Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10-6), FHR-2 (p = 1.47 × 10-4), FHR-3 (p = 1.05 × 10-5) and FHR-4A (p = 1.22 × 10-2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10-17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10-3 and p = 2.81 × 10-6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10-16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.

Genetic sex determination in three closely related hydrothermal vent gastropods, including one species with intersex individuals.

Molluscs have undergone many transitions between separate sexes and hermaphroditism, which is of interest in studying the evolution of sex determination and differentiation. Here, we combined multi-locus genotypes obtained from restriction site-associated DNA (RAD) sequencing with anatomical observations of the gonads of three deep-sea hydrothermal vent gastropods of the genus Alviniconcha living in the southwest Pacific. We found that all three species (Alviniconcha boucheti, Alviniconcha strummeri, and Alviniconcha kojimai) share the same male-heterogametic XY sex-determination system but that the gonads of XX A. kojimai individuals are invaded by a variable proportion of male reproductive tissue. The identification of Y-specific RAD loci (found only in A. boucheti) and the phylogenetic analysis of three sex-linked loci shared by all species suggested that X-Y recombination has evolved differently within each species. This situation of three species showing variation in gonadal development around a common sex-determination system provides new insights into the reproductive mode of poorly known deep-sea species and opens up an opportunity to study the evolution of recombination suppression on sex chromosomes and its association with mixed or transitory sexual systems.

Peer Support for Chronic Pain in Online Health Communities: Quantitative Study on the Dynamics of Social Interactions in a Chronic Pain Forum.

BACKGROUND: Peer support for chronic pain is increasingly taking place on social media via social networking communities. Several theories on the development and maintenance of chronic pain highlight how rumination, catastrophizing, and negative social interactions can contribute to poor health outcomes. However, little is known regarding the role web-based health discussions play in the development of negative versus positive health attitudes relevant to chronic pain. OBJECTIVE: This study aims to investigate how participation in online peer-to-peer support communities influenced pain expressions by examining how the sentiment of user language evolved in response to peer interactions. METHODS: We collected the comment histories of 199 randomly sampled Reddit (Reddit, Inc) users who were active in a popular peer-to-peer chronic pain support community over 10 years. A total of 2 separate natural language processing methods were compared to calculate the sentiment of user comments on the forum (N=73,876). We then modeled the trajectories of users' language sentiment using mixed-effects growth curve modeling and measured the degree to which users affectively synchronized with their peers using bivariate wavelet analysis. RESULTS: In comparison to a shuffled baseline, we found evidence that users entrained their language sentiment to match the language of community members they interacted with (t198=4.02; P<.001; Cohen d=0.40). This synchrony was most apparent in low-frequency sentiment changes unfolding over hundreds of interactions as opposed to reactionary changes occurring from comment to comment (F2,198=17.70; P<.001). We also observed a significant trend in sentiment across all users (ß=-.02; P=.003), with users increasingly using more negative language as they continued to interact with the community. Notably, there was a significant interaction between affective synchrony and community tenure (ß=.02; P=.02), such that greater affective synchrony was associated with negative sentiment trajectories among short-term users and positive sentiment trajectories among long-term users. CONCLUSIONS: Our results are consistent with the social communication model of pain, which describes how social interactions can influence the expression of pain symptoms. The difference in long-term versus short-term affective synchrony observed between community members suggests a process of emotional coregulation and social learning. Participating in health discussions on Reddit appears to be associated with both negative and positive changes in sentiment depending on how individual users interacted with their peers. Thus, in addition to characterizing the sentiment dynamics existing within online chronic pain communities, our work provides insight into the potential benefits and drawbacks of relying on support communities organized on social media platforms.

Multidecadal mangrove forest change in Macajalar Bay, Northern Mindanao, Philippines (1950-2020) using remote sensing and geographic information systems.

