Computer-guided concentration-controlled trials in autoimmune disorders

A randomized concentration-controlled clinical trial (RCCCT) is an alternate experimental design to the standard dose-controlled study. In a RCCCT, patients are randomly assigned to predefined plasma or blood drug concentration ranges (low, medium, and high). With the caveat that concentration ranges are sufficiently separated, this design should enhance the ability to discover important concentration response relationships. FK-506, a potent and promising immunosuppressive agent for prevention and treatment of graft rejection, has shown significant clinical activity in some immune-mediated disorders. To implement the RCCCT design, a novel FK-506 intelligent dosing system (IDS) was used to guide all doses to prospectively achieve the target concentration range specified in the study protocol. Patients enrolled in these trials suffered from a variety of autoimmune disorders, including multiple sclerosis, primary biliary cirrhosis, psoriasis, autoimmune chronic active hepatitis, and nephrotic syndrome. We observed excellent predictive performance of the IDS for all patients. The accuracy (mean prediction error) of the IDS was −0.022 ng/ml and the precision (standard deviation of the prediction error) was 0.119 ng/ml. Thus, the IDS is both accurate and reproducible for autoimmune patients. We conclude that the RCCCT design, guided by an accurate and precise IDS, is an informative and cost-effective approach for evaluation of efficacy and safety of effective but highly toxic agents. © 1993 Raven Press, Ltd., New York

Evidence for the Gompertz Curve in the Income Distribution of Brazil 1978-2005

This work presents an empirical study of the evolution of the personal income distribution in Brazil. Yearly samples available from 1978 to 2005 were studied and evidence was found that the complementary cumulative distribution of personal income for 99% of the economically less favorable population is well represented by a Gompertz curve of the form $G(x)=\exp [\exp (A-Bx)]$, where $x$ is the normalized individual income. The complementary cumulative distribution of the remaining 1% richest part of the population is well represented by a Pareto power law distribution $P(x)= \beta x^{-\alpha}$. This result means that similarly to other countries, Brazil's income distribution is characterized by a well defined two class system. The parameters $A$, $B$, $\alpha$, $\beta$ were determined by a mixture of boundary conditions, normalization and fitting methods for every year in the time span of this study. Since the Gompertz curve is characteristic of growth models, its presence here suggests that these patterns in income distribution could be a consequence of the growth dynamics of the underlying economic system. In addition, we found out that the percentage share of both the Gompertzian and Paretian components relative to the total income shows an approximate cycling pattern with periods of about 4 years and whose maximum and minimum peaks in each component alternate at about every 2 years. This finding suggests that the growth dynamics of Brazil's economic system might possibly follow a Goodwin-type class model dynamics based on the application of the Lotka-Volterra equation to economic growth and cycle.Comment: 22 pages, 15 figures, 4 tables. LaTeX. Accepted for publication in "The European Physical Journal B

A Census of Rotating Radio Transients at 150 MHz with the Irish LOFAR Station

Rotating radio transients (RRATs) are neutron stars that emit detectable radio bursts sporadically. They are statistically distinct in the neutron star population, in many observable properties, but by their nature are practically difficult to study in depth. In this paper, we present the results from 1408 h of observations of RRAT candidates using the Irish station of the Low Frequency Array (LOFAR) at 150 MHz. As of October 2022, this census involved observing 113 sources, leading to 29 detections which were then followed up systematically. Single-pulse emission was detected from 25 sources, and periodic emission from 14 sources. 18 sources were found to have emission behaviour that is not discussed in prior works using LOFAR instruments. Four novel or modified source periods have been determined, ranging from 1.5-3.9 s, and 8 new or updated phase-coherent pulsar timing ephemerides have been produced using detected bursts. One unexpected single-pulse with a clearly-Galactic dispersion measure was detected as a part of this work, but has not been re-detected in follow-up observations. Observations are ongoing to expand the number of observed sources and further characterise and improve ephemerides for the detected sources. This census has demonstrated the capability for international LOFAR stations to detect, monitor and characterise a significant fraction of these unique sources.Comment: Accepted by MNRAS. 24 pages, 7 figures, 8 table

