Borrelia miyamotoi is a relapsing fever Borrelia group spirochete that is transmitted by the same hard-bodied (ixodid) tick species that transmit the agents of Lyme disease. It was discovered in 1994 ...in Ixodes persulcatus ticks in Japan. B. miyamotoi species phylogenetically cluster with the relapsing fever group spirochetes, which usually are transmitted by soft-bodied (argasid) ticks or lice. B. miyamotoi infects at least six Ixodes tick species in North America and Eurasia that transmit Lyme disease group spirochetes and may use small rodents and birds as reservoirs. Human cases of B. miyamotoi infection were first reported in 2011 in Russia and subsequently in the United States, Europe and Japan. These reports document the public health importance of B. miyamotoi, as human B. miyamotoi infection appears to be comparable in frequency to babesiosis or human granulocytic anaplasmosis in some areas and may cause severe disease, including meningoencephalitis. The most common clinical manifestations of B. miyamotoi infection are fever, fatigue, headache, chills, myalgia, arthralgia, and nausea. Symptoms of B. miyamotoi infection generally resolve within a week of the start of antibiotic therapy. B. miyamotoi infection should be considered in patients with acute febrile illness who have been exposed to Ixodes ticks in a region where Lyme disease occurs. Because clinical manifestations are nonspecific, etiologic diagnosis requires confirmation by blood smear examination, PCR, antibody assay, in vitro cultivation, and/or isolation by animal inoculation. Antibiotics that have been used effectively include doxycycline for uncomplicated B. miyamotoi infection in adults and ceftriaxone or penicillin G for meningoencephalitis.
Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug ...repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance.
We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel.
We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent.
There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.
•Genome analysis revealed that treatment biomarkers are shared across solid tumours, highlighting repurposing opportunities.•Comprehensive panels detect most known biomarkers; however, WGS detects more biomarkers for treatments in clinical trials.•TMB is well correlated between sequencing methods, but absolute values vary and are dependent on mutation types considered.
The parasite Fasciola hepatica infects a broad range of mammals with impunity. Following ingestion of parasites (metacercariae) by the host, newly excysted juveniles (NEJ) emerge from their cysts, ...rapidly penetrate the duodenal wall and migrate to the liver. Successful infection takes just a few hours and involves negotiating hurdles presented by host macromolecules, tissues and micro-environments, as well as the immune system. Here, transcriptome and proteome analysis of ex vivo F. hepatica metacercariae and NEJ reveal the rapidity and multitude of metabolic and developmental alterations that take place in order for the parasite to establish infection. We found that metacercariae despite being encased in a cyst are metabolically active, and primed for infection. Following excystment, NEJ expend vital energy stores and rapidly adjust their metabolic pathways to cope with their new and increasingly anaerobic environment. Temperature increases induce neoblast proliferation and the remarkable up-regulation of genes associated with growth and development. Cysteine proteases synthesized by gastrodermal cells are secreted to facilitate invasion and tissue degradation, and tegumental transporters, such as aquaporins, are varied to deal with osmotic/salinity changes. Major proteins of the total NEJ secretome include proteases, protease inhibitors and anti-oxidants, and an array of immunomodulators that likely disarm host innate immune effector cells. Thus, the challenges of infection by F. hepatica parasites are met by rapid metabolic and physiological adjustments that expedite tissue invasion and immune evasion; these changes facilitate parasite growth, development and maturation. Our molecular analysis of the critical processes involved in host invasion has identified key targets for future drug and vaccine strategies directed at preventing parasite infection.
Proteolytic processing of the amyloid precursor protein (APP) generates amyloid β (Aβ) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's ...disease. Cleavage by β-secretase at the amino terminus of the Aβ peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of β-cleaved soluble APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by γ-secretase(s) leads to the formation of Aβ. The pathogenic mutation K670M671 → N670L671 at the β-secretase cleavage site in APP, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased β-secretase cleavage of the mutant substrate. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the β-secretase cleavage site, and find it to be the predominant β-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for β-secretase. Cloning and expression of the enzyme reveals that human brain β-secretase is a new membrane-bound aspartic proteinase.
The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in ...maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health care payers.
A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health care payer with a life-time time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced cost biosimilar rituximab.
Rituximab for the treatment of membranous nephropathy was cost-effective (assuming a willingness-to-pay threshold of ${\$}$50 000 per quality adjusted life year (QALY) gained; ${\$}$US 2021) compared with cyclosporine, with an ICER of ${\$}$8 373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was ${\$}$28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favourable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine.
Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.
Hydration of Passive Oxide Films on Aluminum Bunker, B. C; Nelson, G. C; Zavadil, K. R ...
The journal of physical chemistry. B,
05/2002, Letnik:
106, Številka:
18
Journal Article
Recenzirano
Secondary ion mass spectrometry (SIMS) has been used in conjunction with isotopic labeling to determine the extent and rate of passive film hydration on aluminum. The rates at which oxygen- and ...hydrogen-containing species migrate through the film have been determined as a function of temperature and applied potential (cathodic and anodic polarization). The results suggest that defects such as hydroxide ions are prevalent and mobile in the oxide film, influencing the kinetics and mechanisms of corrosion and pitting processes.
The influence of plant lipids on the equilibrium sorption of three aromatic solutes from water was studied. The plant−water sorption isotherms of benzene, 1,2-dichlorobenzene, and phenanthrene were ...measured over a large range of solute concentrations using sealed vessels containing water, dried plant material, and solute. The plant materials studied include the shoots of annual rye, tall fescue, red fescue, and spinach as well as the roots of annual rye. Seven out of eight sorption isotherms were linear with no evidence of competitive effects between the solutes. For a given plant type, the sorption coefficient increased with decreasing solute water solubility. For a given solute, sorption increased with increasing plant lipid content. The estimated lipid−water partition coefficients of individual solutes were found to be significantly greater than the corresponding octanol−water partition coefficients. This indicates that plant lipids are a more effective partition solvent than octanol for the studied aromatic compounds. As expected, the solute lipid−water partition coefficients were log-linearly related to the respective water solubilities. For the compounds studied, partitioning into the lipids is believed to be the primary sorption mechanism.
