Guillain-Barré syndrome (GBS) is an acute inflammatory disorder of the peripheral nervous system thought to be due to autoimmunity for which immunotherapy is usually prescribed. To provide the best ...evidence on which to base clinical practice, we systematically reviewed the results of randomized trials of immunotherapy for GBS. We searched the Cochrane Library, MEDLINE and EMBASE in July 2006 and used the methods of the Cochrane Neuromuscular Disease Group to extract and synthesize data. Almost all trials used a 7-point disability grade scale. In four trials with altogether 585 severely affected adult participants, those treated with plasma exchange (PE) improved significantly more on this scale 4 weeks after randomization than those who did not, weighted mean difference (WMD) −0.89 (95% confidence interval (CI) −1.14 to −0.63). In five trials with altogether 582 participants, the improvement on the disability grade scale with intravenous immunoglobulin (IVIg) was very similar to that with PE, WMD −0.02 (95% CI −0.25 to 0.20). There was also no significant difference between IVIg and PE for any of the other outcome measures. In one trial with 148 participants, following PE with IVIg did not produce significant extra benefit. Limited evidence from three open trials in children suggested that IVIg hastens recovery compared with supportive care alone. Corticosteroids were compared with placebo or supportive treatment in six trials with altogether 587 participants. There was significant heterogeneity in the analysis of these trials which could be accounted for by analysing separately four small trials of oral corticosteroids with altogether 120 participants, in which there was significantly less improvement after 4 weeks with corticosteroids than without, WMD −0.82 (95% CI −0.17 to −1.47), and two large trials of intravenous methylprednisolone with altogether 467 participants, in which there was no significant difference between corticosteroids and placebo WMD −0.17 (95% CI 0.06 to −0.39). None of the treatments significantly reduced mortality. Since ∼20% of patients die or have persistent disability despite immunotherapy, more research is needed to identify better treatment regimens and new therapeutic strategies.
Genomic selection is becoming a standard tool in livestock breeding programs, particularly for traits that are hard to measure. Accuracy of genomic selection can be improved by increasing the ...quantity and quality of data and potentially by improving analytical methods. Adding genotypes and phenotypes from additional breeds or crosses often improves the accuracy of genomic predictions but requires specific methodology. A model was developed to incorporate breed composition estimated from genotypes into genomic selection models. This method was applied to age at puberty data in female beef cattle (as estimated from age at first observation of a corpus luteum) from a mix of Brahman and Tropical Composite beef cattle. In this dataset, the new model incorporating breed composition did not increase the accuracy of genomic selection. However, the breeding values exhibited slightly less bias (as assessed by deviation of regression of phenotype on genomic breeding values from the expected value of 1). Adding additional Brahman animals to the Tropical Composite analysis increased the accuracy of genomic predictions and did not affect the accuracy of the Brahman predictions.
Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted ...therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient's tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient's tumor identified several therapeutic choices, including Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient's CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient's CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.
The HIV reservoir is a population of 1–10 million anatomically dispersed, latently infected memory CD4+ T cells in which HIV DNA is quiescently integrated into human chromosomal DNA. When ...antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The detection of many populations of identical HIV sequences at unique integration sites implicates CD4+ T cell proliferation as the critical driver of reservoir sustainment after a prolonged period of effective ART. Initial reservoir formation occurs during the first week of primary infection usually before ART is started. While empirical data indicates that both de novo infection and cellular proliferation generate latently infected cells during early untreated infection, it is not known which of these mechanisms is predominant. We developed a mathematical model that recapitulates the profound depletion and brisk recovery of CD4+ T cells, reservoir creation, and viral load trajectory during primary HIV infection. We extended the model to stochastically simulate individual HIV reservoir clones. This model predicts the first detection of HIV infected clones approximately 5 weeks after infection as has recently been shown in vivo and suggests that substantial, uneven proliferation among clones during the recovery from CD4+ lymphopenia is the most plausible explanation for the observed clonal reservoir distribution during the first year of infection.