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

H9N2 avian influenza viruses are primarily a disease of poultry; however, they occasionally infect humans and are considered a potential pandemic threat. Little work has been performed to assess the intrinsic biochemical properties related to zoonotic potential of H9N2 viruses. The objective of this study, therefore, was to investigate H9N2 haemagglutinins (HAs) using two well-known correlates for human adaption: receptor-binding avidity and pH of fusion. Receptor binding was characterized using bio-layer interferometry to measure virus binding to human and avian-like receptor analogues and the pH of fusion was assayed by syncytium formation in virus-infected cells at different pHs. We characterized contemporary H9N2 viruses of the zoonotic G1 lineage, as well as representative viruses of the zoonotic BJ94 lineage. We found that most contemporary H9N2 viruses show a preference for sulphated avian-like receptor analogues. However, the ‘Eastern’ G1 H9N2 viruses displayed a consistent preference in binding to a human-like receptor analogue. We demonstrate that the presence of leucine at position 226 of the HA receptor-binding site correlated poorly with the ability to bind a human-like sialic acid receptor. H9N2 HAs also display variability in their pH of fusion, ranging between pH 5.4 and 5.85 which is similar to that of the first wave of human H1N1pdm09 viruses but lower than the pH of fusion seen in zoonotic H5N1 and H7N9 viruses. Our results suggest possible molecular mechanisms that may underlie the relatively high prevalence of human zoonotic infection by particular H9N2 virus lineages

Tacrolimus rescue therapy for renal allograft rejection - Five-year experience

Over the 5 year period from 7/14/1989 until 5/24/1994, we have attempted graft salvage with tacrolimus conversion in a total of 169 patients (median age 33 years, range 2-75 years) with ongoing rejection on baseline CsA immunosuppression after failure of high dose corticosteroids and/or antilymphocyte preparations to reverse rejection. The indications for conversion to tacrolimus were ongoing, biopsy confirmed rejection in all patients. The median interval to tacrolimus conversion was 2 months (range 2 days to 55 months; mean 4.3±2.6 months) after transplantation. All patients had failed high dose corticosteroid therapy and 144 (85%) of the 169 patients had received at least one course of an antilymphocyte preparation plus high dose corticosteroid therapy prior to conversion. Twenty-eight patients (17%) were dialysis-dependent at the time of conversion owing to the severity of rejection. With a mean follow-up of 30.0±2.4 months (median 36.5 months, range 12-62 months), 125 of 169 patients (74%) have been successfully rescued and still have functioning grafts with a mean serum creatinine (SCR) of 2.3±1.1 mg/dl. Of the 144 patients previously treated with antilymphocyte preparations, 117 (81%) were salvaged. Of the 28 patients on dialysis at the time of conversion to tacrolimus, 13 (46%) continue to have functioning grafts (mean SCR 2.15±0.37 mg/dl) at a mean follow-up of 37.3±16.7 months. In the 125 patients salvaged, prednisone doses have been lowered from 28.0±9.0 mg/d (median 32, range 4-60 mg/d) preconversion to 8.5±4.1 mg/d (median 12 mg/d, range 2.5-20 mg/d) postconversion. Twenty-eight patients (22.4%) are currently receiving no steroids. This 5 year experience demonstrates that tacrolimus has sustained efficacy as a rescue agent for ongoing renal allograft rejection. Based on these data, we recommend that tacrolimus be used as an alternative to the conventional drugs used for antirejection therapy in renal transplantation

Niche partitioning among and within sympatric tropical seabirds revealed by stable isotope analysis

The low productivity and unpredictable nature of resources in tropical waters would appear to make resource partitioning among predators difficult. Yet, stable isotope data from the present study suggest that substantial resource partitioning occurs among tropical seabird communities, both between and within species. In the present study, we compared δ13C and δ15N levels among 8 sympatric tropical seabird species. For a subset of these species, we also examined isotopic levels across years, breeding periods, and sexes. When breeding and non-breeding periods were both considered, we found that all species occupied distinct isotopic niches across at least one time period. Resource partitioning by age (within the same year) and year studied (for birds of the same age), within species was observed in all the species we examined. However, niche separation by sex appeared to be relatively uncommon even in sexually dimorphic species. As a group, seabirds were isotopically distinct from other marine predators. There was a strong correlation between both body mass and wing loading ratios and foraging area, as evaluated using δ13C levels. Cumulatively, the isotopic patterns observed are consistent with diet-based surveys of resource partitioning during the breeding period. Importantly, these data provide additional evidence to suggest that substantial niche partitioning among tropical seabird species persists even during non-breeding periods in open ocean environments, when direct diet-based surveys are difficult to conduct