Ecosystems in the North American Arctic-Boreal Zone (ABZ) experience a diverse set of disturbances associated with wildfire, permafrost dynamics, geomorphic processes, insect outbreaks and pathogens, ...extreme weather events, and human activity. Climate warming in the ABZ is occurring at over twice the rate of the global average, and as a result the extent, frequency, and severity of these disturbances are increasing rapidly. Disturbances in the ABZ span a wide gradient of spatiotemporal scales and have varying impacts on ecosystem properties and function. However, many ABZ disturbances are relatively understudied and have different sensitivities to climate and trajectories of recovery, resulting in considerable uncertainty in the impacts of climate warming and human land use on ABZ vegetation dynamics and in the interactions between disturbance types. Here we review the current knowledge of ABZ disturbances and their precursors, ecosystem impacts, temporal frequencies, spatial extents, and severity. We also summarize current knowledge of interactions and feedbacks among ABZ disturbances and characterize typical trajectories of vegetation loss and recovery in response to ecosystem disturbance using satellite time-series. We conclude with a summary of critical data and knowledge gaps and identify priorities for future study.
One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that ...place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).
Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.
We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.
These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations ...in multiple histologic subtypes concurrently.
We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification.
Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years).
This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.
There has been considerable controversy about pre- versus postsynaptic expression of memory-related long-term potentiation (LTP), with corresponding disputes about underlying mechanisms. We report ...here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type 1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within the hippocampus depending upon the pattern of activity arriving over the parent axon.
To promote antimicrobial stewardship, many institutions have implemented a policy of reflexing to a urine culture based on a positive urinalysis result. The rehabilitation patient population, ...including individuals with brain and spinal cord injuries, may have atypical presentations of urinary tract infections. The study objective is to determine the effects of implementing a urine culture reflex policy in this specific patient population.
In an inpatient rehabilitation unit, 348 urinalyses were analyzed from August 2019 to June 2021. Urinalysis with greater than or equal to 10 white blood cells per high power field was automatically reflexed to a urine culture in this prospective study. Primary outcome was return to acute care related to urinary tract infection. Secondary outcomes included adherence to reflex protocol, antibiotic utilization and appropriateness, adverse outcomes related to antibiotic use, and reduction in urine cultures processed and the associated reduction in healthcare costs.
There was no statistically significant difference before and after intervention related to the primary outcome. Urine cultures processed were reduced by 58% after intervention.
Urine culture reflex policy is likely an effective intervention to reduce the frequency of urine cultures without significantly affecting the need to transfer patients from inpatient rehabilitation back to the acute care setting.
Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of ...failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies.
This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression.
A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio OR, 2.34; 95% confidence interval CI, 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02).
Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.
In the present study, we show a biphasic activation of hypoxia inducible factor 1alpha (HIF-1) after stroke that lasts for up to 10 d, suggesting the involvement of the HIF pathway in several aspects ...of the pathophysiology of cerebral ischemia. We provide evidence that HIF-1-mediated responses have an overall beneficial role in the ischemic brain as indicated by increased tissue damage and reduced survival rate of mice with neuron-specific knockdown of HIF-1alpha that were subjected to transient focal cerebral ischemia. In addition, we demonstrated that drugs known to activate HIF-1 in cultured cells as well as in vivo had neuroprotective properties in this model of cerebral ischemia. This protective effect was significantly attenuated but not completely abolished in neuron-specific HIF-1alpha-deficient mice, suggesting that alternative mechanisms of neuroprotection are also implicated. Last, our study showed that hypoxia-induced tolerance to ischemia was preserved in neuron-specific HIF-1alpha-deficient mice, indicating that the neuroprotective effects of hypoxic preconditioning do not depend on neuronal HIF-1 activation.
Confounding variables are a recurrent challenge for causal discovery and inference. In many situations, complex causal mechanisms only manifest themselves in extreme events, or take simpler forms in ...the extremes. Stimulated by data on extreme river flows and precipitation, we introduce a new causal discovery methodology for heavy-tailed variables that allows the effect of a known potential confounder to be almost entirely removed when the variables have comparable tails, and also decreases it sufficiently to enable correct causal inference when the confounder has a heavier tail. We also introduce a new parametric estimator for the existing causal tail coefficient and a permutation test. Simulations show that the methods work well and the ideas are applied to the motivating dataset.
Laguna de Bay, the largest and nationally significant freshwater lake ecosystem in the Philippines, has been increasingly subjected to anthropogenic pressures over the years. Domestic, agricultural, ...and industrial activities in the surrounding areas have contributed directly and indirectly to the deterioration of the lake’s overall ecological health and integrity. This study assessed the chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), lead (Pb), and cadmium (Cd) contamination in Asiatic clam,
Corbicula fluminea
, using quadrupole inductively coupled plasma–mass spectrometry. Estimated daily consumption of Asiatic clam was determined through a social survey. The data from analytical analysis and social surveys were utilized to calculate the target hazard quotient (THQ) to determine the potential health risks of consuming heavy metal–enriched clams to fishing households. Results from the Knowledge, Attitude, and Practices (KAP) survey indicated that the majority of the respondents have an acceptable level of knowledge on the hazards posed by the intake of contaminated clams but disapproved the banning of its collection and consumption. Sampled households with high consumption rates in all municipalities except Victoria were also found to be exposed to imminent health risk due to the high toxicity level of As based on their THQ values. Overall, one-third of the fishing households exposed to elevated health risk based on their total target hazard quotient (TTHQ) values already warrant a concern. The potential human health risks validate the worsening condition of Laguna de Bay. Integrative and holistic management of the lake through collaborative efforts of various stakeholders and institutions is necessary, to restore the health of the ecosystem and safeguard the health of the public.
Aim
To assess the effect of immersion in distilled water or phosphate‐buffered saline (PBS) on the solubility, volumetric change and presence of voids of calcium silicate‐based root canal sealers ...(TotalFill BC, Sealer Plus BC and Bio‐C), in comparison with the gold standard epoxy resin‐based sealer (AH Plus).
Methodology
All properties were evaluated after immersion in distilled water or PBS. Solubility was determined by the percentage of mass loss, whereas volumetric change and presence of voids were evaluated by micro‐computed tomography, after 7 days of immersion. The volumetric change and percentage of voids between the baseline (after setting) and the experimental period were calculated. Statistical analysis was performed using one‐way anova and Tukey's or Student's t‐tests (α = 0.05).
Results
The calcium silicate‐based sealers had significantly greater solubility and volumetric loss than AH Plus, after immersion in distilled water or PBS (P < 0.05). Bio‐C had the greatest solubility (P < 0.05), followed by TotalFill BC and Sealer Plus BC, which were similar (P > 0.05). Regarding the volumetric change, AH Plus had a volume increase, with similar values in distilled water and PBS (P > 0.05). TotalFill BC, Sealer Plus BC and Bio‐C had a similar volumetric change (P > 0.05). The calcium silicate‐based materials had the greatest solubility and volume loss after immersion in distilled water (P < 0.05). There was no difference in the percentage of voids amongst the sealers, before and after immersion in distilled water or PBS (P > 0.05).
Conclusions
TotalFill BC, Sealer Plus BC and Bio‐C had significantly greater solubility and volumetric loss than AH Plus. Although storage in PBS significantly reduced the solubility and volumetric change of calcium silicate‐based sealers, their solubility remained above that recommend by ISO 6876. All the sealers evaluated had low and similar voids, even after immersion in distilled water or PBS.
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