The mangrove forest in Macajalar Bay is regarded as an important coastal ecosystem since it provides numerous ecosystem services. Despite their importance, the clearing of mangroves has been rampant and has reached critical rates. Addressing this problem and further advancing its conservation require accurate mangrove mapping. However, current spatial information related to mangroves is sparse and insufficient to understand the historical change dynamics. In this study, the synergy of 1950 vegetation maps and Landsat images was explored to provide multidecadal monitoring of mangrove forest change dynamics in Macajalar Bay, Philippines. Vegetation maps containing the 1950 mangrove extent and Landsat images were used as input data to monitor the rates of loss over 70 years. In 2020, the mangrove forest cover was estimated to be 201.73 ha, equivalent to only 61.99% of the 325.43 ha that was estimated in 1950. Between 1950 and 2020, net mangrove loss in Macajalar Bay totaled 324.29 ha. The highest clearing rates occurred between 1950 and 1990 when it recorded a total of 258.51 ha, averaging 6.46 ha/year. The original mangrove forest that existed in 1950 only represents 8.56% of the 2020 extent, suggesting that much of the old-growth mangrove had been cleared before 2000 and the existing mangrove forest is mainly composed of secondary mangrove forest stands. Across Macajalar Bay, intensified clearing that happened between 1950 and 1990 has been driven by large-scale aquaculture developments. Mangrove gains on the other hand were evident and have increased the total extent by 79.84 ha since 2000 as a result of several afforestation programs. However, approximately half of these gains that were observed since 2010 exhibited low canopy cover. As of writing, approximately 85% of the 2020 mangrove forest stands fall outside the 1950 original mangrove extent. Examining the viability of the original mangrove forest for mangrove reforestation together with promoting site-species matching, and biophysical assessment are necessary undertakings to advance current mangrove conservation initiatives in Macajalar Bay.

Childhood Lead Poisoning 1970-2022: Charting Progress and Needed Reforms.

CONTEXT: Childhood lead poisoning prevention in the United States was marked by a largely failed medical approach from 1971 to 1990; an emergent (but small) healthy housing primary prevention strategy from 1991 to 2015; and implementation of large-scale proven interventions since then. PROGRAM: Childhood Lead Poisoning Prevention & Healthy Housing. METHODS: Historic and recent health and housing data from the National Health and Nutrition Examination Survey (NHANES) and the American Healthy Homes Survey (AHHS) were retrieved to analyze trends and associated policy gaps. EVALUATION: Approximately 590 000 US children aged 1 through 5 years had elevated blood lead levels of 3.5 µg/dL and greater in 2016, and 4.3 million children resided in homes with lead paint in 2019. Despite large improvements, racial and other disparities remain stubbornly and statistically significant. The NHANES and the AHHS require larger sample sizes. The Centers for Disease Control and Prevention has not published children's blood lead surveillance and NHANES data in several years; the Department of Housing and Urban Development (HUD) has no analogous housing surveillance system; and the Environmental Protection Agency (EPA) and the Occupational Safety and Health Administration (OSHA) have not updated training, Superfund, and occupational standards in decades. DISCUSSION: The nation has been without a plan and an associated budget for more than 2 decades. Congress has not reformed the nation's main lead poisoning prevention laws in more than 30 years. Such reforms include stopping US companies from producing new residential lead paint in other countries; enabling the disclosure law to identify all residential lead hazards; closing loopholes in federally assisted housing regulations and mortgage insurance standards; harnessing tax policy to help homeowners mitigate lead hazards; streamlining training requirements; increasing the size of health and housing surveys and surveillance systems; and updating housing codes, medical guidance, dust lead standards, training, Superfund, and worker exposure limits. Congress and the president should reauthorize a cabinet-level task force (dormant since 2010) to develop a new strategic plan with an interagency budget to implement it. These reforms will scale and optimize markets, subsidies, enforcement, and other proven interventions to end ineffective, costly, harmful, and irrational cost shifting that threatens children, workers, and affordable housing.

STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD.

BACKGROUND: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD. METHODS: Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale. RESULTS: In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth. CONCLUSIONS: STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.

Validation and Update of the Lémann Index to Measure Cumulative Structural Bowel Damage in Crohn's Disease.

BACKGROUND & AIMS: The Lémann Index is a tool measuring cumulative structural bowel damage in Crohn's disease (CD). We reported on its validation and updating. METHODS: This was an international, multicenter, prospective, cross-sectional observational study. At each center, 10 inclusions, stratified by CD duration and location, were planned. For each patient, the digestive tract was divided into 4 organs, upper tract, small bowel, colon/rectum, anus, and subsequently into segments, explored systematically by magnetic resonance imaging and by endoscopies in relation to disease location. For each segment, investigators retrieved information on previous surgical procedures, identified predefined strictures and penetrating lesions of maximal severity (grades 1-3) at each organ investigational method (gastroenterologist and radiologist for magnetic resonance imaging), provided segmental damage evaluation ranging from 0.0 to 10.0 (complete resection). Organ resection-free cumulative damage evaluation was then calculated from the sum of segmental damages. Then investigators provided a 0-10 global damage evaluation from the 4-organ standardized cumulative damage evaluations. Simple linear regressions of investigator damage evaluations on their corresponding Lémann Index were studied, as well as calibration plots. Finally, updated Lémann Index was derived through multiple linear mixed models applied to combined development and validation samples. RESULTS: In 15 centers, 134 patients were included. Correlation coefficients between investigator damage evaluations and Lémann Indexes were >0.80. When analyzing data in 272 patients from both samples and 27 centers, the unbiased correlation estimates were 0.89, 0,97, 0,94, 0.81, and 0.91 for the 4 organs and globally, and stable when applied to one sample or the other. CONCLUSIONS: The updated Lémann Index is a well-established index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials.

