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Life cycles with a prolonged haploid phase are thought to be correlated with greater rates of selfing and asexual reproduction. In red algae, recent population genetic studies have aimed to test this prediction but have mostly focused on marine species with separate sexes. We characterized the reproductive system of the obligately monoicous (i.e., hermaphroditic) freshwater red alga Batrachospermum gelatinosum and predicted that we would find genetic signatures of uniparental reproduction because of its haploid‐diploid life cycle. We sampled 18 sites and genotyped 311 gametophytes with 10 polymorphic microsatellite loci to describe the reproductive system. Genotypic richness was low (<0.5) and pareto β values (describing clonal membership) were <0.7 for most sites. In taxa with separate sexes, these patterns are typically indicative of asexual reproduction. However, the genetic consequences of selfing in monoicous gametophytes are indistinguishable from those caused by asexual processes. Since we sampled gametophytes and have not yet genotyped the chantransia (i.e., the diploid phase), we interpreted low diversity as a signature of intragametophytic selfing. Additionally, to understand the factors that drive selfing, we tested latitude and several other environmental variables, but none was significantly correlated with the genetic variation we observed. Nevertheless, future studies should genotype the chantransia to measure observed heterozygosity among other summary statistics to disentangle the effects of selfing versus asexual reproduction. Together, these data, coupled with further characterization of abiotic factors that influence population genetic patterns, will allow us to test potential drivers of reproductive system evolution. [ABSTRACT FROM AUTHOR]

The freshwater red alga Batrachospermum gelatinosum has a well‐documented distribution spanning historically glaciated and unglaciated eastern North America. This alga has no known desiccation‐resistant propagule; thus, long‐distance dispersal events are likely rare. We predicted strong genetic structure among drainage basins and admixture among sites within basins. We predicted greater genetic diversity at lower latitude sites because they likely serve as refugia and the origin of northward, post‐Pleistocene range expansion. We used 10 microsatellite loci to investigate genetic diversity from 311 gametophytes from 18 sites in five major drainage basins: South Atlantic Gulf, Mid‐Atlantic, Ohio River, Great Lakes, and Northeast. Our data showed strong genetic partitioning among drainage basins and among sites within basins, yet no isolation by distance was detected. Genetic diversity varied widely among sites and was not strictly related to latitude as predicted. The results from B. gelatinosum provide strong support that each stream site contributes to the unique genetic variation within the species, potentially due to limited dispersal and the prevailing reproductive mode of intragametophytic selfing. Simulations of migration suggested post‐Pleistocene dispersal from the Mid‐Atlantic. Batrachospermum gelatinosum potentially persisted in refugia that were just south of the ice margins rather than in the southernmost part of its range. Research of other taxa with similar ranges could determine whether these results are generally applicable for freshwater red algae. Nevertheless, these results from B. gelatinosum add to the growing literature focused on the patterns and genetic consequences of post‐Pleistocene range expansion by eastern North American biota. [ABSTRACT FROM AUTHOR]

This paper empirically tests the Decision-Making Ecology (DME) framework to explore which characteristics of child maltreatment cases are most influential in the decision to refer children to services. We used latent profile analysis (LPA) to identify latent groups of child welfare organizations based on their climate and culture. We then use logistic regression models to determine whether organizational, external, case, and caseworker characteristics were predictive of children’s service referrals. Our findings revealed that organizational characteristics were a significant predictor of service referrals, as well as caseworker and external characteristics. These results support the DME framework in understanding service referral decisions. [ABSTRACT FROM AUTHOR]