In southern New South Wales, Australia, farming operations using tractors often occur when the soils are moist and prone to soil compaction. However, the extent of soil compaction and its relative ...impact on crop yield have not been quantified in the region. In this experiment, re-compaction due to tractor wheel traffic in a sodic brown clay (Vertisol) was monitored under simulated controlled traffic conditions after removal of a pre-existing subsoil pan by deep tillage. Soil physical properties under wheel tracks were compared to those between wheel tracks in terms of bulk density, penetrometer resistance, water content, air-filled porosities and changes in “least limiting water range”. Differences in the growth and yield of canola (
Brassica napus) and wheat (
Triticum aestivum) in the two areas were also measured. Although deep ripping increased canola yield by 20% (from 2.0 to 2.4
t
ha
−1), reformation of a compaction pan under the wheel tracks was already detected in the first season of cropping. In the second cropping year, soil in the 0.05–0.10
m layer under wheel tracks had significantly higher penetrometer resistance (>2000
kPa) and bulk density (1.5–1.58
Mg
m
−3) and lower air-filled porosity (0.07–0.09
m
3
m
−3) compared to that measured between wheel tracks (<1000
kPa and 1.25–1.29
Mg
m
−3, and 0.187–0.226
m
3
m
−3, respectively). The ‘least limiting water range’ was essentially reduced to zero under wheel tracks and hence was unfavourable to plant roots. By contrast, favourable conditions were maintained in the area between wheel tracks throughout the whole available water range. This finding was supported by a significant reduction in canola and wheat root growth in the layer under the wheel tracks. While there was no difference in wheat yield (5.3–5.5
t
ha
−1), canola grain yield on the wheel track was only 34% of that between wheel tracks (1.1
t
ha
−1 versus 3.2
t
ha
−1). The canola results highlight the potential loss in grain yield due to compaction by tractor wheel traffic and indicate the likely benefits of adopting controlled traffic in farming systems for the sodic brown clay soils of this region. However, to fully realise the benefits of controlled traffic on these soil types it may first be necessary to remove the underlying compaction generated by previous farming practices. Conversely, adoption of controlled traffic systems should greatly assist in slowing the rate of recompaction of cropping soils following deep ripping.
Genotype by environment interaction influences the effectiveness of dairy cattle breeding programs in developing countries. This study aimed to investigate the optimization of dairy cattle breeding ...programs for three different environments within Kenya. Multi-trait selection index theory was applied using deterministic simulation in SelAction software to determine the optimum strategy that would maximize genetic response for dairy cattle under low, medium, and high production systems. Four different breeding strategies were simulated: a single production system breeding program with progeny testing bulls in the high production system environment (HIGH); one joint breeding program with progeny testing bulls in three environments (JOINT); three environment-specific breeding programs each with testing of bulls within each environment (IND); and three environment-specific breeding programs each with testing of bulls within each environment using both phenotypic and genomic information (IND-GS). Breeding strategies were evaluated for the whole industry based on the predicted genetic response weighted by the relative size of each environment. The effect of increasing the size of the nucleus was also evaluated for all four strategies using 500, 1500, 2500, and 3000 cows in the nucleus. Correlated responses in the low and medium production systems when using a HIGH strategy were 18% and 3% lower, respectively, compared to direct responses achieved by progeny testing within each production system. The JOINT strategy with one joint breeding program with bull testing within the three production systems produced the highest response among the strategies using phenotypes only. The IND-GS strategy using phenotypic and genomic information produced extra responses compared to a similar strategy (IND) using phenotypes only, mainly due to a lower generation interval. Going forward, the dairy industry in Kenya would benefit from a breeding strategy involving progeny testing bulls within each production system.
