High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

Comparison of Frailty Indices and the Charlson Comorbidity Index in Traumatic Brain Injury.

BACKGROUND: Comorbidity scales for outcome prediction in traumatic brain injury (TBI) include the 5-component modified Frailty Index (mFI-5), the 11-component modified Frailty Index (mFI-11), and the Charlson Comorbidity Index (CCI). OBJECTIVE: To compare the accuracy in predicting clinical outcomes in TBI of mFI-5, mFI-11, and CCI. METHODS: The National Trauma Data Bank (NTDB) of the American College of Surgeons (ACS) was utilized to study patients with isolated TBI for the years of 2017 and 2018. After controlling for age and injury severity, individual multivariable logistic regressions were conducted with each of the 3 scales (mFI-5, mFI-11, and CCI) against predefined outcomes, including any complication, home discharge, facility discharge, and mortality. RESULTS: All 3 scales demonstrated adequate internal consistency throughout their individual components (0.63 for mFI-5, 0.60 for CCI, and 0.56 for mFI-11). Almost all studied complications were significantly more likely in frail patients. mFI-5 and mFI-11 had similar areas under the curve (AUC) for all outcomes, while CCI had lower AUCs (0.62-0.61-0.53 for any complication, 0.72-0.72-0.52 for home discharge, 0.78-0.78-0.53 for facility discharge, and 0.71-0.70-0.52 for mortality, respectively). CONCLUSION: mFI-5 and mFI-11 demonstrated similar accuracy in predicting any complication, home discharge, facility discharge, and mortality in TBI patients across the NTDB. In addition, CCI's performance was poor for the aforementioned metrics. Since mFI-5 is simpler, yet as accurate as the 2 other scales, it may be the most practical both for clinical practice and for future studies with the NTDB.

Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures.

BACKGROUND: Three clusters of coronavirus disease 2019 (COVID-19) linked to a tour group from China, a company conference, and a church were identified in Singapore in February, 2020. METHODS: We gathered epidemiological and clinical data from individuals with confirmed COVID-19, via interviews and inpatient medical records, and we did field investigations to assess interactions and possible modes of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Open source reports were obtained for overseas cases. We reported the median (IQR) incubation period of SARS-CoV-2. FINDINGS: As of Feb 15, 2020, 36 cases of COVID-19 were linked epidemiologically to the first three clusters of circumscribed local transmission in Singapore. 425 close contacts were quarantined. Direct or prolonged close contact was reported among affected individuals, although indirect transmission (eg, via fomites and shared food) could not be excluded. The median incubation period of SARS-CoV-2 was 4 days (IQR 3-6). The serial interval between transmission pairs ranged between 3 days and 8 days. INTERPRETATION: SARS-CoV-2 is transmissible in community settings, and local clusters of COVID-19 are expected in countries with high travel volume from China before the lockdown of Wuhan and institution of travel restrictions. Enhanced surveillance and contact tracing is essential to minimise the risk of widespread transmission in the community. FUNDING: None.

May Measurement Month 2018: an analysis of blood pressure screening in the Philippines.

Building on the gains of May Measurement Month 2017 (MMM17), the Philippine Society of Hypertension once again took part in MMM18 to raise awareness of high blood pressure (BP) in the country and to harness opportunistic BP screening in detecting unaware hypertensive individuals and referring them for treatment. We followed the standard MMM18 protocol designed by the International Society of Hypertension, utilizing convenience sampling with volunteer investigators, taking three sitting BP measurements of volunteer adults (≥18 years). Basic data on demographic, lifestyle, and environmental factors were also taken. We analysed 177 176 screened individuals from the Philippines. Of these, 29.1% (51 527) had also participated in MMM17, whereas 68.8% (121 893) were new screenees; and 14.2% (25 232) had their BP taken for the first time ever. After multiple imputation, 39.0% (69 126) were hypertensive. Of these, 50.3% (34 795) were aware they were hypertensive. 49.9% (34 491) were on antihypertensive medication, 58.0% (20 010) of whom had controlled BP <140/90 mmHg. Only 28.9% of all participants with hypertension had controlled BP. Systolic BPs and diastolic BPs were significantly higher in the overweight and obese, in those receiving antihypertensive medications, in patients with diabetes, and significantly lower in pregnant women. MMM18 has again shown that opportunistic BP screening, harnessing volunteers, is a pragmatic public health measure to improve awareness and treatment rates of raised BP.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors.

The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.

Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution.

The optimal management of recurrent glioblastoma (GBM) has yet to be determined. We aim to assess the benefits of re-operation and salvage therapies (chemotherapy and/or re-irradiation) for recurrent GBM and to identify prognostic factors associated with better survival. All patients who underwent surgery for GBM between January 2005 and December 2012 followed by adjuvant radiotherapy, and who developed GBM recurrence on imaging were included in this retrospective study. Univariate and multivariate analysis was performed using Cox models in order to identify factors associated with overall survival (OS). One hundred and eighty patients treated to a dose of 60 Gy were diagnosed with recurrent GBM. At a median follow-up time of 6.2 months, the median survival (MS) from time of recurrence was 6.6 months. Sixty-nine patients underwent repeat surgery for recurrence based on imaging. To establish the benefits of repeat surgery and salvage therapies, 68 patients who underwent repeat surgery were matched to patients who did not based on extent of initial resection and presence of subventricular zone involvement at recurrence. MS for patients who underwent re-operation was 9.6 months, compared to 5.3 months for patients who did not have repeat surgery (p < 0.0001). Multivariate analysis in the matched pairs confirmed that repeat surgery with the addition of other salvage treatment can significantly affect patient outcome (HR 0.53). Re-operation with additional salvage therapies for recurrent GBM provides survival prolongation at the time of progression.