We examine the association of structured and unstructured extracurricular activities on academic achievement for youth with a history of child welfare system involvement. Using longitudinal data from the National Survey of Child and Adolescent Well-being II (NSCAW II) and fixed effects ordinary least squares regression models we examine this association for 905 youth aged 11–17 years old. We find that even moderate levels of participation in structured extracurricular activities are associated with improvements in both math and reading achievement. Specifically, moving from non-participation to involvement in structured activities leads to a 4.46-point increase in applied problem solving and a 2.99-point increase in letter-word identification scores, net of the other controls. These findings suggest that children and youth with child welfare system involvement can benefit from participation in structured activities. This finding is significant in light of federal policy recognizing the importance of "normalizing" activities that enhance the well-being of children and youth in the child welfare system. [ABSTRACT FROM AUTHOR]

Haploid-diploid life cycles impose unique eco-evolutionary consequences, rendering commonly used proxies difficult to use (e.g. separate sexes prevent selfing). Population genetic analyses are therefore required to explore patterns of reproductive system variation. However, there are still few haploiddiploid species for which polymorphic, nuclear loci exist. This problem is particularly acute for algae. Here, we describe the development of the first microsatellite loci in a freshwater red alga. We tested 73 candidate loci against a panel of Batrachospermum gelatinosum (L.) De Candolle gametophytes that encompass much of its North American range. Ten loci consistently amplified and were characterized by clean peak architectures on a capillary sequencer with one allele per locus, as expected in a haploid gametophyte. We then explored some basic population genetic indices in gametophytes collected from one site and obtained good resolution based on the probability of identity (pid). Yet, we observed a pattern of clumped repeated genotypes throughout the stream reach sampled. The pattern of moderate genotypic richness could be due to intragametophytic selfing resulting in the complete loss of genetic diversity from a single gamete union. Future studies will need to sample more populations to determine if intragametophytic selfing is the dominant reproductive mode in this monoicous taxon. The loci developed here represent an important tool for studying freshwater red algal populations in specific as well as enhancing our understanding of reproductive system variation and the haploid-diploid life cycle of algae in general. [ABSTRACT FROM AUTHOR]

The relative frequency of sexual versus asexual reproduction governs the distribution of genetic diversity within and among populations. Most studies on the consequences of reproductive variation focus on the mating system (i.e., selfing vs. outcrossing) of diploid‐dominant taxa (e.g., angiosperms), often ignoring asexual reproduction. Although reproductive systems are hypothesized to be correlated with life‐cycle types, variation in the relative rates of sexual and asexual reproduction remains poorly characterized across eukaryotes. This is particularly true among the three major lineages of macroalgae (green, brown, and red). The Rhodophyta are particularly interesting, as many taxa have complex haploid–diploid life cycles that influence genetic structure. Though most marine reds have separate sexes, we show that freshwater red macroalgae exhibit patterns of switching between monoicy and dioicy in sister taxa that rival those recently shown in brown macroalgae and in angiosperms. We advocate for the investigation of reproductive system evolution using freshwater reds, as this will expand the life‐cycle types for which these data exist, enabling comparative analyses broadly across eukaryotes. Unlike their marine cousins, species in the Batrachospermales have macroscopic gametophytes attached to filamentous, often microscopic sporophytes. While asexual reproduction through monospores may occur in all freshwater reds, the Compsopogonales are thought to be exclusively asexual. Understanding the evolutionary consequences of selfing and asexual reproduction will aid in our understanding of the evolutionary ecology of all algae and of eukaryotic evolution generally. [ABSTRACT FROM AUTHOR]

This review paper summarizes the epidemiology of hepatitis C virus (HCV) and chronic HCV infection, including HCV virology and treatment regimens. Specifically, we focus on the evolution of past, current, and future HCV treatment options, the reasons for treatment failure, and the impact of resistance-associated variants on treatment success. [ABSTRACT FROM AUTHOR]