Some mutations (or ‘major genes’) have a desirable effect in heterozygous carriers but an undesirable effect in homozygous carriers. When these mutations affect a trait of significant economic ...importance, their eradication, depending on their effect and frequency, may be counterproductive. This is especially the case of major genes affecting the ovulation rate and thus the prolificacy in meat sheep populations. To manage such situations, a mating design based on the major genotypes of reproducers has to be optimized. Both the effect of the major gene and the cost of genotyping candidates at this locus influence the expected genetic progress and profitability of the breeding plan. The aim of this study was to determine the optimal combination of matings that maximizes profitability at the level of the whole population (nucleus + commercial flocks). A deterministic model was developed and, using sequential quadratic programming methodology, the optimal strategy (optimal combination of matings) that maximized the economic gain achieved by the population across a range of genotype effects and genotyping costs was determined. The optimal strategy was compared with simpler and more practical strategies based on a limited number of parental genotype mating types. Depending on the genotype effect and genotyping costs, the optimal strategy varied, such that either the heterozygous frequency and/or polygenic gain was maximized with a large number of animals genotyped, or when genotyping costs were higher, the optimization led to lower heterozygous frequency and/or polygenic gain with fewer animals genotyped. Comparisons showed that some simpler strategies were close to the optimal strategy. An overlapping model was then derived as an application of the real case of the French Lacaune meat sheep OVI-TEST breeding program. Results showed that a practical strategy based on mating non-carriers to heterozygous carriers was only slightly less effective than the optimal strategy, with a reduction in efficiency from 3% to 8%, depending on the genotyping costs. Based on only two different parental genotype mating types, this strategy would be easy to implement.
The building industry accounts for up to 40% of the earth’s energy usage from material extraction through building operation; housing constitutes roughly 30% of energy use in North America. Owners ...and consumers are looking for more efficient building systems that would decrease this use of energy. The material chosen to construct the structure of a building has the potential to reduce the building’s initial environmental impact and its life cycle energy use. However, this is rarely considered during conceptual design. Sustainable construction materials that have low embodied energy include earthen construction and straw bale construction. However, these materials are not widely accepted alternatives in North America because they are included only in select building codes in North America and around the world. In this paper, an extensive review of the current construction practice of sustainable construction materials is summarized. Durability concerns and limitations of the methods of construction are discussed, and areas of future research are identified.
Aims/hypothesis Type 1 diabetes results from the autoimmune destruction of pancreatic beta cells. Exogenous insulin therapy cannot achieve precise physiological control of blood glucose ...concentrations, and debilitating complications develop. Lentiviral vectors are promising tools for liver-directed gene therapy. However, to date, transduction rates in vivo remain low in hepatocytes, without the induction of cell cycling. We investigated long-term transgene expression in quiescent hepatocytes in vitro and determined whether the lentiviral delivery of furin-cleavable insulin to the liver could reverse diabetes in rats. Materials and methods To improve transduction efficiency in vitro, we optimised hepatocyte isolation and maintenance protocols and, using an improved surgical delivery method, delivered furin-cleavable insulin alone or empty vector to the livers of streptozotocin-induced diabetic rats by means of a lentiviral vector. Rats were monitored for changes in body weight and blood glucose, and intravenous glucose tolerance tests were performed. Expression of insulin was determined by RT-PCR, immunohistochemistry and electron microscopy. Results We achieved long-term transgene expression in quiescent hepatocytes in vitro (87 ± 1.2% transduction efficiency), with up to 60 ± 3.2% transduction in vivo. We normalised blood glucose for 500 days--a significantly longer period than previously reported--making this the first successful study using a lentiviral vector. This procedure resulted in the expression of genes encoding several beta cell transcription factors, some pancreatic endocrine transdifferentiation, hepatic insulin storage in granules, and restoration of glucose tolerance. Liver function tests remained normal. Importantly, pancreatic exocrine transdifferentiation did not occur. Conclusions/interpretation Our data suggest that this regimen may ultimately be employed for the treatment of type 1 diabetes.
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