the newly launched Global Abortion Policies Database-an open-access repository that seeks to promote transparency and state accountability by providing clear and comprehensive information about national laws, policies, health standards, and guidelines, and by creating the capacity for comparative analysis and cross-referencing to health indicators, WHO recommendations, and human rights standards.

Provision of medical abortion by midlevel healthcare providers in Kyrgyzstan: testing an intervention to expand safe abortion services to underserved rural and periurban areas.

OBJECTIVE: To demonstrate the feasibility and safety of training midlevel healthcare providers (midwives and family nurses) to provide medical abortion and postabortion contraception in underserved areas in Kyrgyzstan. STUDY DESIGN: This was an implementation study at four referral facilities and 28 Felsher Obstetric Points in two districts to train their midwives and family nurses to deliver safe and effective abortion care with co-packaged mifepristone-misoprostol and provide contraceptives postabortion. The outcome of abortion - complete abortion, incomplete abortion or o-going pregnancy - was the primary end point measured. An international consultant trained 18 midwives and 14 family nurses (with midwifery diplomas) to provide medical abortion care. Supervising gynecologists based in the referral centers and study investigators based in Bishkek provided monthly monitoring of services and collection of patient management forms. A voluntary self-administered questionnaire at the follow-up visit documented women's acceptability of medical abortion services. All study data were cross-checked and entered into an online data management system for descriptive analysis. RESULTS: Between August 2014 and September 2015, midwives provided medical abortion to 554 women with a complete abortion rate of 97.8%, of whom 62% chose to use misoprostol at home. No women were lost to follow-up. Nearly all women (99.5%) chose a contraceptive method postabortion; 61% of women receiving services completed the acceptability form, of whom more than 99% indicated a high level of satisfaction with the service and would recommend it to a friend. CONCLUSION: This study demonstrates that trained Kyrgyz midwives and nurses can provide medical abortion safely and effectively. This locally generated evidence can be used by the Kyrgyz Ministry of Health to reduce unintended pregnancy and expand safe abortion care to women in underserved periurban and rural settings. IMPLICATIONS: Success in scaling up midwife/nurse provision of medical abortion in Kyrgyzstan will require registration of mifepristone-misoprostol, regulations permanently allowing midwife/nurse provision, strengthened procurement and distribution systems to prevent stockouts of supplies, preservice training of midwives/nurses and their involvement in district level supervision, monitoring and reporting, and support from supervisors.

Correction to: Study protocol on establishment of sentinel sites network for contraceptive and abortion trends, needs and utilization of services in Zika virus affected countries.

CORRECTION: The original version of this article [1] unfortunately contained a mistake. All occurrences in the main text referring to the research carried out in the following countries: Brazil, Honduras and Columbia should instead be replaced with "Brazil, Honduras and Panama". The original version of this article has been updated to reflect this change.

Global, regional, and subregional classification of abortions by safety, 2010-14: estimates from a Bayesian hierarchical model.

BACKGROUND: Global estimates of unsafe abortions have been produced for 1995, 2003, and 2008. However, reconceptualisation of the framework and methods for estimating abortion safety is needed owing to the increased availability of simple methods for safe abortion (eg, medical abortion), the increasingly widespread use of misoprostol outside formal health systems in contexts where abortion is legally restricted, and the need to account for the multiple factors that affect abortion safety. METHODS: We used all available empirical data on abortion methods, providers, and settings, and factors affecting safety as covariates within a Bayesian hierarchical model to estimate the global, regional, and subregional distributions of abortion by safety categories. We used a three-tiered categorisation based on the WHO definition of unsafe abortion and WHO guidelines on safe abortion to categorise abortions as safe or unsafe and to further divide unsafe abortions into two categories of less safe and least safe. FINDINGS: Of the 55·â€ˆ7 million abortions that occurred worldwide each year between 2010-14, we estimated that 30·6 million (54·9%, 90% uncertainty interval 49·9-59·4) were safe, 17·1 million (30·7%, 25·5-35·6) were less safe, and 8·0 million (14·4%, 11·5-18·1) were least safe. Thus, 25·1 million (45·1%, 40·6-50·1) abortions each year between 2010 and 2014 were unsafe, with 24·3 million (97%) of these in developing countries. The proportion of unsafe abortions was significantly higher in developing countries than developed countries (49·5% vs 12·5%). When grouped by the legal status of abortion, the proportion of unsafe abortions was significantly higher in countries with highly restrictive abortion laws than in those with less restrictive laws. INTERPRETATION: Increased efforts are needed, especially in developing countries, to ensure access to safe abortion. The paucity of empirical data is a limitation of these findings. Improved in-country data for health services and innovative research to address these gaps are needed to improve future estimates. FUNDING: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction; David and Lucile Packard Foundation; UK Aid from the UK Government; Dutch Ministry of Foreign Affairs; Norwegian Agency for Development Cooperation.