Comparison of Blood Concentration and Weight-Based Heparin and Protamine Dosing Strategies for Cardiopulmonary Bypass: A Systematic Review and Meta-Analysis.

BACKGROUND:  The conventional method of heparin and protamine management during cardiopulmonary bypass (CPB) is based on total body weight which fails to account for the heterogeneous response to heparin in each patient. On the other hand, the literature is inconclusive on whether individualized anticoagulation management based on real-time blood heparin concentration improves post-CBP outcomes. METHODS:  We searched databases of Medline, Excerpta Medica dataBASE (EMBASE), PubMed, Cumulative Index to Nursing and Allied Health Literature (CINHL), and Google Scholar, recruiting randomized controlled trials (RCTs) and prospective studies comparing the outcomes of dosing heparin and/or protamine based on measured heparin concentration versus patient's total body weight for CPB. Random effects meta-analyses and meta-regression were conducted to compare the outcome profiles. Primary endpoints include postoperative blood loss and the correlation with heparin and protamine doses, the reversal protamine and loading heparin dose ratio; secondary endpoints included postoperative platelet counts, antithrombin III, fibrinogen levels, activated prothrombin time (aPTT), incidences of heparin rebound, and re-exploration of chest wound for bleeding. RESULTS:  Twenty-six studies, including 22 RCTs and four prospective cohort studies involving 3,810 patients, were included. Compared to body weight-based dosing, patients of individualized, heparin concentration-based group had significantly lower postoperative blood loss (mean difference (MD)=49.51 mL, 95% confidence interval (CI): 5.33-93.71), lower protamine-to-heparin dosing ratio (MD=-0.20, 95% CI: -0.32 ~ -0.12), and higher early postoperative platelet counts (MD=8.83, 95% CI: 2.07-15.59). The total heparin doses and protamine reversal were identified as predictors of postoperative blood loss by meta-regression. CONCLUSIONS:  There was a significant correlation between the doses of heparin and protamine with postoperative blood loss; therefore, précised dosing of both could be critical for reducing bleeding and transfusion requirements. Data from the enrolled studies indicated that compared to conventional weight-based dosing, individualized, blood concentration-based heparin and protamine dosing may have outcome benefits reducing postoperative blood loss. The dosing calculation of heparin based on the assumption of a one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model and linear relationship between the calculated dose and blood heparin concentration may be inaccurate. With the recent advancement of the technologies of machine learning, individualized, precision management of anticoagulation for CPB may be possible in the near future.

A retrospective study of conjunctival lesions in the Paediatric Eye Clinic over 12 years.

BACKGROUND: Paediatric conjunctival lesions are rare and diverse. Though often indolent and asymptomatic, they can in some cases be sight or life-threatening. Awareness of concerning features of conjunctival lesions is key to optimal management. We aim to provide insight into management of paediatric conjunctival lesions though a review of cases in our service in last 12 years. METHODS: We present a retrospective analysis of our population-based cohort of children with conjunctival lesions presenting to our regional service in Belfast between 2011 and 2022 inclusive. We detail three rare cases of paediatric conjunctival lesions; a congenital intrascleral cyst leading to astigmatic amblyopia, a rapidly changing salmon-pink lesion confirmed as an embryonal rhabdomyosarcoma and an unusual presentation of a chronic granuloma arising from the caruncle. RESULTS: 85 conjunctival lesions were identified in <16 year olds giving a cumulative incidence of 27 cases per 100,000 population over 12 years. Mean age at presentation was 7 years old. Most common lesions were naevi (40%), limbal dermoids (21%), conjunctival melanosis (14%), conjunctival cysts (7%) and phlycten (6%). When seen at presentation 8% of cases were immediately listed for surgery, 28% were discharged and 64% entered a phase of observation. CONCLUSION: Paediatric conjunctival lesions have potential to cause visual manifestations, whilst some may undergo malignant transformation. Anterior segment photography is crucial in monitoring change and facilitating early discharge in the absence of sinister features. Malignant transformation must be considered in changing lesions which ought to have histological diagnosis obtained to prevent potentially sight and life-threatening conditions.

Healthcare utilization, costs, and epidemiology of Huntington's disease in Israel.

