School-related sedentary behaviours and indicators of health and well-being among children and youth: a systematic review.

BACKGROUND: The purpose of this systematic review was to examine the associations between school-related sedentary behaviours and indicators of health and well-being in children and youth (~ 5-18 years) attending school. METHODS: This review was conducted to inform the development of School-Related Sedentary Behaviour Recommendations. Peer-reviewed, published, or in-press articles in English were included. Reviews, meta-analyses, and case studies were excluded; all other study designs were eligible. Further, articles had to meet the a priori study criteria for population, intervention, comparator (PROSPERO ID: CRD42021227600). Embase, MEDLINE® ALL, and PsycINFO were searched. Risk of bias was assessed for individual experimental studies using the Cochrane risk of bias assessment tool, and in observational studies based on the GRADE framework and in line with previous systematic reviews examining sedentary behaviours in children. Overall quality of evidence was assessed using the GRADE framework for each outcome category and study design. Results were synthesized narratively, grouped by study design and outcome category. Further, several high-level summaries were conducted to help interpret results. RESULTS: Evidence was synthesized from 116 reports, including 1,385,038 participants and 1173 extracted associations. More school-related sedentary behaviour was favourably associated with nearly one-third of extracted associations for cognitive (33%) and social-emotional (32%) indicators (e.g., less anxiety), but unfavourably associated with other movement behaviours (e.g., less physical activity) (35%). Active lessons were favourable (72%), compared to more school-related sedentary behaviours, when examining associations for all health and well-being indicators. More homework was favourable across all health and well-being indicators in 4% of extracted associations for primary school children, and 25% of extracted associations for secondary school children. However, ≥2 h/day of homework appeared to be unfavourable for health and well-being. Limitations for synthesized studies included generally low quality of evidence and a lack of studies in South American, African, or low-middle income countries. CONCLUSIONS: Findings can help inform policy makers, schools, and teachers, regarding the amount of homework assigned and the introduction of active lessons into the classroom to enhance health and well-being of children. More research is needed examining school-related sedentary behaviours and indicators of health and well-being in low- and middle-income countries.

International school-related sedentary behaviour recommendations for children and youth.

BACKGROUND: Existing sedentary behaviour guidelines for children and youth target overall sedentary behaviour and recreational screen time, without any specific recommendations regarding school-related sedentary behaviours (i.e., sedentary behaviours performed during the school day, or within the influence of school). The purpose of this paper is to describe the development of international evidence-based recommendations for school-related sedentary behaviours for children and youth, led by the Sedentary Behaviour Research Network (SBRN). METHODS: A panel of international experts was convened by SBRN in November 2020 to guide the development of these recommendations for children and youth aged ~ 5-18 years. The recommendations were informed by 1) age-relevant existing sedentary behaviour guidelines, 2) published research on the relationship between overall sedentary behaviour and health, 3) a de novo systematic review on the relationship between school-related sedentary behaviours and health and/or academic outcomes, and 4) a de novo environmental scan of the grey literature to identify existing recommendations for school-related sedentary behaviours. Draft recommendations were presented to the Expert Panel in June 2021. Following thorough discussion and modifications, updated recommendations were distributed for stakeholder feedback from July 9-26. Feedback was received from 148 stakeholders across 23 countries, leading to additional updates to the recommendations. Following further rounds of discussion and updates with the Expert Panel in August and September 2021, consensus was achieved on the final recommendations. RESULTS: A healthy day includes breaking up extended periods of sedentary behaviour and incorporating different types of movement into homework whenever possible, while limiting sedentary homework. School-related screen time should be meaningful, mentally or physically active, and serve a specific pedagogical purpose that enhances learning. Replacing sedentary learning activities with movement-based learning activities, and replacing screen-based learning activities with non-screen-based learning activities, can further support students' health and wellbeing. DISCUSSION: This paper presents the first evidence-based recommendations for school-related sedentary behaviours for children and youth. These recommendations will support the work of parents, caregivers, educators, school system administrators, policy makers, researchers and healthcare providers interested in promoting student health and academic success.

Development and psychometric evaluation of the Aversion to Bowel Cancer Screening Scale.

