Race and obesity disparities among adults living in gentrifying neighborhoods.

There is a paucity of research seeking to understand race disparities in obesity among individuals living in a gentrifying neighborhood. American Community Survey data were used to identify gentrifying neighborhoods. In a cross-sectional analysis, these data were then linked to the 2014 Medical Expenditure Panel Survey, yielding an analytic sample of 887 Black and White adults. Obesity was based on body mass index ≥ 30 kg/m2. After controlling for potential confounders, Black adults living in gentrifying neighborhoods had a higher prevalence of obesity (PR: 1.39; 95% CI: 1.03, 1.88) than White adults living in gentrifying neighborhoods. Gentrification may have no impact on reducing Black-White obesity disparities in the US.

WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval. The meeting participants applauded the leading role taken by the WHO in providing a much-needed streamlined approach for development and evaluation of SBPs which will provide efficient and cost-effective product development and increase patient access to treatments. It was recognized that the principles as currently described in the draft WHO guidelines are based on sound science and experience gained over the last fifteen years of biosimilar approvals. However, since these guidelines when finalised will constitute the global standard for biosimilar evaluation and assist national regulatory authorities in establishing revised guidance and regulatory practice in this complex area, it was felt that further revision and clarity on certain perspectives in specific areas was necessary to dispel uncertainties arising in the current revised version. This report describes the principles in the draft guidelines, including topics discussed and consensus reached.

Quantifying Older Black Americans' Exposure to Structural Racial Discrimination: How Can We Measure the Water In Which We Swim?

The USA was built on legalized racism that started with enslavement and continues in the form of structural racial discrimination. This discrimination is difficult to measure because its many manifestations are hard to observe and dynamic. A useful tool would measure across settings, institutions, time periods in a person's life and the country's history. The purpose of this study was to design a measure of structural racial discrimination that meets those criteria and can be used in large national datasets. To do this, we started with an exploratory mixed-methods instrument design, including qualitative interviews with 15 older Black adults and focus groups with 38 discrimination researchers and other key stakeholders. We then identified 27 indicators of structural racial discrimination across nine theorized discrimination contexts. We matched these with historical administrative data sets to develop an instrument that could quantify older Black Americans' exposure to structural racial discrimination across contexts, the life course, and geographies. These can be mapped to the life course of structural discrimination based on the home addresses of those surveyed. Linking these to available indicators is a promising approach. It is a low burden for participants and enables increasingly multifaceted and focused measurement as more national datasets become available. A flexible, feasible comprehensive measure of structural discrimination could allow not only more thorough documentation of inequities but also allow informed decision making about policies and programs intended to promote racial equity. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study that presents a framework for assessing structural racial discrimination across contexts, life course, and geography that is grounded in theory and in the lived experience of intended participants. Leading researchers and policy makers have called for improved measures of structural racism and discrimination and specifically for a lifecourse approach to measurement. This study is a step in that direction. CLASSIFICATION: Social Sciences.

Racism and Older Black Americans' Health: a Systematic Review.

We reviewed research that examines racism as an independent variable and one or more health outcomes as dependent variables in Black American adults aged 50 years and older in the USA. Of the 43 studies we reviewed, most measured perceived interpersonal racism, perceived institutional racism, or residential segregation. The only two measures of structural racism were birth and residence in a "Jim Crow state." Fourteen studies found associations between racism and mental health outcomes, five with cardiovascular outcomes, seven with cognition, two with physical function, two with telomere length, and five with general health/other health outcomes. Ten studies found no significant associations in older Black adults. All but six of the studies were cross-sectional. Research to understand the extent of structural and multilevel racism as a social determinant of health and the impact on older adults specifically is needed. Improved measurement tools could help address this gap in science.

Anaerobic digestion of untreated and treated process water from the hydrothermal carbonisation of spent coffee grounds.