Introduction: Data on Huntington's disease (HD) epidemiology, treatment patterns, and economic burden in Israel are scarce. Methods: Annual prevalence and incidence of HD (ICD-9-CM 333.4) were assessed in the Israel-based Maccabi Healthcare Services (MHS) database 2016-2018. Adherence (medication possession rate [MPR], proportion of disease covered) were assessed for adult people with HD (PwHD) 2013-2018. Healthcare resources utilization (HCRU) and costs related to inpatient and outpatient visits and all medications in 2018 were assessed for PwHD, who were randomly matched to MHS members without HD (1:3) by birth-year and sex. Results: Overall, 164 patients had at least one HD diagnosis. Annual prevalence and incidence were 4.45 and 0.24/100,000, respectively. A total of 67.0% of adult patients (n = 106) were taking tetrabenazine (median MPR and proportion of disease covered, 74.3% and 30.2%, respectively), 65.1% benzodiazepines (75.8% and 32.3%), and 11.3% amantadine (79.2% and 6.0%). Over a 1-year follow-up, PwHD (n = 81) had significantly more neurologist, psychiatrist, physiotherapist, and speech therapist visits (P < 0.05 for each) and more hospitalization days (P < 0.0001) compared with matched controls (n = 243). Total healthcare and medication costs per patient (US dollars) were significantly higher for PwHD than controls ($7,343 vs. $3,625; P < 0.001). Discussion/Conclusion: PwHD have greater annual HCRU and medical costs than MHS members without HD in Israel. Among those who have taken medications, adherence was lower than 80% (both MPR and proportion of disease covered), which may translate into suboptimal symptom relief and quality of life.

Movement and population dispersal of dolphinfish (Coryphaena hippurus) across the Eastern Tropical Pacific inferred from carbon and nitrogen stable isotope analyses.

The dolphinfish (Coryphaena hippurus) is a globally distributed marine predator that supports one of the most important coastal fisheries along the Eastern Tropical Pacific (ETP), but its spatial movements in this area are poorly understood. Stable isotope values (δ13 C and δ15 N) of white muscle from dolphinfish (n = 220) captured at different locations across the ETP (i.e., Mexico, Costa Rica, Ecuador, Peru and oceanic areas) were normalized to copepod baseline stable isotope values to estimate dolphinfish trophic position, movements and population dispersal. Movement or residence patterns were inferred from the difference in δ15 N values (Δ15 Ndolphinfish-copepod ‰) between copepods and dolphinfish muscle. Baseline corrected isotope values (δ13 Cdolphinfish-copepod and δ15 Ndolphinfish-copepod ) of dolphinfish muscle were used to estimate isotopic niche metrics and infer population dispersal across isoscapes. Values of δ13 C and δ15 N differed between juvenile and adult dolphinfish and across the ETP. Trophic position estimates ranged from 3.1 to 6.0 with a mean of 4.6. Adults and juveniles had similar trophic position estimates, whereas isotopic niche areas (SEA ‰2 ) of adults were greater relative to juveniles in every location. Adult dolphinfish showed "moderate movement by some individuals" in all locations based on Δ15 Ndolphinfish-copepod values, except for Costa Rica where adults were classified with "high degree of movement by some individuals" whereas juveniles showed "limited movement" in all areas except Mexico. Population dispersal based on Δ15 Ndolphinfish-copepod values showed "moderate" and "high" dispersal for adults and "no dispersal" for most juveniles, except for Mexico. This study provides insight into potential dolphinfish spatial mobility across an area of interest for multiple nations, which can help to improve stock assessments and management of the species.

The Role of Suburbanization in Metropolitan Segregation After 1940.

The three decades from 1940 through 1970 mark a turning point in the spatial scale of Black-White residential segregation in the United States compared with earlier years. We decompose metropolitan segregation into three components: segregation within the city, within the suburbs, and between the city and its suburbs. We then show that extreme levels of segregation were well established in most cities by 1940, and they changed only modestly by 1970. In this period, changes in segregation were greater at the metropolitan scale, driven by racially selective population growth in the suburbs. We also examine major sources of rising segregation, including region, metropolitan total, and Black population sizes, and indicators of redlining in the central cities based on risk maps prepared by the Home Owners Loan Corporation (HOLC) in the late 1930s. In addition to overall regional differences, segregation between the city and suburbs and within suburbia increased more in metropolitan areas with larger Black populations, but this relationship was found only in the North. In contrast to some recent theorizing, there is no association between preparation of an HOLC risk map or the share of city neighborhoods that were redlined and subsequent change in any component of segregation.