OBJECTIVE: Avoidance of colorectal cancer (CRC) screening is well documented with emotional barriers deterring screening intention and uptake. However, the assessment of such aversion is limited by the available instruments focusing on siloed emotions or screening procedures, limiting relevance to the complete process of decision-making in the CRC context. METHODS: To address this gap, psychometric properties of the newly developed Aversion to Bowel Cancer Screening Scale (ABCSS) were assessed using data from 640 CRC screening eligible asymptomatic community members. Item review and piloting reduced 179 items to the initial 29-item scale. Using a holdout sample technique, exploratory and confirmatory factor analysis, reliability and validity checks were conducted. RESULTS: A three-factor model (Fecal Occult Blood Test [FOBT] Aversion, Colonoscopy Aversion and Health Conscientiousness) with 21 items was identified. Analyses of the 21-item ABCSS indicated excellent reliabilities for the scale and subscales (α = .91 to .95). Correlations with relevant existing measures, intention and behaviour indicated good construct validity. CONCLUSION: The ABCSS is a valid measure of aversion to CRC screening for asymptomatic community members facing the decision to undertake CRC screening. This instrument may provide a more comprehensive understanding of the decision-making process for CRC screening.

Propensity score matching for multilevel spatial data: accounting for geographic confounding in health disparity studies.

BACKGROUND: Diabetes is a public health burden that disproportionately affects military veterans and racial minorities. Studies of racial disparities are inherently observational, and thus may require the use of methods such as Propensity Score Analysis (PSA). While traditional PSA accounts for patient-level factors, this may not be sufficient when patients are clustered at the geographic level and thus important confounders, whether observed or unobserved, vary by geographic location. METHODS: We employ a spatial propensity score matching method to account for "geographic confounding", which occurs when the confounding factors, whether observed or unobserved, vary by geographic region. We augment the propensity score and outcome models with spatial random effects, which are assigned scaled Besag-York-Mollié priors to address spatial clustering and improve inferences by borrowing information across neighboring geographic regions. We apply this approach to a study exploring racial disparities in diabetes specialty care between non-Hispanic black and non-Hispanic white veterans. We construct multiple global estimates of the risk difference in diabetes care: a crude unadjusted estimate, an estimate based solely on patient-level matching, and an estimate that incorporates both patient and spatial information. RESULTS: In simulation we show that in the presence of an unmeasured geographic confounder, ignoring spatial heterogeneity results in increased relative bias and mean squared error, whereas incorporating spatial random effects improves inferences. In our study of racial disparities in diabetes specialty care, the crude unadjusted estimate suggests that specialty care is more prevalent among non-Hispanic blacks, while patient-level matching indicates that it is less prevalent. Hierarchical spatial matching supports the latter conclusion, with a further increase in the magnitude of the disparity. CONCLUSIONS: These results highlight the importance of accounting for spatial heterogeneity in propensity score analysis, and suggest the need for clinical care and management strategies that are culturally sensitive and racially inclusive.

Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma.

BACKGROUND: Among patients with cervical cancer, little is known about the significance of persistent human papillomavirus (HPV) expression after chemoradiation (CRT). This study evaluated associations between early posttreatment HPV clearance and patient outcomes with an added focus on the value of posttherapy positron emission tomography (PET) imaging. METHODS: Included patients underwent pretreatment testing indicating a high-risk HPV infection and posttreatment testing with a messenger RNA (mRNA)-based genital swab after CRT. Posttherapy responses were stratified on the basis of HPV mRNA detection into an early clearance (EC) group (no mRNA) and a persistent expression (PE) group (detectable mRNA) on the basis of an evaluation at a median of 6 weeks after therapy. The Kaplan-Meier method was used to compare outcomes, and multivariable analysis was used to identify predictors of outcomes. RESULTS: Seventy-two of the 97 eligible patients (74.2%) had EC. The mean follow-up time was 25 months (range, 4-56 months), and 2-year pelvic control (76.9% vs 50.2%; P = .01) and overall survival (OS; 80.9% vs 52.2%; P < .01) were superior among EC patients. In the multivariable analysis, EC predicted for improved survival (hazard ratio [HR] for mortality, 0.46; 95% confidence interval [CI], 0.21-0.96; P = .047), as did a complete response (CR) on posttherapy PET (HR for less than a CR on PET, 6.17; 95% CI, 2.58-14.72; P < .01). In a subset analysis of patients with a posttherapy PET CR, HPV clearance retained prognostic significance (2-year OS, 95.6% with EC vs 66.7% with PE; P = .04), whereas PE patients without a PET CR had the worst survival (35.9%; P < .01 for trend). CONCLUSIONS: Early posttherapy clearance of HPV is associated with improved survival in cervical cancer. Evaluating HPV expression at this 6-week time point provides prognostic information beyond posttherapy PET imaging and may aid in risk stratification and decisions for treatment escalation.

Maturational timing, physical self-perceptions and physical activity in UK adolescent females: investigation of a mediated effects model.