This study investigates the long-term performance of the mesophilic (35 °C) anaerobic mono-digestion of process waters (PW) from the hydrothermal carbonisation (HTC) of spent coffee grounds. At an organic loading rate (OLR) of 0.4 gCOD L-1 d-1, initial instability was seen, but after 40 days and supplementary alkalinity, the digestion stabilised with the chemical oxygen demand (COD) in the untreated PW degraded with 37.8-64.6% efficiency and the yield of methane at 0.16 L gCOD-1. An increase in OLR to 0.8 gCOD L-1 d-1 caused a collapse in biogas production, and resulted in severe instability in the reactor, characterised by falling pH and an increasing volatile fatty acid concentration. Comparatively, the digestion of a treated PW (concentrated in nanofiltration and reverse osmosis after removal of the fouling fraction), at OLR between 0.4 and 0.8 gCOD L-1 d-1, was stable over the entire 117 days of treated PW addition, yielded methane at 0.21 L gCOD-1 and the COD was degraded with an average efficiency of 93.5% - the highest efficiency the authors have seen for HTC PW. Further anaerobic digestion of untreated PW at an average OLR of 0.95 gCOD L-1 d-1 was stable for 38 days, with an average COD degradation of 69.6%, and methane production between 0.15 and 0.19 L gCOD-1. The digestion of treated PW produced significantly higher COD degradation and methane yield than untreated PW, which is likely to be related to the removal of refractory and inhibitory organic material in the post-HTC treatment by adsorption of hydrophobic material.

The knowledge and attitudes of South African-based runners regarding the use of analgesics during training and competition.

Background: The use of analgesics is prevalent in runners, with the associated potential for serious harm. However, there is limited information regarding runners' knowledge and attitudes towards the use of analgesics in relation to running. Objectives: To describe South African-based runners' knowledge and attitudes regarding running-related analgesic use. Methods: This study has a descriptive, cross-sectional design. South African-based runners, over the age of 18 who ran at least one race in the year preceding the study were included in this study. Participants completed an online questionnaire, including sections on demographic information, training and competition history, pain medication use, and knowledge and attitudes regarding running-related analgesic use. Results: Data from 332 participants were analysed. Attitudes regarding the use of analgesics in relation to running were generally positive; however, knowledge was poor, with only 20% of participants achieving adequate knowledge scores (75% or above). Very few (n=49; 15%) had both adequate knowledge and positive attitudes, with most respondents (n=188; 58%) having inadequate knowledge and negative attitudes. Negative attitudes towards the use of analgesics were found to increase the odds of running-related analgesic use (OR 2.32; 95% CI:1.31-4.11). Conclusion: Knowledge regarding running-related use of analgesics was inadequate. Despite a lack of knowledge, attitudes were positive. Participants displayed positive attitudes towards safe practice regarding running-related analgesic use, but these did not translate into good practice. Targeted interventions are required to educate runners and improve their knowledge of all the effects associated with running-related analgesic use.

Analgesic practices and predictors of use in South Africa-based runners.

BACKGROUND: The use of analgesics is prevalent in runners, with an associated potential for serious harm. More information is needed regarding runners' practices and the factors that may influence their use of analgesics, to identify potential sources of misuse or abuse. OBJECTIVES: To describe South Africa (SA)-based runners' practices regarding use of analgesics, focusing on the types used, sources of information, and factors predicting use. METHODS: This study had a descriptive, cross-sectional design. SA-based runners aged ≥18 years, who had run at least one race during the year preceding the study, were included. Participants were recruited via social media and SA running clubs. They completed an online survey that included demographic information, training and competition history, and analgesic usage practices. RESULTS: Data from 332 participants (196 females, 136 males) were analysed. There was a high rate of analgesic use (64%), with 17% of users reporting concomitant use of more than one type of analgesic. The highest rate of analgesic use was after a run (80%). Non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently used analgesics before (71%), during (50%) and after a run (74%). Importantly, NSAIDs and a combination NSAID-containing analgesic were the most common analgesics used concomitantly (19%). Most participants (90%) used over-the-counter analgesics, 41% of them receiving no input from any health professional. Sustaining a running-related injury increased the likelihood of analgesic use almost three-fold (Exp(B)=2.6; 95% confidence interval 1.59 - 2.41; p=0.0001). CONCLUSIONS: A large percentage of runners in our study displayed unsafe practices regarding analgesic use during training and competition, predominantly for perceived injury management. Importantly, the lack of education and recommendations regarding analgesics from health professionals is very concerning, as there is a risk of potentially life-threatening analgesic-induced adverse effects, especially as a high percentage were using two NSAIDs concomitantly. Knowledge of these practices, gained through this study, could allow for the development and implementation of corrective strategies to promote education and safe practice of analgesic use in runners.

Longitudinal and reciprocal associations between financial strain, home characteristics and mobility in the National Health and Aging Trends Study.