Ethical and regulatory issues of stem cell-derived 3-dimensional organoid and tissue therapy for personalised regenerative medicine.

BACKGROUND: Regenerative medicine has the potential to treat genetic disorders and replace damaged or missing tissue. The use of donor or animal tissue raises many well-known issues, including limited tissue availability, the possibility of rejection and patient infection. Stem cell therapy raised hope of overcoming these issues, but created new risks including tumour formation and limited benefit if the desired target tissue does not form. The recent development of 3-dimensional tissues, including organoids, allows the creation of more complex tissues for personalised regenerative medicine. METHODS: This article details the potential health risks of 3-dimensional organoid and tissue therapy versus dissociated stem cell therapy. The current ethical and regulatory issues surrounding 3-dimensional organoid and tissue therapy are presented with a focus on the highly influential FDA and International Society of Stem Cell Research (ISSCR) guidelines. CONCLUSIONS: The potential use of 3-dimensional organoid and tissue therapy may deliver greater patient benefits than other regenerative medicine approaches, but raises new health and ethical risks. Preclinical testing of these therapies will not mitigate some of their risks; they may only be understood after first-in-human trials. The potential irreversibility and high risk of these therapies affects how clinical trials should be structured, including post-trial care for participants.

Proximal tubular dysfunction in pregnant women receiving tenofovir disoproxil fumarate to prevent mother-to-child transmission of hepatitis B virus.

BACKGROUND: Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of HBV are scarce. OBJECTIVES: To assess the risk of proximal tubulopathy in pregnant women receiving tenofovir disoproxil fumarate for PMTCT of HBV. PATIENTS AND METHODS: We used urine samples collected from HBV monoinfected pregnant women who participated in a Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trial assessing a tenofovir disoproxil fumarate short course from 28 weeks gestational age (28-wk-GA) to 2 months post-partum (2-months-PP) for PMTCT of HBV in Thailand. Markers of tubular dysfunction, including retinol binding protein, kidney injury molecule-1, α1-microglobuin and ß2-microglobulin, were assayed at 28- and 32-wk-GA and 2-months-PP visits. Proximal tubulopathy was defined as the presence of ≥2 of the following: tubular proteinuria, euglycaemic glycosuria and increased urinary phosphate. RESULTS: A total of 291 women participated in the study. No kidney-related adverse events were severe, and none led to tenofovir disoproxil fumarate discontinuation. At 2-months-PP, 3 of the 120 (3%) evaluated women in the tenofovir disoproxil fumarate group experienced proximal tubulopathy versus 3 of 125 (2%) in the placebo group (P = 1.00). None of the six women met the criteria for proximal tubulopathy at 12-months-PP but proteinuria persisted in three of them. No growth abnormalities were found at 1 year of age in infants born to mothers with proximal tubulopathy at 2-months-PP. CONCLUSIONS: In these HBV-infected pregnant and breastfeeding women, tenofovir disoproxil fumarate administered from 28-wk-GA to 2-months-PP was not associated with a higher risk of proximal tubulopathy.

Characterization of vitellogenin concentration in male fathead minnow mucus compared to plasma, and liver mRNA.

The objective of this study was to characterize vitellogenin (VTG) protein in male fathead minnow (Pimephales promelas) mucus compared with more conventional measures in plasma and mRNA isolated from liver. To assess the intensity and duration of changes in mucus VTG concentrations, male fathead minnows were exposed to 17α-ethinylestradiol (EE2) for 7 days with a subsequent depuration period of 14 days. The experiment was conducted in a flow-through system to maintain a consistent concentration of EE2 at a nominal EC50 concentration of 2.5 ng/L and high concentration of 10 ng/L as a positive control. Mucus, plasma and liver were sampled at regular intervals throughout the study. Relative abundance of vtg mRNA increased after 2 days of exposure and returned to control levels after 4 days of depuration. VTG protein concentration displayed similar induction kinetics in both mucus and plasma, however, it was found to be significantly increased after 2 days of exposure using the mucus-based assays and 7 days with the plasma-based assay. Significantly elevated levels of VTG were detected by both assays throughout the 14-day depuration period. The elimination of the laborious plasma collection step in the mucus-based workflow allowed sampling of smaller organisms where blood volume is limiting. It also resulted in significant gains in workflow efficiency, decreasing sampling time without loss of performance.