BACKGROUND: Advanced (early) biological maturation may be a risk factor for inactivity among adolescent girls. AIM: To test the mediational effects of body attractiveness and physical self-worth on the relationship between biological maturity and accelerometer assessed moderate-to-vigorous physical activity (MVPA) in a large multi-ethnic sample of girls from the Midlands area in the UK (11-14 years). SUBJECTS AND METHODS: Biological maturity (predicting age at peak height velocity (APHV)); self-perceptions of body attractiveness, physical self-worth, and minutes spent in MVPA were assessed in 1062 females aged 11-14 years. RESULTS: Structural equation modelling using maximum likelihood estimation and boot- strapping procedures supported the hypothesised model. Later maturation predicted higher perceptions of body attractiveness (ß = 0.25, p < .001) which, in turn, predicted higher perceptions of physical self-worth (ß = 0.91, p < .001) and, significantly higher MVPA (ß = 0.22, p < .001). Examination of the bootstrap-generated bias-corrected confidence intervals suggested that perceptions of body attractiveness and physical self-worth partially mediated a positive association between predicted APHV and MVPA (ß = 0.05, p < .001). CONCLUSIONS: Greater biological maturity (i.e. early maturity) in adolescent girls is associated with less involvement in MVPA and appears to be partly explained by lower perceptions of body attractiveness and physical self-worth. Physical activity interventions should consider girls' perceptions of their pubertal related physiological changes during adolescence, particularly among early maturing girls.

Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eµ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.

A measurable impact of a self-practice/self-reflection programme on the therapeutic skills of experienced cognitive-behavioural therapists.

The need for effective training methods for enhancing cognitive-behavioural therapist competency is not only relevant to new therapists but also to experienced therapists looking to retain and further enhance their skills. Self-practice/self-reflection (SP/SR) is a self-experiential cognitive-behavioural therapy (CBT) training programme, which combines the experience of practicing CBT methods on oneself with structured reflection on the implications of the experience for clinical practice. In order to build on previous qualitative studies of SP/SR, which have mainly focused on trainee CBT therapists, the aim of the current study was to quantify the impact of SP/SR on the therapeutic skills of an experienced cohort of CBT therapists. Fourteen CBT therapists were recruited to participate in an SP/SR programme specifically adapted for experienced therapists. In the context of a quasi-experimental design including multiple baselines within a single-case methodology, therapists provided self-ratings of technical cognitive therapy skill and interpersonal empathic skill at four critical time points: baseline, pre-SP/SR and post-SP/SR and follow-up. Analysis of programme completers (n = 7) indicated that SP/SR enhances both technical skill and interpersonal therapeutic skill. Further intention-to-treat group (n = 14) analyses including both those who left the programme early (n = 3) and those who partially completed the programme (n = 4) added to the robustness of findings with respect to technical cognitive therapy skills but not interpersonal empathic skills. It was concluded that SP/SR, as a training and development programme, could offer an avenue to further therapeutic skill enhancement in already experienced CBT therapists.

Allochthonous marsh subsidies enhances food web productivity in an estuary and its surrounding ecosystem mosaic.

Terrestrial organic matter is believed to play an important role in promoting resilient estuarine food webs, but the inherent interconnectivity of estuarine systems often obscures the origins and importance of these terrestrial inputs. To determine the relative contributions of terrestrial (allochthonous) and aquatic (autochthonous) organic matter to the estuarine food web, we analyzed carbon, nitrogen, and sulfur stable isotopes from multiple trophic levels, environmental strata, and habitats throughout the estuarine habitat mosaic. We used a Bayesian stable isotope mixing model (SIMM) to parse out relationships among primary producers, invertebrates, and a pelagic and demersal fish species (juvenile Chinook salmon and sculpin, respectively). The study was carried out in the Nisqually River Delta (NRD), Washington, USA, a recently-restored, macrotidal estuary with a diverse habitat mosaic. Plant groupings of macroalgae, eelgrass, and tidal marsh plants served as the primary base components of the NRD food web. About 90% of demersal sculpin diets were comprised of benthic and pelagic crustaceans that were fed by autochthonous organic matter contributions from aquatic vegetation. Juvenile salmon, on the other hand, derived their energy from a mix of terrestrial, pelagic, and benthic prey, including insects, dipterans, and crustaceans. Consequently, allochthonous terrestrial contributions of organic matter were much greater for salmon, ranging between 26 and 43%. These findings demonstrate how connectivity among estuarine habitat types and environmental strata facilitates organic matter subsidies. This suggests that management actions that improve or restore lateral habitat connectivity as well as terrestrial-aquatic linkages may enhance allochthonous subsidies, promoting increased prey resources and ecosystem benefits in estuaries.