BACKGROUND: Older adults need homes that suit their physical capacity. Financial strain may limit home repairs and modifications and prompt relocations; repairing, relocating or modifying may increase financial strain. Likewise, reciprocal relationships may exist between financial strain and home characteristics and mobility; financial strain and home characteristics may influence mobility and mobility declines may increase financial strain, limit home repairs and modifications and prompt relocations. We test cross-lagged associations between financial strain, home disorder, relocation, home modifications and mobility. METHODS: In the National Health and Aging Trends Study, ability to complete a walking test, speed among those able to complete, financial strain, home disorder, relocating and modifying the home were recorded annually for 3 years (2012-2014). Structural equation models separately examined ability to walk and walking speed among those able, accounting for sociodemographic characteristics, social support, health prior health characteristics and autoregressive effects. Sampling weights accounted for the complex survey design and non-response over time. RESULTS: In both models (n = 3234 and n = 2467), financial strain predicted greater home disorder and vice versa, but cross-lagged associations were not found with relocating and modifications. Greater home disorder predicted lower odds of ability to walk and slower speed among those able. Financial strain and home modifications predicted lower odds of ability to walk. Also, faster walking speed predicted lower odds of subsequent financial strain and lower subsequent home disorder scores and ability to walk predicted less subsequent home disorder and lower odds of relocating. CONCLUSIONS: Home disorder links financial strain with reduced mobility in a national sample of U.S. older adults. Cross-lagged associations between financial strain and home disorder and between home disorder and mobility suggest reciprocal effects that may accumulate over time. Also, financial strain, reduced mobility, relocations and modifications predicted greater home disorder. Together, these results highlight home disorder as a social determinant of mobility for older adults. Greater attention should be given to repairing and modifying home environments and supporting stable housing for older adults with financial strain.

Treatment of discontinuous emission of sewage sludge odours by a full scale biotrickling filter with an activated carbon polishing unit.

A SULPHUSTM biotrickling filter (BTF) and an ACTUSTM polishing activated carbon filter (ACF) were used at a wastewater treatment plant to treat 2,432 m3·h-1 of air extracted from sewage sludge processes. The project is part of Thames Water's strategy to reduce customer odour impact and, in this case, is designed to achieve a maximum discharge concentration of 1,000 ouE·m-3. The odour and hydrogen sulphide concentration in the input air was more influenced by the operation of the sludge holding tank mixers than by ambient temperature. Phosphorus was found to be limiting the performance of the BTF during peak conditions, hence requiring additional nutrient supply. Olfactometry and pollutant measurements demonstrated that during the high rate of change of intermittent odour concentrations the ACF was required to reach compliant stack values. The two stage unit outperformed design criteria, with 139 ouE·m-3 measured after 11 months of operation. At peak conditions and even at very low temperatures, the nutrient addition considerably increased the performance of the BTF, extending the time before activated carbon replacement over the one year design time. During baseline operation, the BTF achieved values between 266-1,647 ouE·m-3 even during a 6 day irrigation failure of the biofilm.

Race, Medical Mistrust, and Segregation in Primary Care as Usual Source of Care: Findings from the Exploring Health Disparities in Integrated Communities Study.

Compared to White Americans, African-Americans are less likely to use primary care (PC) as their usual source of care. This is generally attributed to race differences in socioeconomic status and in access to primary care services. Little is known about the relationship between race differences in medical mistrust and the usual source of care disparity. Using data from the Exploring Health Disparities in Integrated Communities (EHDIC) study, we examined the role of medical mistrust in choosing usual source of care in 1408 black and white adults who were exposed to the same healthcare facilities and low-income racially integrated community. Multinomial logistic regression models were estimated to examine the relationship between race, medical mistrust, and usual source of care. After adjusting for demographic and health-related factors, African-Americans were more likely than whites to use the emergency department (ED) (relative risk ratio [RRR] = 1.43 (95 % confidence interval (CI) [1.06-1.94])) and hospital outpatient department (RRR1.50 (95 %CI [1.10-2.05])) versus primary care as a usual source of care. When medical mistrust was added to the model, the gap between African-Americans' and whites' risk of using the ED versus primary care as a usual source of care closed (RRR = 1.29; 95 % CI [0.91-1.83]). However, race differences in the use of the hospital outpatient department remained even after accounting for medical mistrust (RRR = 1.67; 95 % CI [1.16-2.40]). Accounting for medical mistrust eliminated the ED-as-usual-source of care disparity. This study highlights the importance of medical mistrust as an intervention point for decreasing ED use as a usual source of care by low-income, urban African-Americans.

