Trends in testing behaviours for hepatitis C virus infection and associated determinants: results from population-based laboratory surveillance in Alberta, Canada (1998-2001)

Little is currently known about hepatitis C virus (HCV) test seeking behaviours at the population level. Given the centralized nature of testing for HCV infection in the province of Alberta, Canada, we had an opportunity to examine HCV testing behaviour at the population level on all newly diagnosed HCV-positive cases using laboratory data to validate the time and number of prior tests for each case. Record linkage identified 3323, 2937, 2660 and 2703 newly diagnosed cases of HCV infections in Alberta during 1998, 1999, 2000 and 2001, respectively, corresponding to age-adjusted rates of 149.8, 129, 114.3 and 113.7 per 100,000 population during these years, respectively. Results from secondary analyses of laboratory data suggest that the majority of HCV cases (95.3%) who were newly diagnosed between 1998 and 2001 were first-time testers for HCV infection. Among repeat testers, analysis of a negative test result within 1 year prior to a first of a positive test report suggests that 211 (38.4%) may be seroconvertors. These findings suggest that 339 or 61.7% of repeat testers may not have discovered their serostatus within 1 year of infection. Among this group, HCV testing was sought infrequently, with a median interval of 2.3 years between the last negative and first positive test. This finding is of concern given the risks for HCV transmission, particularly if risk-taking behaviours are not reduced because of unknown serostatus. These findings also reinforce the need to make the most of each test-seeking event with proper counselling and other appropriate support services.     

Lower-extremity muscle cross-sectional area after incomplete spinal cord injury

OBJECTIVES: (1) To quantify skeletal muscle size in lower-extremity muscles of people after incomplete spinal cord injury (SCI), (2) to assess differences in muscle size between involved lower limbs, (3) to determine the impact of ambulatory status (using wheelchair for community mobility vs not using a wheelchair for community mobility) on muscle size after incomplete SCI, and (4) to determine if differential atrophy occurs among individual muscles after incomplete SCI. DESIGN: Case-control study. SETTING: University research setting. PARTICIPANTS: Seventeen people with incomplete SCI and 17 age-, sex-, weight-, and height-matched noninjured controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Maximum cross-sectional area (CSA) of individual lower-extremity muscles (soleus, medial gastrocnemius, lateral gastrocnemius, tibialis anterior, quadriceps femoris, hamstrings) as assessed by magnetic resonance imaging. RESULTS: Overall, subjects with incomplete SCI had significantly smaller (24%-31%) average muscle CSA in affected lower-extremity muscles as compared with control subjects (P<.05). Mean differences were highest in the thigh muscles ( approximately 31%) compared with the lower-leg muscles ( approximately 25%). No differences were noted between the self-reported more- and less-involved limbs within the incomplete SCI group. Dichotomizing the incomplete SCI group showed significantly lower muscle CSA values in both the wheelchair (range, 21%-39%) and nonwheelchair groups (range, 24%-38%). In addition, the wheelchair group exhibited significantly greater plantarflexor muscle atrophy compared with the dorsiflexors, with maximum atrophy in the medial gastrocnemius muscle (39%). CONCLUSIONS: Our results suggest marked and differential atrophic response of the affected lower-extremity muscles that is seemingly affected by ambulatory status in people with incomplete SCI.     

Pyroglutamate aminopeptidase activity in human cerebrospinal fluid decreases with age

The activity of pyroglutamate aminopeptidase, the major enzyme catalyzing thyrotropin-releasing hormone (TRH) metabolism in human CSF, decreased with age. This decrement is not due to age-dependent appearance of any enzyme inhibitor in CSF. The results of these studies underline the importance of using age-matched controls in assessing abnormalities of TRH metabolism in CSF during disease states.     