Geographic, Patient, and VA Medical Center Variation in the Receipt and Mode of Primary Care in a National Sample of Veterans with Diabetes during 2020.

While telemedicine infrastructure was in place within the Veterans Health Administration (VHA) healthcare system before the onset of the COVID-19 pandemic, geographically varying ordinances/closures disrupted vital care for chronic disease patients such as those with type 2 diabetes. We created a national cohort of 1,647,158 non-Hispanic White, non-Hispanic Black, and Hispanic veterans with diabetes including patients with at least one primary care visit and HbA1c lab result between 3.5% and 20% in the fiscal year (FY) 2018 or 2019. For each VAMC, the proportion of telehealth visits in FY 2019 was calculated. Two logistic Bayesian spatial models were employed for in-person primary care or telehealth primary care in the fourth quarter of the FY 2020, with spatial random effects incorporated at the VA medical center (MC) catchment area level. Finally, we computed and mapped the posterior probability of receipt of primary care for an "average" patient within each catchment area. Non-Hispanic Black veterans and Hispanic veterans were less likely to receive in-person primary care but more likely to receive tele-primary care than non-Hispanic white veterans during the study period. Veterans living in the most socially vulnerable areas were more likely to receive telehealth primary care in the fourth quarter of FY 2020 compared to the least socially vulnerable group but were less likely to receive in-person care. In summary, racial minorities and those in the most socially vulnerable areas were less likely to receive in-person primary care but more likely to receive telehealth primary care, potentially indicating a disparity in the impact of the pandemic across these groups.

Effect of expectancy and personality on cortical excitability in Parkinson's disease.

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Geographic variation in diabetic retinopathy screening within the Veterans Health Administration.

AIMS: Diabetic retinopathy (DR) remains the leading cause of vision impairment among working-age adults in the United States. The Veterans Health Administration (VA) supplemented its DR screening efforts with teleretinal imaging in 2006. Despite its scale and longevity, no national data on the VA's screening program exists since 1998. Our objective was to determine the influence of geography on diabetic retinopathy screening adherence. METHODS: Setting: VA national electronic medical records. STUDY POPULATION: A national cohort of 940,654 veterans with diabetes (defined as two or more diabetes ICD-9 codes (250.xx)) without a history of DR. EXPOSURES: 125 VA Medical Center catchment areas, demographics, comorbidity burden, mean HbA1c levels, medication use and adherence, as well as utilization and access metrics. MAIN OUTCOME MEASURE: Screening for diabetic retinopathy within the VA medical system within a 2-year period. RESULTS: Within a 2-year time frame 74 % of veterans without a history of DR received retinal screenings within the VA system. After adjustment for age, gender, race-ethnic group, service-connected disability, marital status, and the van Walraven Elixhauser comorbidity score, the prevalence of DR screening varied by VA catchment area with values ranging from 27 % to 86 %. These differences persisted after further adjusting for mean HbA1c level, medication use and adherence as well as utilization and access metrics. CONCLUSIONS: The wide variability in DR screening across 125 VA catchment areas indicates the presence of unmeasured determinants of DR screening. These results are relevant to clinical decision making in DR screening resource allocation.

Implementation of Magnetic Resonance Safety Program for Radiation Oncology.

During the last decade, radiation oncology departments have integrated magnetic resonance imaging (MRI) equipment, procedures, and expertise into their practices. MRI safety is an important consideration because a large percentage of patients receiving radiation therapy have histories of multiple surgeries and implanted devices. However, MRI safety guidelines and workflows were traditionally designed for radiology departments. This report presents an MR safety program designed for a radiation oncology department to address its specific needs.

Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab.

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.).

The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo.

Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC(50) (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

Geographic and Racial/Ethnic Variation in Glycemic Control and Treatment in a National Sample of Veterans With Diabetes.

OBJECTIVE: Geographic and racial/ethnic disparities related to diabetes control and treatment have not previously been examined at the national level. RESEARCH DESIGN AND METHODS: A retrospective cohort study was conducted in a national cohort of 1,140,634 veterans with diabetes, defined as two or more diabetes ICD-9 codes (250.xx) across inpatient and outpatient records. Main exposures of interest included 125 Veterans Administration Medical Center (VAMC) catchment areas as well as racial/ethnic group. The main outcome measure was HbA1c level dichotomized at ≥8.0% (≥64 mmol/mol). RESULTS: After adjustment for age, sex, racial/ethnic group, service-connected disability, marital status, and the van Walraven Elixhauser comorbidity score, the prevalence of uncontrolled diabetes varied by VAMC catchment area, with values ranging from 19.1% to 29.2%. Moreover, these differences largely persisted after further adjusting for medication use and adherence as well as utilization and access metrics. Racial/ethnic differences in diabetes control were also noted. In our final models, compared with non-Hispanic Whites, non-Hispanic Blacks (odds ratio 1.11 [95% credible interval 1.09-1.14]) and Hispanics (1.36 [1.09-1.14]) had a higher odds of uncontrolled HBA1c level. CONCLUSIONS: In a national cohort of veterans with diabetes, we found geographic as well as racial/ethnic differences in diabetes control rates that were not explained by adjustment for demographics, comorbidity burden, use or type of diabetes medication, health care utilization, access metrics, or medication adherence. Moreover, disparities in suboptimal control appeared consistent across most, but not all, VAMC catchment areas, with non-Hispanic Black and Hispanic veterans having a higher odds of suboptimal diabetes control than non-Hispanic White veterans.