The inequitable distribution of tobacco outlet density: the role of income in two Black Mid-Atlantic geopolitical areas.

OBJECTIVES: Studies have shown that communities with higher concentrations of low-income racial and ethnic minorities correlate with a greater presence of tobacco outlets. Community-level income has consistently been among the strongest predictors of tobacco outlet density. This study analyzes two Maryland geopolitical areas with similar racial concentrations yet differing income levels in an attempt to disentangle the race-income relationship with tobacco outlet density. STUDY DESIGN: In this cross-sectional examination of tobacco outlet and census tract-level sociodemographic data, Baltimore City, Maryland, and Prince George's County, Maryland, were geocoded to determine tobacco outlet density. METHODS: Tobacco outlet density was defined as the mean number of tobacco outlets per 1000 persons per census tract. Comparisons of tobacco outlet density and sociodemographic variables were analysed via two-sample t-tests, and the direct effect of sociodemographic variables on tobacco outlet density for each area was analysed via spatial lag regressions. RESULTS: Prince George's County, the area with the higher income level ($77,190 vs $43,571), has a significantly lower tobacco outlet density than Baltimore City (P < 0.001). Prince George's County has a 67.5% Black population and an average of 3.94 tobacco outlets per 1000 persons per tract. By contrast, Baltimore City has a 65.3% Black population and an average of 7.95 tobacco outlets per 1000 persons per tract. Spatial lag regression model results indicate an inverse relationship between income and tobacco outlet density in Baltimore City and Prince George's County (ß = -0.03, P < 0.01 &ß = -0.01, P = 0.02, respectively), and a significant interaction term indicating a greater magnitude in the relationship between income and tobacco outlet density in Baltimore City (ß = -0.05, P < 0.01). CONCLUSION: Results suggest that higher socio-economic status, even in primarily underrepresented racial and ethnic geopolitical areas, is linked to lower tobacco outlet density.

Cytokine release assays for the prediction of therapeutic mAb safety in first-in man trials--Whole blood cytokine release assays are poorly predictive for TGN1412 cytokine storm.

The therapeutic monoclonal antibody (mAb) TGN1412 (anti-CD28 superagonist) caused near-fatal cytokine release syndrome (CRS) in all six volunteers during a phase-I clinical trial. Several cytokine release assays (CRAs) with reported predictivity for TGN1412-induced CRS have since been developed for the preclinical safety testing of new therapeutic mAbs. The whole blood (WB) CRA is the most widely used, but its sensitivity for TGN1412-like cytokine release was recently criticized. In a comparative study, using group size required for 90% power with 5% significance as a measure of sensitivity, we found that WB and 10% (v/v) WB CRAs were the least sensitive for TGN1412 as these required the largest group sizes (n = 52 and 79, respectively). In contrast, the peripheral blood mononuclear cell (PBMC) solid phase (SP) CRA was the most sensitive for TGN1412 as it required the smallest group size (n = 4). Similarly, the PBMC SP CRA was more sensitive than the WB CRA for muromonab-CD3 (anti-CD3) which stimulates TGN1412-like cytokine release (n = 4 and 4519, respectively). Conversely, the WB CRA was far more sensitive than the PBMC SP CRA for alemtuzumab (anti-CD52) which stimulates FcγRI-mediated cytokine release (n = 8 and 180, respectively). Investigation of potential factors contributing to the different sensitivities revealed that removal of red blood cells (RBCs) from WB permitted PBMC-like TGN1412 responses in a SP CRA, which in turn could be inhibited by the addition of the RBC membrane protein glycophorin A (GYPA); this observation likely underlies, at least in part, the poor sensitivity of WB CRA for TGN1412. The use of PBMC SP CRA for the detection of TGN1412-like cytokine release is recommended in conjunction with adequately powered group sizes for dependable preclinical safety testing of new therapeutic mAbs.

Community Characteristics are Associated with Blood Pressure Levels in a Racially Integrated Community.

