The Role of CMC Statisticians: Co-Practitioners of the Scientific Method.

Chemistry, manufacturing, and control (CMC) statisticians play a key role in the development and lifecycle management of pharmaceutical and biological products, working with their non-statistician partners to manage product quality. Information used to make quality decisions comes from studies, where success is facilitated through adherence to the scientific method. This is carried out in four steps: (1) an objective, (2) design, (3) conduct, and (4) analysis. Careful consideration of each step helps to ensure that a study conclusion and associated decision is correct. This can be a development decision related to the validity of an assay or a quality decision like conformance to specifications. Importantly, all decisions are made with risk. Conventional statistical risks such as Type 1 and Type 2 errors can be coupled with associated impacts to manage patient value as well as development and commercial costs. The CMC statistician brings focus on managing risk across the steps of the scientific method, leading to optimal product development and robust supply of life saving drugs and biologicals.

Synthesis and Evaluation of Functionalized Polyurethanes for pH-Responsive Delivery of Compounds in Chronic Wounds.

Chronic wounds, depending on the bacteria that caused the infection, can be associated with an extreme acidic or basic pH. Therefore, the application of pH-responsive hydrogels has been instigated for the delivery of therapeutics to chronic wounds. Herein, with the aim of developing a flexible pH-responsive hydrogel, we functionalized hydrophilic polyurethanes with either cationic (polyethylene imine) or anionic (succinic anhydride) moieties. A comprehensive physicochemical characterization of corresponding polymers was carried out. Particularly, when tested in aqueous buffers, the surface charge of hydrogel films was closely correlated with the pH of the buffers. The loading of the cationic and anionic hydrogel films with various compound models (bromophenol blue; negatively charged or Pyronin Y; positively charged) showed that the electrostatic forces between the polymeric backbone and the compound model will determine the ultimate release rate at any given pH. The potential application of these films for chronic wound drug delivery was assessed by loading them with an antibiotic (ciprofloxacin). In vitro bacterial culturing was performed using Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Results showed that at the same drug dosage, different release profiles achievable from cationic and anionic polyurethanes can yield different degrees of an antibacterial effect. Overall, our results suggest the potential application of cationic and anionic hydrophilic polyurethanes as flexible pH-responsive materials for the delivery of therapeutics to chronic wounds.

Targeted postnatal knockout of Sclerostin using a bone-targeted adeno-associated viral vector increases bone anabolism and decreases canalicular density.

PURPOSE: The creation of murine gene knockout models to study bone gene functions often requires the resource intensive crossbreeding of Cre transgenic and gene-floxed strains. The developmental versus postnatal roles of genes can be difficult to discern in such models. For example, embryonic deletion of the Sclerostin (Sost) gene establishes a high-bone mass phenotype in neonatal mice that may impact on future bone growth. To generate a postnatal skeletal knockout of Sost in adult mice, this study used a single injection of a bone-targeted recombinant adeno-associated virus (rAAV) vector. METHODS: 8-week-old Sostflox/flox mice were injected with saline (control) or a single injection containing 5 × 1011 vg AAV8-Sp7-Cre vector. Ai9 fluorescent Cre reporter mice were dosed in parallel to confirm targeting efficiency. After 6 weeks, detailed bone analysis was performed via microCT, biomechanical testing, and bone histology on vertebral and long bone specimens. RESULTS: The AAV8-Sp7-Cre vector induced widespread persistent recombination in the bone compartment. Regional microCT analyses revealed significant increases in bone with vector treatment. In the L3 vertebrae, Sostflox/flox:AAV-Cre showed a 22 % increase in bone volume and 21 % in trabecular bone fraction compared to controls; this translated to a 17 % increase in compressive strength. In the tibiae, Sostflox/flox:AAV-Cre led to small but statistically significant increases in cortical bone volume and thickness. These were consistent with a 25 % increase in mineral apposition rate, but this did not translate into increased four-point bending strength. Ploton silver nitrate stain on histological sections revealed an unexpected increase in canalicular density associated with Sost ablation. CONCLUSION: This report demonstrates a proof-of-concept that the AAV8-Sp7-Cre vector can efficiently produce postnatal skeletal knockout mice using gene-floxed strains. This technology has the potential for broad utility in the bone field with existing conditional lines. These data also confirm an important postnatal role for Sost in regulating bone homeostasis, consistent with prior studies using neutralizing Sclerostin antibodies, and highlights a novel role of Sost in canalicular remodeling.

Does receipt of unemployment benefits change recruiter perceptions of candidates' personality, work relevant skills and employability?

