High exposure to warming from climate change is expected to threaten biodiversity by pushing many species toward extinction. Such exposure is often assessed for all taxa at a location from climate ...projections, yet species have diverse strategies for buffering against temperature extremes. We compared changes in species occupancy and site-level richness of small mammal and bird communities in protected areas of the Mojave Desert using surveys spanning a century. Small mammal communities remained remarkably stable, whereas birds declined markedly in response to warming and drying. Simulations of heat flux identified different exposure to warming for birds and mammals, which we attribute to microhabitat use. Estimates from climate projections are unlikely to accurately reflect species' exposure without accounting for the effects of microhabitat buffering on heat flux.
Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of ...immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants.
Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells.
No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P < 0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell-receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients.
The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.
The joint Russian (Mayak Production Association) and British (Sellafield) plutonium worker epidemiological analysis, undertaken as part of the European Union Framework Programme 7 (FP7) SOLO project, ...aims to investigate potential associations between cancer incidence and occupational exposures to plutonium using estimates of organ/tissue doses. The dose reconstruction protocol derived for the study makes best use of the most recent biokinetic models derived by the International Commission on Radiological Protection (ICRP) including a recent update to the human respiratory tract model (HRTM). This protocol was used to derive the final point estimates of absorbed doses for the study. Although uncertainties on the dose estimates were not included in the final epidemiological analysis, a separate Bayesian analysis has been performed for each of the 11 808 Sellafield plutonium workers included in the study in order to assess: A. The reliability of the point estimates provided to the epidemiologists and B. The magnitude of the uncertainty on dose estimates. This analysis, which accounts for uncertainties in biokinetic model parameters, intakes and measurement uncertainties, is described in the present paper. The results show that there is excellent agreement between the point estimates of dose and posterior mean values of dose. However, it is also evident that there are significant uncertainties associated with these dose estimates: the geometric range of the 97.5%:2.5% posterior values are a factor of 100 for lung dose, 30 for doses to liver and red bone marrow, and 40 for intakes: these uncertainties are not reflected in estimates of risk when point doses are used to assess them. It is also shown that better estimates of certain key HRTM absorption parameters could significantly reduce the uncertainties on lung dose in future studies.
Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty ...regarding its clinical value persists. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) to determine optimum thresholds for TB risk grouping; and (3) to determine whether TB influences responsiveness to chemotherapy.
TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified log-rank analyses on exploratory (n = 504), hypothesis-testing (n = 478), and final (n = 593) data sets.
The optimal threshold for high-grade TB (HGTB) was ≥ 10 buds per 1.23 mm2. High-grade TB tumors had significantly worse outcomes than those with lower TB: 10-year recurrence 36% versus 22% (risk ratio, 2.00 95% CI, 1.62-2.45; 2P < .0001) and 10-year mortality 50% vs. 37% (risk ratio, 1.53 95% CI, 1.34-1.76; 2P < .0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend toward increasing chemotherapy efficacy with increasing bud counts.
TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB; hence, absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with ≥ 10 than < 10 TB counts.
This study confirms the prognostic significance of tumor budding in colorectal carcinoma and shows a nonsignificant trend toward increasing chemotherapy efficacy with increasing tumor bud counts. The findings suggest that evaluation of tumor budding in stage II colorectal carcinoma can identify patients who may benefit from adjuvant therapy.
Process evaluation is increasingly recognized as an important component of effective implementation research and yet, there has been surprisingly little work to understand what constitutes best ...practice. Researchers use different methodologies describing causal pathways and understanding barriers and facilitators to implementation of interventions in diverse contexts and settings. We report on challenges and lessons learned from undertaking process evaluation of seven hypertension intervention trials funded through the Global Alliance of Chronic Diseases (GACD).
Preliminary data collected from the GACD hypertension teams in 2015 were used to inform a template for data collection. Case study themes included: (1) description of the intervention, (2) objectives of the process evaluation, (3) methods including theoretical basis, (4) main findings of the study and the process evaluation, (5) implications for the project, policy and research practice and (6) lessons for future process evaluations. The information was summarized and reported descriptively and narratively and key lessons were identified.
The case studies were from low- and middle-income countries and Indigenous communities in Canada. They were implementation research projects with intervention arm. Six theoretical approaches were used but most comprised of mixed-methods approaches. Each of the process evaluations generated findings on whether interventions were implemented with fidelity, the extent of capacity building, contextual factors and the extent to which relationships between researchers and community impacted on intervention implementation. The most important learning was that although process evaluation is time consuming, it enhances understanding of factors affecting implementation of complex interventions. The research highlighted the need to initiate process evaluations early on in the project, to help guide design of the intervention; and the importance of effective communication between researchers responsible for trial implementation, process evaluation and outcome evaluation.
This research demonstrates the important role of process evaluation in understanding implementation process of complex interventions. This can help to highlight a broad range of system requirements such as new policies and capacity building to support implementation. Process evaluation is crucial in understanding contextual factors that may impact intervention implementation which is important in considering whether or not the intervention can be translated to other contexts.
To generate the full diversity of antibody heavy-chain genes, hundreds of dispersed germline V segments must undergo recombination following D-J segment joining. Here we report that this process is ...regulated by the α-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis. D-J joining occurs normally in immature B lymphocytes from mice lacking the α-chain of the interleukin-7 receptor (IL-7Rα). But recombination of V segments is progressively impaired as their distance increases upstream of D/J, causing infrequent rearrangement of most V segments, which markedly reduces diversity. This is not simply due to defective cell proliferation or impaired recombinase expression. Rather, germline transcripts from distal, unrearranged V segments, a marker of chromatin changes that precede recombination, are specifically silenced. So too is expression of Pax-5, which binds to heavy-chain locus control elements and normally stimulates recombination, suggesting a mechanism for these effects. Thus ligands of the interleukin-7 receptor deliver an extrinsic signal that targets V segment recombination in the heavy-chain locus by altering the accessibility of DNA substrates to the recombinase. This mechanism augments the recombinational diversity of the primary antibody repertoire.
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease is the alignment of potency, drug-like ...properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.
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