Community problems have been associated with higher, and community resources and social cohesion with lower, blood pressure. However, prior studies have not accounted for potential confounding by residential racial segregation. This study tested associations between community characteristics and blood pressure levels and prevalent hypertension in a racially integrated community. The Exploring Health Disparities in Integrated Communities Study measured blood pressure in residents of two contiguous racially integrated and low-income US Census Tracts. Community characteristics included a standardized community problem score and binary indicators for community social cohesion, having a community leader available, and having at least one community resource observed on the participant's block. In adjusted models, greater community problems and proximity to resources were associated with lower systolic (ß = -2.020, p = 0.028; ß = -4.132, p = 0.010) and diastolic (ß = -1.261, p = 0.038; ß = -2.290, 0.031) blood pressure, respectively, among whites (n = 548). Social cohesion was associated with higher systolic (ß = 4.905, p = 0.009) and diastolic blood pressure (ß = 3.379, p = 0.008) among African Americans (n = 777). In one racially integrated low-income community, community characteristics were associated with blood pressure levels, and associations differed by race. Directions of associations for two findings differed from prior studies; greater community problem was associated with lower blood pressure in whites and community social cohesion was associated with higher blood pressure in African Americans. These findings may be due to exposure to adverse environmental conditions and hypertensive risk factors in this low-income community.

The association of neighborhood characteristics with obesity and metabolic conditions in older women.

OBJECTIVE: Previous studies exploring the relationship of neighborhood characteristics with metabolic conditions have focused on middle-aged adults but none have comprehensively investigated associations in older adults, a potentially vulnerable population. The aim was to explore the relationship of neighborhood characteristics with metabolic conditions in older women. DESIGN: Cross-sectional analysis. SETTING/PARTICIPANTS: We studied 384 women aged 70-79 years, representing the two-thirds least disabled women in the community, enrolled in the Women's Health and Aging Study II at baseline. Neighborhood scores were calculated from census-derived data on median household income, median house value, percent earning interest income, percent completing high school, percent completing college, and percent with managerial or executive occupation. Participants were categorized by quartile of neighborhood score with a higher quartile representing relative neighborhood advantage. Logistic regression models were created to assess the association of neighborhood quartiles to outcomes, adjusting for key covariates. MEASUREMENTS: Primary outcomes included metabolic conditions: obesity, diabetes, hypertension, and hyperlipidemia. Secondary outcomes included BMI, HbA1c, blood pressure and lipids. RESULTS: Higher neighborhood quartile score was associated with a lower prevalence of obesity (highest quartile=13.5% versus lowest quartile=36.5%; p<0.001 for trend). A lower prevalence of diabetes was also observed in highest (6.3%) versus lowest (14.4%) neighborhood quartiles, but was not significantly different (p= 0.24 for trend). Highest versus lowest neighborhood quartile was associated with lower HbA1c (-0.31%, p=0.02) in unadjusted models. Women in the highest versus lowest neighborhood quartile had lower BMI (-2.01 kg/m2, p=0.001) and higher HDL-cholesterol (+6.09 mg/dL, p=0.01) after accounting for age, race, inflammation, and smoking. CONCLUSION: Worse neighborhood characteristics are associated with adiposity, hyperglycemia, and low HDL. Further longitudinal studies are needed and can inform future interventions to improve metabolic status in older adults.

CAPABLE trial: a randomized controlled trial of nurse, occupational therapist and handyman to reduce disability among older adults: rationale and design.

BACKGROUND: As the population ages, it is increasingly important to test new models of care that improve life quality and decrease health costs. This paper presents the rationale and design for a randomized clinical trial of a novel interdisciplinary program to reduce disability among low income older adults based on a previous pilot trial of the same design showing strong effect. METHODS: The CAPABLE (Community Aging in Place, Advancing Better Living for Elders) trial is a randomized controlled trial in which low income older adults with self-care disability are assigned to one of two groups: an interdisciplinary team of a nurse, occupational therapist, and handyman to address both personal and environmental risk factors for disability based on participants' functional goals, or an attention control of sedentary activities of choice. Both groups receive up to 10 home visits over 4 months. OUTCOMES: The primary outcome is decreased disability in self-care (ADL). Secondary outcomes are sustained decrease in self care disability as well as improvement in instrumental ADLS, strength, balance, walking speed, and health care utilization. Careful cost tracking and analysis using intervention data and claims data will enable direct measurement of the cost impact of the CAPABLE approach. CAPABLE has the potential to leverage current health care spending in Medicaid waivers, Accountable Care Organizations and other capitated systems to save the health care system costs as well as improving low income older adults' ability to age at home with improved life quality.

Environmental & economic life cycle assessment of current & future sewage sludge to energy technologies.