Validation of an LC-MS based approach for profiling histones in chronic lymphocytic leukemia.

The in vitro evaluation of histones and their PTMs has drawn substantial interest in the development of epigenetic therapies. The differential expression of histone isoforms may serve as a potential marker in the classification of diseases affected by chromatin abnormalities. In this study, protein profiling by LC and MS was used to explore differences in histone composition in primary chronic lymphocytic leukemia (CLL) cells. Extensive method validations were performed to determine the experimental variances that would impact histone relative abundance. The resulting data demonstrated that the proposed methodology was suitable for the analysis of histone profiles. In 4 normal individuals and 40 CLL patients, a significant decrease in the relative abundance of histone H2A variants (H2AFL and H2AFA/M*) was observed in primary CLL cells as compared to normal B cells. Protein identities were determined using high mass accuracy MS and shotgun proteomics.

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.

MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC(50) (concentration lethal to 50%) of 0.23 micromol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0-12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3-4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.

Non-reactive solute diffusion in unconfined and confined specimens of a compacted soil.

The effect of specimen confinement on the determination of the effective diffusion coefficients, D*, for chloride, a non-reactive (non-adsorbing) solute, diffusing in a compacted soil was evaluated. The diffusion tests were performed by placing an acetic acid/sodium acetate buffer solution containing ZnCl2 (pH approximately 4.8) in a reservoir in contact with unconfined and confined specimens of a compacted sand-clay mixture for test durations of 7 or 14 d. The concentrations of chloride in the reservoir were measured as a function of time during the test, as well as a function of depth within the specimen at the end of the test. The resulting concentration distributions were analyzed using two models to Fick's second law for non-reactive solute diffusion in porous media, viz., (1) an analytical model assuming the porosity distribution could be represented by a single, weighted mean porosity and (2) a commercially available model, POLLUTE, that directly accounted for the measured porosity distribution. The D* for unconfined specimens based on the analytical model tended to be overestimated by a factor ranging from 1.13 to 1.59 relative to the D* using POLLUTE, whereas the D* values based on both methods for confined specimens typically were more consistent. In addition, the D* for unconfined specimens was greater than the D* for confined specimens when soil concentrations were used for the analysis, presumably due to the higher porosity for the unconfined specimens relative to the confined specimens. Analyses based on reservoir concentrations were inconsistent and contradictory in some cases, suggesting that the D* values based on soil concentrations were more reliable.

Addressing geographic confounding through spatial propensity scores: a study of racial disparities in diabetes.

Motivated by a study exploring differences in glycemic control between non-Hispanic black and non-Hispanic white veterans with type 2 diabetes, we aim to address a type of confounding that arises in spatially referenced observational studies. Specifically, we develop a spatial doubly robust propensity score estimator to reduce bias associated with geographic confounding, which occurs when measured or unmeasured confounding factors vary by geographic location, leading to imbalanced group comparisons. We augment the doubly robust estimator with spatial random effects, which are assigned conditionally autoregressive priors to improve inferences by borrowing information across neighboring geographic regions. Through a series of simulations, we show that ignoring spatial variation results in increased absolute bias and mean squared error, while the spatial doubly robust estimator performs well under various levels of spatial heterogeneity and moderate sample sizes. In the motivating application, we construct three global estimates of the risk difference between race groups: an unadjusted estimate, a doubly robust estimate that adjusts only for patient-level information, and a hierarchical spatial doubly robust estimate. Results indicate a gradual reduction in the risk difference at each stage, with the inclusion of spatial random effects providing a 20% reduction compared to an estimate that ignores spatial heterogeneity. Smoothed maps indicate poor glycemic control across Alabama and southern Georgia, areas comprising the so-called "stroke belt." These results suggest the need for community-specific interventions to target diabetes in geographic areas of greatest need.