There is currently much interest in the characterisation of wear debris from different types of artificial hip joints. There have been numerous studies on the wear of UHMWPE in hip joint simulators, ...but relatively few studies on the wear of alternative materials such as metal-on-metal (MOM) and ceramic-on-ceramic (COC). The aim of this study was to compare the wear volumes and wear debris generated from zirconia ceramic-on-UHMWPE, MOM and COC hip joints under identical conditions in the same hip joint simulator.
All prostheses showed an initial higher ‘bedding in’ wear rate, which was followed by a lower steady state wear rate. The zirconia ceramic-on UHMWPE prostheses showed the highest wear rates (31±4.0mm3/million cycles), followed by the MOM (1.23±0.5mm/million cycles), with the COC prostheses showing significantly (P<0.01) lower wear rates at 0.05±0.02mm3/million cycles. The mode (±95% confidence limits) of the size distribution of the UHMWPE wear debris was 300±200, 30±2.25nm for the metal particles, and 9±0.5nm for the ceramic wear particles. The UHMWPE particles were significantly larger (P<0.05) than the metal and ceramic wear particles, and the metal particles were significantly larger (P<0.05) than the ceramic wear particles. A variety of morphologies and sizes were observed for the UHMWPE wear particles, including submicrometer granules and large flakes in excess of 50μm. However, the wear particles generated in both the MOM and COC articulations were very uniform in size and oval or round in shape.
This investigation has demonstrated substantial differences in volumetric wear. The in vitro wear rates for the zirconia-on-UHMWPE and MOM are comparable with clinical studies and the UHMWPE and metal wear particles were similar to the wear debris isolated from retrieved tissues. However, the alumina/alumina wear rate was lower than some clinical retrieval studies, and the severe wear patterns and micrometer-sized particles described in vivo were not reproduced here.
This study revealed significant differences in the wear volumes and particle sizes from the three different prostheses. In addition, this study has shown that the alternative bearing materials such as MOM and COC may offer a considerable advantage over the more traditional articulations which utilise UHMWPE as a bearing material, both in terms of wear volume and osteolytic potential.
The National Veterans Affairs Surgical Risk Study was designed to collect reliable, valid data on patient risk and outcomes for major surgery in the Veterans Health Administration and to report ...comparative risk-adjusted postoperative mortality rates for surgical services in Veterans Health Administration.
This cohort study was conducted in 44 Veterans Affairs Medical Centers. Included were 87,078 major noncardiac operations performed under general, spinal, or epidural anesthesia between October 1, 1991, and December 31, 1993. The main outcomes measure was all-cause mortality within 30 days after the index procedure. Multivariable logistic regression risk-adjustment models for all operations and for eight surgical subspecialties were developed. Risk-adjusted surgical mortality rates were expressed as observed-to-expected ratios and were compared with unadjusted 30-day postoperative mortality rates.
Patient risk factors predictive of postoperative mortality included serum albumin level, American Society of Anesthesia class, emergency operation, and 31 additional preoperative variables. Considerable variability in unadjusted mortality rates for all operations was observed across the 44 hospitals (1.2-5.4%). After risk adjustment, observed-to-expected ratios ranged from 0.49 to 1.53. Rank order correlation of the hospitals by unadjusted and risk-adjusted mortality rates for all operations was 0.64. Ninety-three percent of the hospitals changed rank after risk adjustment, 50% by more than 5 and 25% by more than 10.
The Department of Veterans Affairs has successfully implemented a system for the prospective collection and comparative reporting of risk-adjusted postoperative mortality rates after major noncardiac operations. Risk adjustment had an appreciable impact on the rank ordering of the hospitals and provided a means for monitoring and potentially improving the quality of surgical care.
The National Veterans Affairs Surgical Risk Study was designed to collect reliable, valid data on patient risk and outcomes for major surgery in the Veterans Health Administration and to report ...comparative risk-adjusted postoperative mortality and morbidity rates for surgical services in the Veterans Health Administration.
This was a cohort study conducted at 44 Veterans Affairs Medical Centers closely affiliated with university medical centers. Included were 87,078 major noncardiac operations performed under general, spinal, or epidural anesthesia between October 1, 1991, and December 31, 1993. The main outcomes measures in this report are 21 postoperative adverse events (morbidities) occurring within 30 days after the index procedure. Multivariable logistic regression risk-adjustment models for all operations and for eight surgical subspecialties were developed.
Patient risk factors predictive of postoperative morbidity included serum albumin level, American Society of Anesthesia class, the complexity of the operation, and 17 other preoperative risk variables. Wide variation in the unadjusted rates of one or more postoperative morbidities for all operations was observed across the 44 hospitals (7.4-28.4%). Risk-adjusted observed-to-expected ratios ranged from 0.49 to 1.46. The Spearman rank order correlation between the ranking of the hospitals based on unadjusted morbidity rates and risk-adjusted observed-to-expected ratios for all operations was 0.87. There was little or no correlation between the rank order of the hospitals by risk-adjusted morbidity and risk-adjusted mortality.
The Department of Veterans Affairs has successfully implemented a system for the prospective collection and comparative reporting of postoperative mortality and morbidity rates after major noncardiac operations. Risk adjustment had only a modest effect on the rank order of the hospitals.
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