The UK Water Industry currently generates approximately 800GWh pa of electrical energy from sewage sludge. Traditionally energy recovery from sewage sludge features Anaerobic Digestion (AD) with biogas utilisation in combined heat and power (CHP) systems. However, the industry is evolving and a number of developments that extract more energy from sludge are either being implemented or are nearing full scale demonstration. This study compared five technology configurations: 1 - conventional AD with CHP, 2 - Thermal Hydrolysis Process (THP) AD with CHP, 3 - THP AD with bio-methane grid injection, 4 - THP AD with CHP followed by drying of digested sludge for solid fuel production, 5 - THP AD followed by drying, pyrolysis of the digested sludge and use of the both the biogas and the pyrolysis gas in a CHP. The economic and environmental Life Cycle Assessment (LCA) found that both the post AD drying options performed well but the option used to create a solid fuel to displace coal (configuration 4) was the most sustainable solution economically and environmentally, closely followed by the pyrolysis configuration (5). Application of THP improves the financial and environmental performance compared with conventional AD. Producing bio-methane for grid injection (configuration 3) is attractive financially but has the worst environmental impact of all the scenarios, suggesting that the current UK financial incentive policy for bio-methane is not driving best environmental practice. It is clear that new and improving processes and technologies are enabling significant opportunities for further energy recovery from sludge; LCA provides tools for determining the best overall options for particular situations and allows innovation resources and investment to be focused accordingly.

After TGN1412: recent developments in cytokine release assays.

The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a 'Cytokine Storm'. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.

Regulatory requirements for therapeutic proteins: the relationship between the conformation and biological activity of filgrastim.

Higher order structure, including conformation, is considered a critical quality parameter of therapeutic proteins, and is mandatory information in development of first use and bio-similar therapeutic protein drugs, the assumption being that the biological activity of a protein is directly dependent on its adoption of a 'correct' conformation. Studies on the relationship between conformation and activity depend on the ability to induce conformational changes in proteins, and conventional approaches such as thermal or chemical denaturation are incompatible with bioactivity measurements. To explore the relationship between bio-activity and conformational studies, we have studied variants of the therapeutic protein filgrastim (rec met huGCSF) which have been mutated by the replacement of helical alanine residues with glycine, to destabilise the conformation of the molecule. In the GCSF A-G mutant series studied, single conformation-destabilising amino-acid substitutions significantly reduced the biological activity. These effects were not, however correlated with changes in secondary structure measurable by far-UV Circular Dichroism (CD) spectroscopy. Only the more extensively mutated double and triple substitutions showed measurable reductions in alpha-helical structure by CD. We conclude that in this system, GCSF does not readily adopt a reduced-activity altered conformational state which can be detected by low resolution techniques such as CD. In contrast, reductions in biological activity do reflect reductions in conformational stability, possibly caused by time-dependent degradation of the protein in the cell-proliferation bioassay. Although not a formal model of biosimilarity, we suggest that our results could inform the regulatory process in determining appropriate experimental approaches to meeting regulatory requirements for higher order structural analysis of therapeutic proteins.

Prevention of anastrozole induced bone loss with monthly oral ibandronate: Final 5 year results from the ARIBON trial.

PURPOSE: The ARIBON trial is a double blind, randomised, placebo controlled study designed to evaluate the impact of ibandronate on bone mineral density (BMD) in women taking anastrozole for adjuvant treatment of breast cancer. METHODS: 131 postmenopausal women with early breast cancer were recruited to the study. Of these, 13 had osteoporosis, 50 osteopenia and 68 normal BMD. Patients with osteoporosis at baseline were treated with monthly oral ibandronate 150 mg for 5 years; osteopenic patients were randomised to receive either ibandronate or placebo for two years and offered open label ibandronate depending upon the results of their 2-year BMD result. RESULTS: Of the 20 patients with osteopenia who were randomised to ibandronate and evaluable at the 2 year visit, 17/20 were not offered a bisphosphonate and the improvements in BMD accrued during the first 2 years were lost both at the LS (-3.21%) and TH (-5.0%). Of the 16 patients randomised to placebo 8/16 with high rates of bone loss during years 0-2 received ibandronate over the next 3 years with improvements in BMD of +5.01 and +1.19 at the LS and TH respectively. The 8 patients who were not offered a bisphosphonate experienced relatively little change in BMD throughout the 5 years of the study (LS +0.15%, TH -2.72%). BMD increased steadily in the 9/13 patients initially identified as having osteoporosis (LS +9.65%, TH +2.72%). CONCLUSIONS: Monthly oral ibandronate provides an option to clinicians considering use of a bisphosphonate to prevent bone loss during aromatase inhibitor therapy.