BACKGROUND: Growing experimental evidence shows that unemployment benefit recipients are generally perceived negatively in terms of their personality and employability by the general public. Welfare stigma tied to unemployment or receipt of income support may disproportionately negatively impact individuals who have been out of work due to disability, or chronic health conditions. OBJECTIVE: The current study examined whether welfare stigma and/or unemployment stigma, translate to perceptions and hiring decisions made by individuals working in recruitment, potentially creating barriers to re-employment for those without work and relying on unemployment benefits. METHODS: We used a vignette-based experiment (N = 213) where participants working in recruitment rated personality and employment capabilities of characters who were described as employed, unemployed or unemployed and receiving benefits. RESULTS: Characters who were employed were generally rated more positively on employability and work-relevant skills, compared to the unemployed and unemployed benefit recipients, but these differences did not translate into a binary hiring decision (would you hire this person for the job). There were few differences in ratings of personality characteristics between the employed, the unemployed and those who were receiving unemployment benefits. CONCLUSIONS: These results add to knowledge about the determinants of welfare stigma showing that potential bias towards the unemployed and benefit recipients held by recruiters differs from that held by the general public.

Biopolymer-Based Multilayer Microparticles for Probiotic Delivery to Colon.

The potential health benefits of probiotics may not be realized because of the substantial reduction in their viability during food storage and gastrointestinal transit. Microencapsulation has been successfully utilized to improve the resistance of probiotics to critical conditions. Owing to the unique properties of biopolymers, they have been prevalently used for microencapsulation of probiotics. However, majority of microencapsulated products only contain a single layer of protection around probiotics, which is likely to be inferior to more sophisticated approaches. This review discusses emerging methods for the multilayer encapsulation of probiotic using biopolymers. Correlations are drawn between fabrication techniques and the resultant microparticle properties. Subsequently, multilayer microparticles are categorized based on their layer designs. Recent reports of specific biopolymeric formulations are examined regarding their physical and biological properties. In particular, animal models of gastrointestinal transit and disease are highlighted, with respect to trials of multilayer microencapsulated probiotics. To conclude, novel materials and approaches for fabrication of multilayer structures are highlighted.

Unemployment, Employability and COVID19: How the Global Socioeconomic Shock Challenged Negative Perceptions Toward the Less Fortunate in the Australian Context.

Unemployed benefit recipients are stigmatized and generally perceived negatively in terms of their personality characteristics and employability. The COVID19 economic shock led to rapid public policy responses across the globe to lessen the impact of mass unemployment, potentially shifting community perceptions of individuals who are out of work and rely on government income support. We used a repeated cross-sections design to study change in stigma tied to unemployment and benefit receipt in a pre-existing pre-COVID19 sample (n = 260) and a sample collected during COVID19 pandemic (n = 670) by using a vignette-based experiment. Participants rated attributes of characters who were described as being employed, working poor, unemployed or receiving unemployment benefits. The results show that compared to employed characters, unemployed characters were rated substantially less favorably at both time points on their employability and personality traits. The difference in perceptions of the employed and unemployed was, however, attenuated during COVID19 with benefit recipients perceived as more employable and more Conscientious than pre-pandemic. These results add to knowledge about the determinants of welfare stigma highlighting the impact of the global economic and health crisis on perception of others.

The impact of self-control training on neural responses following anger provocation.

Self-control training (SCT) is one way to enhance self-controlled behavior. We conducted a novel and exploratory functional magnetic resonance imaging experiment to examine how SCT affects neural responses in a situation that elicits a self-control response: anger provocation. Forty-five healthy young men and women completed two-weeks of SCT or a behavioral monitoring task and were then insulted during scanning. We found significant changes in functional activation and connectivity using a lenient error threshold, which were not observed using a stricter threshold. Activation in the posterior insula was greater for the control compared to the SCT group at post-provocation, trait aggression correlated with neural responses to SCT, and SCT was associated with specific amygdala-cortical connections. Neural changes occurred even though SCT did not affect participants' performance on an inhibition task, reports of trying to control their anger, or their experience of anger. This dissociation prevented clear interpretation about whether the neural changes were indicative of specific anger or anger control processes. Although replication with high-powered studies is needed, we provide evidence that SCT affects neural responses in the context of anger provocation.

The neural correlates of alcohol-related aggression.

Alcohol intoxication is implicated in approximately half of all violent crimes. Over the past several decades, numerous theories have been proposed to account for the influence of alcohol on aggression. Nearly all of these theories imply that altered functioning in the prefrontal cortex is a proximal cause. In the present functional magnetic resonance imaging (fMRI) experiment, 50 healthy young men consumed either a low dose of alcohol or a placebo and completed an aggression paradigm against provocative and nonprovocative opponents. Provocation did not affect neural responses. However, relative to sober participants, during acts of aggression, intoxicated participants showed decreased activity in the prefrontal cortex, caudate, and ventral striatum, but heightened activation in the hippocampus. Among intoxicated participants, but not among sober participants, aggressive behavior was positively correlated with activation in the medial and dorsolateral prefrontal cortex. These results support theories that posit a role for prefrontal cortical dysfunction as an important factor in intoxicated aggression.

