Youth Mandate The School Board Elections Toolkit: How young people can build power through school board elections for 501(c)(3) Organizations

In the era of COVID-19 and following the 2020 wave of nationwide uprisings contesting white supremacy, United States politics have grown increasingly polarized at every level of government. Communities across the country are waging battles along partisan and ideological lines, from debates over public health measures, such as mask-wearing and vaccines, to whether to teach young people the truth about this country's legacy of enduring systemic racism or "critical race theory" and the need for police free schools. While there are limited opportunities for engagement on these issues at the national level, many community members have sought opportunities to engage in local politics. As a result, school boards – the most local and easily accessible form of government – have become sites of intense political and cultural debate.Indeed, the country has seen a recent flurry of engagement in school board races and increased scrutiny over election outcomes. A recent analysis by Ballotpedia identified at least 84 attempted school board recalls against 215 board members in 2021 – a significant increase from any other year since at least 2009. However, while school board activity has intensified since 2020, local activism in school board politics is not a new phenomenon. Since the 1950s, school board politics have proven meaningful to Black and Brown communities as they organize to dismantle white supremacy and fight for education justice in their communities.At this moment, with heightened levels of community engagement in school boards across the country, there are viable opportunities for young people, parents, and community members to participate in this critical site of local power and uplift their issues through the electoral process. The communities already building their participation in school board advocacy are demanding that school board members address how Black and Brown young people face harm in schools (including the racist and punitive school discipline policies and the presence of police and security in schools). They are calling on school board members to align with their bold vision for a liberatory education system based on inclusion, equity, and racial justice principles

Globalization of Alzheimer's disease clinical trials

Alzheimer's disease (AD) therapies are increasingly being tested in global clinical trials. A search of ClincalTrials.gov revealed that of 269 currently active trials, 28% are currently being conducted in the United States; the majority of trials and the majority of trial sites are ex-US. The US has the largest number of trial sites of any single country; cumulatively, nearly half of all sites are outside the US. The US conducts more trials in all phases of drug development but has a greater proportion of phase 3 trials. The increasing importance of global participants in clinical trials emphasizes the importance of considering the ethnic and international factors that may influence trial outcome. The International Conference on Harmonization guidelines divide ethnic factors that may affect drug development into intrinsic and extrinsic influences. These include language, cultural factors, educational levels, the general level of health and standard of care, as well as nutrition and diet. Ethnic influences on pharmacokinetics are known for some metabolic pathways. The biology of AD may also differ among the world's populations. The frequency of the apolipoprotein e4 allele, a major risk factor for AD, differs internationally. Genetic variations might also affect inflammatory, excitotoxic, and oxidative components of AD. Diagnostic standards and experience vary from country to country. Levels of practitioner training and experience, diagnostic approaches to AD, and attitudes regarding aging and AD may differ. Experience and sophistication with regard to clinical trial conduct also vary within and between countries. Experience with conducting the necessary examinations, as well as the linguistic and cultural validity of instrument translations, may affect trial outcomes. Operational and regulatory aspects of clinical trials vary and provide important barriers to seamless conduct of multiregional clinical trials. Collection and testing of biological samples, continuous provision of drug substance, and protection of the integrity of supply lines may be difficult in some international circumstances. Attention to these potential influences on clinical trials will determine the success of global drug development programs and the utility of global trials for developing new AD therapeutics

Modelling the urban heat island in Birmingham, UK at the neighbourhood scale

Cities have higher peak temperatures compared to surrounding rural areas. The urban-rural surface air temperature difference is known as the urban heat island (UHI). As extreme heat exposure can lead to adverse health effects, information on UHI characteristics of cities is important for future urban climate planning strategies. This study applied the ADMS-Urban Temperature and Humidity model to investigate the key processes driving the UHI in Birmingham, UK, at the neighbourhood scale. This model was configured with a range of input datasets (such as meteorological data, landuse data, building data, anthropogenic heat sources etc) and run on the University of Birmingham’s BlueBEAR HPC. This urban climate modelling was evaluated against the temperature measurement datasets from UK Met Office and Weather Underground. The spatiotemporal variations of surface air temperature in Birmingham, UK were captured by this model. This modelling study can be further applied to explore the impacts of local urban head island mitigation strategies

Using task farming to optimise a street-scale resolution air quality model of the West Midlands (UK)

High resolution air quality models combining emissions, chemical processes, dispersion and dynamical treatments are necessary to develop effective policies for clean air in urban environments, but can have high computational demand. We demonstrate the application of task farming to reduce runtime for ADMS-Urban, a quasi-Gaussian plume air dispersion model. The model represents the full range of source types (point, road and grid sources) occurring in an urban area at high resolution. Here, we implement and evaluate the option to automatically split up a large model domain into smaller sub-regions, each of which can then be executed concurrently on multiple cores of a HPC or across a PC network, a technique known as task farming. The approach has been tested for a large model domain covering the West Midlands, UK (902 km2), as part of modelling work in the WM-Air (West Midlands Air Quality Improvement Programme) project. Compared to the measurement data, overall, the model performs well. Air quality maps for annual/subset averages and percentiles are generated. For this air quality modelling application of task farming, the optimisation process has reduced weeks of model execution time to approximately 35 h for a single model configuration of annual calculations

Alzheimer\u27s Disease Drug Development Pipeline: 2019

Introduction Alzheimer\u27s disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices. Methods We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD. Results There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials. Discussion Drug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline

Bacteria in sputum of stable severe asthma and increased airway wall thickness

<p>Abstract</p> <p>Background</p> <p>Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness.</p> <p>Methods</p> <p>In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (W_T) and area (W_A) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels.</p> <p>Results</p> <p>Positive bacterial cultures were obtained in 29 patients, with <it>H. influenzae, P. aeruginosa </it>and <it>S. aureus </it>being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in W_A(67.5 ± 5.4 vs 66.4 ± 5.4) and W_T/D (21.6 ± 2.7 vs 21.3 ± 2.4) between the culture negative versus positive groups. Similarly, in airways (≤ 2 mm), there were no significant differences in these parameters. The ratio of √wall area to P_iwas negatively correlated with FEV₁% predicted (p < 0.05).</p> <p>Conclusions</p> <p>Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness.</p

Development and validation of a high-throughput cell-based screen to identify activators of a bacterial two-component signal transduction system

CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in Salmonella enterica serovar Typhimurium and Haemophilus ducreyi are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of Escherichia coli strains containing a CpxR-P-responsive lacZ reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimers disease patients.

INTRODUCTION: The A/T/N (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimers disease (AD) diagnosis and can encompass additional changes such as inflammation (I). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. HIGHLIGHTS: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate

Rasagiline Effects on Glucose Metabolism, Cognition, and Tau in Alzheimer’s Dementia

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer\u27s disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose–positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P \u3c 0.025), anterior cingulate (P \u3c 0.041), and striatal (P \u3c 0.023) regions. Clinical measures showed benefit in quality of life (P \u3c 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response