The Clinical and Economic Burden of Tardive Dyskinesia in Israel: Real-World Data Analysis.

PURPOSE/BACKGROUND: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients. METHODS/PROCEDURES: This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed. FINDINGS/RESULTS: Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P < 0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018). IMPLICATIONS/CONCLUSIONS: Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.

Leclercia adecarboxylata catheter-related bacteraemia in an immunocompromised patient.

A 34-year-old man on active chemotherapy was hospitalised with fever, chills and rigours after power-washing a pig pen on a farm. His blood cultures grew Leclercia adecarboxylata, a gram-negative rod in the Enterobacteriaceae family, which has been isolated from a variety of environments including soil, surface water, as well as in the gastrointestinal flora of farm animals. The likely source of infection was his tunnelled central venous catheter exposed to water contaminated by faeces when he was washing the pig pen. While there have been several cases reported of catheter-related L. adecarboxylata bacteraemia, to our knowledge there are very few reports of infection spread in this manner.

Residential Segregation under Jim Crow: Whites, Blacks, and Mulattoes in Southern Cities, 1880-1920.

We study the residential patterns of blacks and mulattoes in 10 Southern cities in 1880 and 1920. researchers have documented the salience of social differences among African Americans in this period, partly related to mulattoes' higher occupational status. Did these differences result in clustering of these two groups in different neighborhoods, and were mulattoes less separated from whites? If so, did the differences diminish in these decades after reconstruction due a Jim Crow system that did not distinguish between blacks and mulattoes? We use geocoded census microdata for 1880 and 1920 to address these questions. Segregation between whites and both blacks and mulattoes was already high in 1880, especially at a fine spatial scale, and it increased sharply by 1920. In this respect, whites did not distinguish between these two groups. However, blacks and mulattoes were quite segregated from one another in 1880, and even more so by 1920. this pattern did not result from mulattoes' moderately higher-class position. Hence, as the color line between whites and all non-whites was becoming harder, blacks and mulattoes were separating further from each other. understanding what led to this pattern remains a key question about racial identities and racialization in the early twentieth century.

Toxic Relationships: The Experiences and Effects of Psychopathy in Romantic Relationships.

Limited research exists on the impact of psychopathy within romantic relationships. We examined mental and physical health consequences reported by intimate partners of individuals with psychopathic traits. Additionally, we explored whether psychopathy severity and coping impacted the severity of posttraumatic stress disorder and depression symptoms. Four hundred fifty-seven former and current intimate partners of individuals with psychopathic traits were recruited from online support groups. Victims reported a variety of abusive experiences and various negative symptomatology involving emotional, biological, behavioral, cognitive, and interpersonal consequences. Psychopathy severity and maladaptive coping were significantly related to increased PTSD and depression, while adaptive coping was only related to decreased depression. Regression analyses revealed that experiencing many forms of victimization predicted increased PTSD and depression symptoms. Examining the specific consequences experienced by intimate partners of individuals with psychopathic traits can aid the development of individualized treatment interventions aimed at symptom mitigation, recovery, and prevention of future victimization.

Improving Estimates of Neighborhood Change with Constant Tract Boundaries.

Social scientists routinely rely on methods of interpolation to adjust available data to their research needs. Spatial data from different sources often are based on different geographies that need to be reconciled, and some boundaries (e.g., administrative or political boundaries) change frequently. This study calls attention to the potential for substantial error in efforts to harmonize data to constant boundaries using standard approaches to areal and population interpolation. The case in point is census tract boundaries in the United States, which are redefined before every decennial census. Research on neighborhood effects and neighborhood change rely heavily on estimates of local area characteristics for a consistent area of time, for which they now routinely use estimates based on interpolation offered by sources such as the Neighborhood Change Data Base (NCDB) and Longitudinal Tract Data Base (LTDB). We identify a fundamental problem with how these estimates are created, and we reveal an alarming level of error in estimates of population characteristics in 2000 within 2010 boundaries. We do this by comparing estimates from one of these sources (the LTDB) to true values calculated by re-aggregating original 2000 census microdata to 2010 tract areas. We then demonstrate an alternative approach that allows the re-aggregated values to be publicly disclosed, using "differential privacy" (DP) methods to inject random noise that meets Census Bureau standards for protecting confidentiality of the raw data. We show that the DP estimates are considerably more accurate than the LTDB estimates based on interpolation, and we examine conditions under which interpolation is more susceptible to error. This study reveals cause for greater caution in the use of interpolated estimates from any source. Until and unless DP estimates can be publicly disclosed for a wide range of variables and years, research on neighborhood change should routinely examine data for signs of estimation error that may be substantial in a large share of tracts that experienced complex boundary changes.

