Report from the pandemic influenza project: expert panel meetings

This report was prepared by the Indiana University Center for Bioethics under contract with the Indiana State Department of Health as a part of the project “Translating Ethics Advice into Practice: Public and Professional Outreach about Pandemic Influenza Planning in Indiana.” The views expressed in this document are those of the authors and may not necessarily reflect the opinions of the Center for Bioethics, Indiana University, or the Indiana State Department of Health.The Indiana University Center for Bioethics convened expert panels for each of the four topics of the Technical Advisory Documents (TADs): altered standards of care, triage, vaccine and antiviral allocation, and healthcare workforce management. The goal of each meeting was to assess the relevance and applicability of the recommendations put forth by the TADs. Participants were encouraged to apply the seven ethical points and assess the feasibility of the recommendations by examining case studies intended to portray real world ethical dilemmas. Engagement from the public was critical for each panel to learn the full ethical and social implications of pandemic influenza preparedness and planning.Indiana University Center for Bioethics; Indiana State Department of Healt

Holes in the walls: primordial black holes as a solution to the cosmological domain wall problem

We propose a scenario in which the cosmological domain wall and monopole problems are solved without any fine tuning of the initial conditions or parameters in the Lagrangian of an underlying filed theory. In this scenario domain walls sweep out (unwind) the monopoles from the early universe, then the fast primordial black holes perforate the domain walls, change their topology and destroy them. We find further that the (old vacuum) energy density released from the domain walls could alleviate but not solve the cosmological flatness problem.Comment: References added; Published in Phys. Rev.

Role of the gerP Operon in Germination and Outgrowth of Bacillus anthracis Spores

Germination of Bacillus anthracis spores occurs when nutrients such as amino acids or purine nucleosides stimulate specific germinant receptors located in the spore inner membrane. The gerPABCDEF operon has been suggested to play a role in facilitating the interaction between germinants and their receptors in spores of Bacillus subtilis and Bacillus cereus. B. anthracis mutants containing deletions in each of the six genes belonging to the orthologue of the gerPABCDEF operon, or deletion of the entire operon, were tested for their ability to germinate. Deletion of the entire gerP operon resulted in a significant delay in germination in response to nutrient germinants. These spores eventually germinated to levels equivalent to wild-type, suggesting that an additional entry point for nutrient germinants may exist. Deletions of each individual gene resulted in a similar phenotype, with the exception of ΔgerPF, which showed no obvious defect. The removal of two additional gerPF-like orthologues was necessary to achieve the germination defect observed for the other mutants. Upon physical removal of the spore coat, the mutant lacking the full gerP operon no longer exhibited a germination defect, suggesting that the GerP proteins play a role in spore coat permeability. Additionally, each of the gerP mutants exhibited a severe defect in calcium-dipicolinic acid (Ca-DPA)–dependent germination, suggesting a role for the GerP proteins in this process. Collectively, these data implicate all GerP proteins in the early stages of spore germination

QUALITY CONTROL FROM A SUBSET OF HUMAN SURGICAL TISSUE SPECIMENS FROM THE IU SIMON CANCER CENTER TISSUE PROCUREMENT AND DISTRIBUTION CORE COLLECTED IN 2009-2010: AN H&E AND RIN VALUE ASSESSMENT

poster abstractQuality control (QC) of human tissue specimens for research is critical for the development of new bio-markers and their ability to determine clinical trial outcomes. In this study, we evaluated sixty-nine samples for both RNA and histology quality control measures from the IU Simon Cancer Center Tissue Bank. The IU Simon Cancer Center Tissue Bank is a centralized tissue procurement resource established to collect high quality tissue for basic clinical and translational research, collecting approximately 550 clinical cases per year using an informed consent and HIPAA signed document. All tissues are collected and processed in liquid nitrogen within 30 minutes of removal. The tissue samples are sliced and diced into 100 to 150 mg sample size. Each sample is placed into individual 2ml cryovials. Two representative samples are placed in 10% neutral buffered formalin. Two investigators QC the slides by microscopy to evaluate the following: percent of tumor, percent of necrosis, percent of fibrosis/inflammation, and percent of normal adjacent tissue. RNA was extracted using the Purescript RNA isolation kit (Gentra). Fifty-four of sixty-nine cases passed both histology and RNA (RIN value) QC. Of the fifteen cases that did not pass our QC criteria, thirteen cases did not pass the histology QC due to lack of tumor content (below 50%) in the sample, while the remaining two cases failed the RNA QC. Seventy-eight percent of samples passed our QC measures. The results were consistent with the existing literature on tissue quality control in human surgical tissue specimens

Low Bone Mineral Density, Renal Dysfunction, and Fracture Risk in HIV Infection: A Cross-Sectional Study