Combination of dietary/herbal spice curcumin (Cur) and COX inhibitors has been tested for improving therapeutic efficacy in pancreatic cancer (PC). The objective of this study was to identify agent with low toxicity and COX-independent mechanism to induce PC cell growth inhibition when used along with Cur. Anticancer NSAID, tolfenamic acid (TA) and Cur combination were evaluated using PC cell lines. L3.6pl and MIA PaCa-2 cells were treated with Cur (5-25μM) or TA (25-100μM) or combination of Cur (7.5μM) and TA (50μM). Cell viability was measured at 24-72h posttreatment using CellTiter-Glo kit. While both agents showed a steady/consistent effect, Cur+TA caused higher growth inhibition. Antiproliferative effect was compared with COX inhibitors, Ibuprofen and Celebrex. Cardiotoxicity was assessed using cordiomyocytes (H9C2). The expression of Sp proteins, survivin and apoptotic markers (western blot), caspase 3/7 (caspase-Glo kit), Annexin-V staining (flow cytometry), reactive oxygen species (ROS) and cell cycle phase distribution (flow cytometry) was measured. Cells were treated with TNF-α, and NF-kB translocation from cytoplasm to nucleus was evaluated (immunofluorescence). When compared to individual agents, combination of Cur+TA caused significant increase in apoptotic markers, ROS levels and inhibited NF-kB translocation to nucleus. TA caused cell cycle arrest in G0/G1, and the combination treatment showed mostly DNA synthesis phase arrest. These results suggest that combination of Cur+TA is less toxic and effectively enhance the therapeutic efficacy in PC cells via COX-independent mechanisms. [ABSTRACT FROM AUTHOR]

Rebound of SARS-CoV-2 shedding or COVID-19 signs and symptoms has been described after treatment with nirmatrelvir/ritonavir (Paxlovid). The direct association of nirmatrelvir/ritonavir to COVID-19 rebound remains unclear because most reports are based on individual cases or nonrandomized studies. Viral RNA shedding data from two phase 2/3, randomized, doubleblind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR] and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients [EPIC-SR]) were analyzed to investigate the role of nirmatrelvir/ritonavir treatment in COVID-19 rebound. Rates of rebound of SARS-CoV-2 RNA shedding, identified based on an increase in nasopharyngeal viral RNA levels from day 5 (end-of-treatment) to day 10 or day 14, were similar between nirmatrelvir/ritonavir and placebo recipients. Among subjects with a virologic response through day 5, viral RNA rebound occurred in 6.4%-8.4% of nirmatrelvir/ritonavir recipients and 5.9%-6.5% of placebo recipients across EPIC-HR and the 2021/pre-Omicron and 2022/Omicron enrollment periods of EPIC-SR. Viral RNA rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19-related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration's determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19. [ABSTRACT FROM AUTHOR]

In clinical trials of interferon-free, direct-acting antiviral treatment of chronic hepatitis C, subjects who received ribavirin had reduced lymphocyte levels (median decline of approximately 0.4-0.5 × 109 cells/L). A modest decline in CD4+ T cells was observed in subjects with human immunodeficiency virus type 1 coinfection without documented opportunistic infections. [ABSTRACT FROM AUTHOR]