Experimental and Statistical Investigation to Evaluate Impact Strength Variability and Reliability of Preplaced Aggregate Concrete Containing Crumped Rubber and Fibres

The proper disposal of used rubber tires has emerged as a primary concern for the environment all over the globe. Millions of tires are thrown away, buried and discarded every year, posing a major environmental concern owing to their slow decomposition. As a result, it is advantageous to use recycled waste rubber aggregates as an additional building resource. Recycling crushed rubber would lead to a long-term solution to the problem of decreasing natural aggregate resources while conserving the environment. This study examines the impact strength variability and reliability of preplaced aggregate concrete containing crumped rubber and fibres. Ten different mixtures were prepared by replacing natural aggregate with crumped rubber (5, 10, 15 and 20%). The crumped rubber was pretreated by the water with sodium hydroxide dilution for 30 min before usage. Hooked-end steel fibres were used at a dosage of 1.5%. The compressive strength, impact strength, impact ductility index and failure pattern were examined and discussed. In addition, a statistical method called Weibull distribution is used to analyze the scattered experimental results. The results showed that when the crumb rubber content was raised, the retained first cracking and failure impact numbers increased. As a result of substituting crumb rubber for 20% of the coarse aggregate in plain and fibrous mixes, the percentage development in first crack and failure was between 33% and 76% and 75% to 129%, respectively.     

Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer

Early stage estrogen receptor α (ERα, ESR1)-positive breast cancer patients can develop more aggressive endocrine-resistant tumors that express constitutively active mutant forms of ERα including ERα-Y537S and ERα-D538G. These patients are treated with selective ER down regulators (SERDs) such as the ERα antagonist fulvestrant. Previous studies show that histone deacetylase (HDAC) inhibitors downregulate ERα and since some dietary derived short chain fatty acids (butyrate, propionate and acetate) exhibit HDAC inhibitory activity we investigated their effects as SERDs in MCF-7 and T47D cells expressing wild-type and mutant ERα-D538G and ERα-Y537S. The SCFAs exhibited SERD-like activity in both cell lines expressing wild-type and mutant ERα. The results for propionate and butyrate correlated with parallel induction of histone acetylation and this was also observed for the HDAC inhibitors Panobinostat, Vorinostat and Entinostat which also downregulated wild-type and mutant ERα and induced histone acetylation. Although acetate induced ERα degradation the mechanisms may be independent of the HDAC inhibitory activity of this compound. These results suggest that high fibre diets that induce formation of SCFAs may have some clinical efficacy for treating ER-positive endocrine resistant breast cancer patients and this is currently being investigated.     

Optimizing Antibody Affinity and Developability Using a Framework–CDR Shuffling Approach—Application to an Anti-SARS-CoV-2 Antibody

The computational methods used for engineering antibodies for clinical development have undergone a transformation from three-dimensional structure-guided approaches to artificial-intelligence- and machine-learning-based approaches that leverage the large sequence data space of hundreds of millions of antibodies generated by next-generation sequencing (NGS) studies. Building on the wealth of available sequence data, we implemented a computational shuffling approach to antibody components, using the complementarity-determining region (CDR) and the framework region (FWR) to optimize an antibody for improved affinity and developability. This approach uses a set of rules to suitably combine the CDRs and FWRs derived from naturally occurring antibody sequences to engineer an antibody with high affinity and specificity. To illustrate this approach, we selected a representative SARS-CoV-2-neutralizing antibody, H4, which was identified and isolated previously based on the predominant germlines that were employed in a human host to target the SARS-CoV-2-human ACE2 receptor interaction. Compared to screening vast CDR libraries for affinity enhancements, our approach identified fewer than 100 antibody framework–CDR combinations, from which we screened and selected an antibody (CB79) that showed a reduced dissociation rate and improved affinity against the SARS-CoV-2 spike protein (7-fold) when compared to H4. The improved affinity also translated into improved neutralization (>75-fold improvement) of SARS-CoV-2. Our rapid and robust approach for optimizing antibodies from parts without the need for tedious structure-guided CDR optimization will have broad utility for biotechnological applications.