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

Broadbill swordfish (Xiphias gladius) foraging and vertical movements in the north-west Atlantic.

The northern edge of Georges Bank is an important seasonal foraging habitat for swordfish (Xiphias gladius) in the North Atlantic, where aggregations support commercial pelagic longline and harpoon fisheries. Following a period of overfishing during the 1990s, the North Atlantic X. gladius stock underwent a period of recovery during the early 2000s and was considered rebuilt in 2009. We analysed stomach contents from X. gladius (n = 39) harvested by the Canadian harpoon fishery on Georges Bank in 2007 to characterize diet in this important foraging habitat. We used electronic tagging data from X. gladius (n = 6) on Georges Bank in 2005-2007 to assess vertical habitat preferences and associated prey composition within those zones. We also used stable isotope analysis (δ13 C and δ15 N) of X. gladius liver (n = 2) and common prey types (Paralepididae, Myctophidae, Merluccidae, Ommastrephidae) as a longer-term record of feeding. Stomach contents were co-dominated by Paralepididae [31.9% weight (W)] and Ommastrephidae (36.8%W) with secondary contributions from hake (Merluccidae, 6.5%W), Myctophidae (2.9%W) and Sebastidae (2.1%W). X. gladius displayed diel vertical migrations, descending to depths of 300-400 m during daytime followed by residence in surface waters at night. X. gladius liver δ15 N values were similar to or lower than values of primary stomach contents, likely due to bias of diet consumed in southerly waters with lower nitrogen isotope baselines prior to arrival on Georges Bank. Diet data are similar to results from historical studies from the late 1950s to the early 1980s. This apparent temporal stability to the underlying food web in this region may explain the high X. gladius site fidelity observed in electronic tagging studies and the consistent aggregation of these fish to this region.

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.

Accelerating functional gene discovery in osteoarthritis.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.

Global data set for nitrogen and carbon stable isotopes of tunas.

Nitrogen and carbon stable isotope data sets are commonly used to assess complex population to ecosystem responses to natural or anthropogenic changes at regional to global spatial scales, and monthly to decadal timescales. Measured in the tissues of consumers, nitrogen isotopes (δ15 N) are primarily used to estimate trophic position while carbon isotopes (δ13 C) describe habitat associations and feeding pathways. Models of both δ15 N and δ13 C values and their associated variance can be used to estimate likely dietary contributions and niche width and provide inferences about consumer movement and migration. Stable isotope data have added utility when used in combination with other empirical data sets (e.g., stomach content, movement tracking, bioregionalization, contaminant, or fisheries data) and are increasingly relied upon in food web and ecosystem models. While numerous regional studies publish tables of mean δ15 N and δ13 C values, limited individual records have been made available for wider use. Such a deficiency has impeded full utility of the data, which otherwise would facilitate identification of macroscale patterns. The data provided here consist of 4,498 records of individuals of three tuna species, Thunnus alalunga, T. obesus, and T. albacares sampled from all major ocean basins from 2000 to 2015. For each individual tuna, we provide a record of the following: species name, sampling date, sampling location, tuna length, muscle bulk and baseline corrected δ15 N values, and muscle bulk and, where available, lipid corrected δ13 C values. We provide these individual records to support comparative studies and more robust modeling projects seeking to improve understanding of complex marine ecosystem dynamics and their responses to a changing environment. There are no copyright restrictions for research and/or teaching purposes. Users are requested to acknowledge their use of the data in publications, research proposals, websites, and other outlets following the citation instructions in Class III, Section B.

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.