Background/Aims: The small molecule, Tolfenamic acid (TA) has shown anti-cancer activity in pre-clinical models and is currently in Phase I clinical trials at MD Anderson Cancer Center Orlando. Since specificity and toxicity are major concerns for investigational agents, we tested the effect of TA on specific targets, and assessed the cellular and organismal toxicity representing pre-clinical studies in cancer. Methods: Panc1, L3.6pl, and MiaPaCa-2 (pancreatic cancer), hTERT-HPNE(normal), and differentiated/un-differentiated SH-SY5Y (neuroblastoma) cells were treated with increasing concentrations of TA. Cell viability and effect on specific molecular targets, Sp1 and survivin were determined. Athymic nude mice were treated with vehicle or TA (50mg/kg, 3times/week for 6 weeks) and alterations in the growth pattern, hematocrit, and histopathology of gut, liver, and stomach were monitored. Results: TA treatment decreased cell proliferation and inhibited the expression of Sp1 and survivin in cancer cells while only subtle response was observed in normal (hTERT-HPNE) and differentiated SH-SY5Y cells. Mice studies revealed no effect on body weight and hematocrit. Furthermore, TA regimen did not cause signs of internal-bleeding or damage to vital tissues in mice. Conclusion: These results demonstrate that TA selectively inhibits malignant cell growth acting on specific targets and its chronic treatment did not cause apparent toxicity in nude mice. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: We aimed to describe the characteristics and outcomes of adults admitted to hospital with suspected COVID-19 according to their DNACPR decisions, and identify factors associated with DNACPR decisions.Methods: We undertook a secondary analysis of 13,977 adults admitted to hospital with suspected COVID-19 and included in the Pandemic Respiratory Infection Emergency System Triage (PRIEST) study. We recorded presenting characteristics and outcomes (death or organ support) up to 30 days. We categorised patients as early DNACPR (before or on the day of admission) or late/no DNACPR (no DNACPR or occurring after the day of admission). We undertook descriptive analysis comparing these groups and multivariable analysis to identify independent predictors of early DNACPR.Results: We excluded 1249 with missing DNACPR data, and identified 3929/12748 (31%) with an early DNACPR decision. They had higher mortality (40.7% v 13.1%) and lower use of any organ support (11.6% v 15.7%), but received a range of organ support interventions, with some being used at rates comparable to those with late or no DNACPR (e.g. non-invasive ventilation 4.4% v 3.5%). On multivariable analysis, older age (p < 0.001), active malignancy (p < 0.001), chronic lung disease (p < 0.001), limited performance status (p < 0.001), and abnormal physiological variables were associated with increased recording of early DNACPR. Asian ethnicity was associated with reduced recording of early DNACPR (p = 0.001).Conclusions: Early DNACPR decisions were associated with recognised predictors of adverse outcome, and were inversely associated with Asian ethnicity. Most people with an early DNACPR decision survived to 30 days and many received potentially life-saving interventions.Registration: ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to derive and validate a triage tool, based on clinical assessment alone, for predicting adverse outcome in acutely ill adults with suspected COVID-19 infection. Methods: We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. The primary outcome was death or organ support (respiratory, cardiovascular, or renal) by record review at 30 days. We split the cohort into derivation and validation sets, developed a clinical score based on the coefficients from multivariable analysis using the derivation set, and the estimated discriminant performance using the validation set. Results: We analysed 11773 derivation and 9118 validation cases. Multivariable analysis identified that age, sex, respiratory rate, systolic blood pressure, oxygen saturation/inspired oxygen ratio, performance status, consciousness, history of renal impairment, and respiratory distress were retained in analyses restricted to the ten or fewer predictors. We used findings from multivariable analysis and clinical judgement to develop a score based on the NEWS2 score, age, sex, and performance status. This had a c-statistic of 0.80 (95% confidence interval 0.79–0.81) in the validation cohort and predicted adverse outcome with sensitivity 0.98 (0.97–0.98) and specificity 0.34 (0.34–0.35) for scores above four points. Conclusion: A clinical score based on NEWS2, age, sex, and performance status predicts adverse outcome with good discrimination in adults with suspected COVID-19 and can be used to support decision-making in emergency care. Registration: ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533 [ABSTRACT FROM AUTHOR]