Using Longitudinal Survey Data to Estimate Mental Health Related Transitions to a Disability Pension: Analysis of an Australian Household Panel Study.

OBJECTIVE: This study examined the association between mental ill-health and subsequent receipt of a disability pension in Australia, and assessed how the strength of the association varied in relation to the duration between mental health measurement and reported disability pension receipt. METHODS: Eight thousand four hundred seventy-four working-age adults not receiving a disability pension at baseline were followed for up to 11 years; 349 transitioned onto a disability pension. Discrete-time survival analysis considered baseline and time-varying (12-month lagged) measures of mental ill-health. RESULTS: Proximal measures of mental ill-health were more strongly associated with subsequent pension receipt than baseline measures (odds ratio: 6.6 vs 3.9) and accounted for a significantly greater proportion of pension transitions (35% vs 21%). CONCLUSION: Mental ill-health is an independent risk factor for disability pension receipt, and proximal circumstances better capture this association than mental health measured earlier.

No experimental evidence for visual prior entry of angry faces, even when feeling afraid.

Threatening stimuli prevent attentional disengagement. Less clear is whether threat captures attention in addition to holding it. One way to measure attentional capture is to examine visual prior entry. Visual prior entry occurs when one stimulus is consciously recognized as appearing prior to other stimuli. Using a temporal order judgments paradigm, we examined whether threatening, angry faces would experience visual prior entry. Such a finding would provide evidence for attentional capture by threat. We further examined whether such attentional capture by threat was contingent on feeling afraid. Using Bayesian analyses, we found moderate support for the null hypothesis in 2 experiments (Ns = 44, 63). Angry faces did not capture attention, and there was no effect of feeling afraid because of watching a horror movie (Experiment 1) or anticipatory fear about giving a speech in front of an expert panel (Experiment 2). These studies were supplemented with a meta-analysis that suggests the visual prior entry effect is very small, if indeed it exists. Thus, the visual prior entry effect for threatening faces is likely a much smaller effect than the extant literature suggests. (PsycINFO Database Record

Time-of-day effects in implicit racial in-group preferences are likely selection effects, not circadian rhythms.

Time-of-day effects in human psychological functioning have been known of since the 1800s. However, outside of research specifically focused on the quantification of circadian rhythms, their study has largely been neglected. Moves toward online data collection now mean that psychological investigations take place around the clock, which affords researchers the ability to easily study time-of-day effects. Recent analyses have shown, for instance, that implicit attitudes have time-of-day effects. The plausibility that these effects indicate circadian rhythms rather than selection effects is considered in the current study. There was little evidence that the time-of-day effects in implicit attitudes shifted appropriately with factors known to influence the time of circadian rhythms. Moreover, even variables that cannot logically show circadian rhythms demonstrated stronger time-of-day effects than did implicit attitudes. Taken together, these results suggest that time-of-day effects in implicit attitudes are more likely to represent processes of selection rather than circadian rhythms, but do not rule out the latter possibility.

Patterns of Welfare Attitudes in the Australian Population.

The study of community attitudes toward welfare and welfare recipients is an area of increasing interest. This is not only because negative attitudes can lead to stigmatization and discrimination, but because of the relevance of social attitudes to policy decisions. We quantify the attitudes toward welfare in the Australian population using attitude data from a nationally representative survey (N = 3243). Although there was broad support for the social welfare system, negative attitudes are held toward those who receive welfare benefits. Using canonical correlation analysis we identify multivariate associations between welfare attitudes and respondent demographic characteristics. A primary attitudinal dimension of welfare positivity was found amongst those with higher levels of education, life instability, and personal exposure to the welfare system. Other patterns of negative welfare attitudes appeared to be motivated by beliefs that the respondent's personal circumstances indicate their deservingness. Moreover, a previously unidentified and unconsidered subset of respondents was identified. This group had positive attitudes toward receiving government benefits despite having no recent experience of welfare. They did, however, possess many of the characteristics that frequently lead to welfare receipt. These results provide insights into not only how attitudinal patterns segment across the population, but are of relevance to policy makers considering how to align welfare reform with community attitudes.

Brief mindfulness induction reduces inattentional blindness.