BackgroundReduced bone mineral density (BMD) is common in adults infected with human immunodeficiency virus (HIV). The role of proximal renal tubular dysfunction (PRTD) and alterations in bone metabolism in HIV-related low BMD are incompletely understood MethodsWe quantified BMD (dual-energy x-ray absorptiometry), blood and urinary markers of bone metabolism and renal function, and risk factors for low BMD (hip or spine T score, −1 or less) in an ambulatory care setting. We determined factors associated with low BMD and calculated 10-year fracture risks using the World Health Organization FRAX equation ResultsWe studied 153 adults (98% men; median age, 48 years; median body mass index, 24.5; 67 [44%] were receiving tenofovir, 81 [53%] were receiving a boosted protease inhibitor [PI]). Sixty-five participants (42%) had low BMD, and 11 (7%) had PRTD. PI therapy was associated with low BMD in multivariable analysis (odds ratio, 2.69; 95% confidence interval, 1.09-6.63). Tenofovir use was associated with increased osteoblast and osteoclast activity (P⩽.002). The mean estimated 10-year risks were 1.2% for hip fracture and 5.4% for any major osteoporotic fracture ConclusionsIn this mostly male population, low BMD was significantly associated with PI therapy. Tenofovir recipients showed evidence of increased bone turnover. Measurement of BMD and estimation of fracture risk may be warranted in treated HIV-infected adult

Growth of structure seeded by primordial black holes

We discuss the possibilities for primordial black holes (PBHs) to grow via the accretion of dark matter. In agreement with previous works, we find that accretion during the radiation-dominated era does not lead to a significant mass increase. However, during matter-domination, PBHs may grow by up to two orders of magnitude in mass through the acquisition of large dark matter halos. We discuss the possibility of PBHs being an important component in dark matter halos of galaxies as well as their potential to explain the ultra-luminous x-ray sources (ULXs) observed in nearby galactic disks. We point out that although PBHs are ruled out as the dominant component of dark matter, there is still a great deal of parameter space open to them playing a role in the modern-day universe. For example, a primordial halo population of PBHs each at $10^{2.5} M_\odot$ making up 0.1% of the dark matter grow to $10^{4.5} M_\odot$ via the accumulation of dark matter halos to account for $\sim 10$ of the dark matter mass by a redshift of $z \approx 30$. These intermediate mass black holes may then ``light up'' when passing through molecular clouds, becoming visible as ULXs at the present day, or they may form the seeds for supermassive black holes at the centers of galaxies.Comment: 10 pages, 5 figures. Submitted to Ap

Anomalous metamagnetism in the low carrier density Kondo lattice YbRh3Si7

We report complex metamagnetic transitions in single crystals of the new low carrier Kondo antiferromagnet YbRh3Si7. Electrical transport, magnetization, and specific heat measurements reveal antiferromagnetic order at T_N = 7.5 K. Neutron diffraction measurements show that the magnetic ground state of YbRh3Si7 is a collinear antiferromagnet where the moments are aligned in the ab plane. With such an ordered state, no metamagnetic transitions are expected when a magnetic field is applied along the c axis. It is therefore surprising that high field magnetization, torque, and resistivity measurements with H||c reveal two metamagnetic transitions at mu_0H_1 = 6.7 T and mu_0H_2 = 21 T. When the field is tilted away from the c axis, towards the ab plane, both metamagnetic transitions are shifted to higher fields. The first metamagnetic transition leads to an abrupt increase in the electrical resistivity, while the second transition is accompanied by a dramatic reduction in the electrical resistivity. Thus, the magnetic and electronic degrees of freedom in YbRh3Si7 are strongly coupled. We discuss the origin of the anomalous metamagnetism and conclude that it is related to competition between crystal electric field anisotropy and anisotropic exchange interactions.Comment: 23 pages and 4 figures in the main text. 7 pages and 5 figures in the supplementary materia

Cohort Profile: The United Kingdom Research study into Ethnicity and COVID-19 outcomes in Healthcare workers (UK-REACH)

The UK-REACH cohort was established to understand why ethnic minority healthcare workers (HCWs) are at risk of poorer outcomes from COVID-19 when compared with their White ethnic counterparts in the UK. Through study design, it contains a uniquely high percentage of participants from ethnic minority backgrounds about whom a wide range of qualitative and quantitative data have been collected. A total of 17 891 HCWs aged 16–89 years (mean age: 44) have been recruited from across the UK via all major healthcare regulators, individual National Health Service hospital trusts and UK HCW membership bodies who advertised the study to their registrants/staff to encourage participation in the study. Data available include linked healthcare records for 25 years from the date of consent and consent to obtain genomic sequencing data collected via saliva. Online questionnaires include information on demographics, COVID-19 exposures at work and home, redeployment in the workforce due to COVID-19, mental health measures, workforce attrition and opinions on COVID-19 vaccines, with baseline (n = 15 119), 6 (n = 5632) and 12-month follow-up (n = 6535) data captured. Request data access and collaborations by following documentation found at https://www.uk-reach.org/main/data_sharing

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease

Healthcare workers’ views on mandatory SARS-CoV-2 vaccination in the UK: A cross-sectional, mixed-methods analysis from the UK-REACH study

Background: Several countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs’ views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination. // Methods: Between 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question “What should society do if people do not get vaccinated against COVID-19?” using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics. // Findings: Of 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36–56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44–2.34 [≥55 years vs 16 years to <40 years]), HCWs vaccinated against influenza (OR 1.49; 95% CI 1.11–2.01 [2 vaccines vs none]), and with more positive vaccination attitudes generally (OR 1.10; 95% CI 1.06–1.15) were more likely to favour mandatory vaccination, whereas female HCWs (OR= 0.79, 95% CI 0.63–0.96, vs male HCWs) and Black HCWs (OR=0.46, 95% CI 0.25–0.85, vs white HCWs) were less likely to. // Interpretation: Only one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating, and supporting HCWs who are hesitant about vaccination may be more acceptable, effective, and equitable