Background: Hospital emergency departments play a crucial role in the initial assessment and management of suspected COVID-19 infection. This needs to be guided by studies of people presenting with suspected COVID-19, including those admitted and discharged, and those who do not ultimately have COVID-19 confirmed. We aimed to characterise patients attending emergency departments with suspected COVID-19, including subgroups based on sex, ethnicity and COVID-19 test results. Methods and findings: We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. Outcomes were admission to hospital, COVID-19 result, organ support (respiratory, cardiovascular or renal), and death, by record review at 30 days. Mean age was 58.4 years, 11200 (50.4%) were female and 11034 (49.6%) male. Adults (age >16 years) were acutely unwell (median NEWS2 score of 4), frequently had limited performance status (46.9%) and had high rates of admission (67.1%), COVID-19 positivity (31.2%), organ support (9.8%) and death (15.5%). Children had much lower rates of admission (27.4%), COVID-19 positivity (1.2%), organ support (1.4%) and death (0.3%). Similar numbers of men and women presented to the ED, but men were more likely to be admitted (72.9% v 61.4%), require organ support (12.2% v 7.7%) and die (18.2% v 13.0%). Black or Asian adults tended to be younger than White adults (median age 54, 50 and 67 years), were less likely to have impaired performance status (43.1%, 26.8% and 51.6%), be admitted to hospital (60.8%, 57.3%, 69.6%) or die (11.6%, 11.2%, 16.4%), but were more likely to require organ support (15.9%, 14.3%, 8.9%) or have a positive COVID-19 test (40.8%, 42.1%, 30.0%). Adults admitted with suspected and confirmed COVID-19 had similar age, performance status and comorbidities (except chronic lung disease) to those who did not have COVID-19 confirmed, but were much more likely to need organ support (22.2% v 8.9%) or die (32.1% v 15.5%). Conclusions: Important differences exist between patient groups presenting to the emergency department with suspected COVID-19. Adults and children differ markedly and require different approaches to emergency triage. Admission and adverse outcome rates among adults suggest that policies to avoid unnecessary ED attendance achieved their aim. Subsequent COVID-19 confirmation confers a worse prognosis and greater need for organ support. Registration: ISRCTN registry, ISRCTN56149622, http://www.isrctn.com/ISRCTN28342533. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Marked decrease in lymphocyte count in HIV/hepatitis C virus (HCV)-coinfected patients with advanced liver disease during anti-HCV treatment with direct-acting antiviral regimens including ribavirin," by M. Merli and colleagues in the 2016 issue.

Background: Intravenous iron therapy is a treatment option for iron deficient patients who are intolerant to oral iron or where oral iron is ineffective, but with possible adverse effects. Currently, prospective studies comparing different intravenous iron formulations are needed to determine safety and efficacy of these agents. Methods: We conducted a prospective, double-blind, randomized controlled trial (RCT) to assess the feasibility of a trial comparing the safety of high molecular weight intravenous iron dextran, Infufer®, with intravenous iron sucrose, Venofer®, in non-hemodialysis adult outpatients. Primary outcome was the occurrence of immediate severe drug reactions. Results: We enrolled 143 patients in a one-year period. Overall, 45/143 (31.5%) patients (20 iron dextran, 25 iron sucrose) developed 48 infusion reactions (14 immediate, 28 delayed, and 3 both). The risk of an immediate reaction was similar in both groups, 9/73 (12.3%) iron dextran versus 8/70 (11.4%) iron sucrose, RR = 0.93 (95% CI; 0.38 to 2.27). The risk of a delayed reaction was significantly higher in the iron sucrose group 22/70 (31.4%) versus the iron dextran group 9/73 (12.3%), RR = 2.55 (95% CI; 1.26 to 5.15; p = 0.0078). Conclusion: In this limited feasibility study, no major differences in immediate reactions were seen, but a significantly higher number of delayed reactions were seen in the iron sucrose group. Further, under our assumptions and design a full RCT to evaluate the safety of different intravenous iron preparations is not feasible. Future studies should consider modifying the clinical outcomes, utilize multiple centers, and consider other emerging parenteral iron formulations. [ABSTRACT FROM AUTHOR]

The article reports on the development of a list of Child-Pugh dosing recommendations to aid clinicians in making appropriate dosage adjustments for patients with hepatic dysfunction. The medications requiring dosing adjustments based on Child-Pugh scores, include abacavir, amprenavir, anagrelide, atazanavir, atomoxetine, caspofungin,and darifenacin.