Prior research has linked mindfulness to improvements in attention, and suggested that the effects of mindfulness are particularly pronounced when individuals are cognitively depleted or stressed. Yet, no studies have tested whether mindfulness improves declarative awareness of unexpected stimuli in goal-directed tasks. Participants (N=794) were either depleted (or not) and subsequently underwent a brief mindfulness induction (or not). They then completed an inattentional blindness task during which an unexpected distractor appeared on the computer monitor. This task was used to assess declarative conscious awareness of the unexpected distractor's presence and the extent to which its perceptual properties were encoded. Mindfulness increased awareness of the unexpected distractor (i.e., reduced rates of inattentional blindness). Contrary to predictions, no mindfulness×depletion interaction emerged. Depletion however, increased perceptual encoding of the distractor. These results suggest that mindfulness may foster awareness of unexpected stimuli (i.e., reduce inattentional blindness).

Temporal alcohol availability predicts first-time drunk driving, but not repeat offending.

Alcohol availability has been linked to drunk driving, but research has not examined whether this relationship is the same for first-time and repeat offenses. We examined the relationship between the business hours of alcohol outlets licensed to serve alcohol for on-premises consumption and misdemeanor-level (first offense) and felony-level drunk driving (repeat offense) charges in New York State in 2009. Longer outlet business hours were associated with more misdemeanor drunk driving charges, but were not associated with felony drunk driving charges. The per capita density of on-premises alcohol outlets did not affect misdemeanor or felony drunk driving charges. The results suggest that temporal alcohol availability may be an impelling factor for first-time drunk driving, but other factors likely influence repeat drunk driving behaviors.

Alcohol outlet business hours and violent crime in New York state.

AIMS: Alcohol-related harm places a significant strain on victims, perpetrators and society. The present research reports on how licensed alcohol outlet business hours may influence the reported incidence of interpersonal violence and the associated burden of disease. METHODS: We examined the relationship between alcohol outlet business hours and violent crime in 2009 in New York State (excluding New York City). Regression analyses modeled the burden of disease for the violence associated with outlet business hours. RESULTS: Every 1 h increase in weekly outlet business hours was associated with a greater reported incidence of violent crimes generally, more reported aggravated assaults and more reported non-gun violence. The estimated cost from having licensed premises open after 1 a.m. was $194 million in 2009. CONCLUSION: The findings suggest that alcohol outlet business hours affect the incidence of reported violence even in regions that would not be considered to have severe problems with alcohol-fueled violence.

Meeting report: applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit.

A biopharmaceutics and Quality by Design (QbD) conference was held on June 10-12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patient's needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward.

A vaccine measured with a highly variable assay: rabies.

Manufacturers and regulators are challenged when evaluating stability of vaccines when potency is measured using a highly variable assay. Participants in the IABS Workshop on Stability Evaluation of Vaccines, a Life Cycle Approach, were offered a case study from a series of stability studies of a rabies vaccine, using the NIH potency assay. The case study was introduced with a scenario in which a new manufacturer was to formulate, lyophilize and fill the vaccine from bulk supplied by another manufacturer. The regulatory authority requested that data from the new manufacturer be supplied, to supplement that of the original producer. Participants were asked to answer a series of questions posed by the regulator, and critique the study design and data analysis according to principles described during the workshop.

Model format for a vaccine stability report and software solutions.

A session of the International Association for Biologicals Workshop on Stability Evaluation of Vaccine, a Life Cycle Approach was devoted to a model format for a vaccine stability report, and software solutions. Presentations highlighted the utility of a model format that will conform to regulatory requirements and the ICH common technical document. However, there need be flexibility to accommodate individual company practices. Adoption of a model format is premised upon agreement regarding content between industry and regulators, and ease of use. Software requirements will include ease of use and protections against inadvertent misspecification of stability design or misinterpretation of program output.

Basic principles of stability.

An understanding of the principles of degradation, as well as the statistical tools for measuring product stability, is essential to management of product quality. Key to this is management of vaccine potency. Vaccine shelf life is best managed through determination of a minimum potency release requirement, which helps assure adequate potency throughout expiry. Use of statistical tools such a least squares regression analysis should be employed to model potency decay. The use of such tools provides incentive to properly design vaccine stability studies, while holding stability measurements to specification presents a disincentive for collecting valuable data. The laws of kinetics such as Arrhenius behavior help practitioners design effective accelerated stability programs, which can be utilized to manage stability after a process change. Design of stability studies should be carefully considered, with an eye to minimizing the variability of the stability parameter. In the case of measuring the degradation rate, testing at the beginning and the end of the study improves the precision of this estimate. Additional design considerations such as bracketing and matrixing improve the efficiency of stability evaluation of vaccines.