Acquiring nutrients from tree leaves: effects of leaf maturity and development type on a generalist caterpillar.

The rapid growth and prolific reproduction of many insect herbivores depend on the efficiencies and rates with which they acquire nutrients from their host plants. However, little is known about how nutrient assimilation efficiencies are affected by leaf maturation or how they vary between plant species. Recent work showed that leaf maturation can greatly decrease the protein assimilation efficiency (PAE) of Lymantria dispar caterpillars on some tree species, but not on species in the willow family (Salicaceae). One trait of many species in the Salicaceae that potentially affects PAE is the continuous (or "indeterminate") development of leaves throughout the growing season. To improve our understanding of the temporal and developmental patterns of nutrient availability for tree-feeding insects, this study tested two hypotheses: nutrients (protein and carbohydrate) are more efficiently assimilated from immature than mature leaves, and, following leaf maturation, nutrients are more efficiently assimilated from indeterminate than determinate tree species. The nutritional physiology and growth of a generalist caterpillar (L. dispar) were measured on five determinate and five indeterminate tree species while their leaves were immature and again after they were mature. In support of the first hypothesis, caterpillars that fed on immature leaves had significantly higher PAE and carbohydrate assimilation efficiency (CAE), as well as higher protein assimilation rates and growth rates, than larvae that fed on mature leaves. Contrary to the second hypothesis, caterpillars that fed on mature indeterminate tree leaves did not have higher PAE than those that fed on mature determinate leaves, while CAE differed by only 3% between tree development types. Instead, "high-PAE" and "low-PAE" tree species were found across taxonomic and development categories. The results of this study emphasize the importance of physiological mechanisms, such as nutrient assimilation efficiency, to explain the large variation in host plant quality for insect herbivores.

Human islet function following 20 years of cryogenic biobanking.

AIMS/HYPOTHESIS: There are potential advantages to the low-temperature (-196 °C) banking of isolated islets, including the maintenance of viable islets for future research. We therefore assessed the in vitro and in vivo function of islets cryopreserved for nearly 20 years. METHODS: Human islets were cryopreserved from 1991 to 2001 and thawed between 2012 and 2014. These were characterised by immunostaining, patch-clamp electrophysiology, insulin secretion, transcriptome analysis and transplantation into a streptozotocin (STZ)-induced mouse model of diabetes. RESULTS: The cryopreservation time was 17.6 ± 0.4 years (n = 43). The thawed islets stained positive with dithizone, contained insulin-positive and glucagon-positive cells, and displayed levels of apoptosis and transcriptome profiles similar to those of freshly isolated islets, although their insulin content was lower. The cryopreserved beta cells possessed ion channels and exocytotic responses identical to those of freshly isolated beta cells. Cells from a subset of five donors demonstrated similar perifusion insulin secretion profiles pre- and post-cryopreservation. The transplantation of cryopreserved islets into the diabetic mice improved their glucose tolerance but did not completely normalise their blood glucose levels. Circulating human insulin and insulin-positive grafts were detectable at 10 weeks post-transplantation. CONCLUSIONS/INTERPRETATION: We have demonstrated the potential for long-term banking of human islets for research, which could enable the use of tissue from a large number of donors with future technologies to gain new insight into diabetes.

Assessing reperfusion with whole-brain arterial spin labeling: a noninvasive alternative to gadolinium.

BACKGROUND AND PURPOSE: Arterial spin labeling (ASL) is a perfusion imaging technique that does not require gadolinium. The study aimed to assess the reliability of ASL for evaluating reperfusion in acute ischemic stroke in comparison with dynamic susceptibility contrast (DSC) imaging. METHODS: The study included 24 patients with acute ischemic stroke on admission and 24-hour follow-up ASL and DSC scans. Two readers rated images for interpretability and evidence of reperfusion. Cohen unweighted κ was used to assess (1) inter-rater reliability between readers for determining interpretability and the presence of reperfusion, (2) agreement between ASL and DSC for determining reperfusion for individual raters, and (3) agreement between ASL and DSC for determining reperfusion after consensus. RESULTS: Inter-rater reliability for both ASL and DSC was moderate to good (κ of 0.67 versus 0.55, respectively). Reader 1 rated 16 patients as having interpretable ASL and DSC when compared with 15 patients for reader 2. The κ between ASL and DSC for determining reperfusion was 0.50 for reader 1 and 0.595 for reader 2. After consensus, 18 ASL and 17 DSC image sets were rated interpretable for reperfusion and 13 had both interpretable ASL and DSC scans, yielding a κ for assessment of reperfusion of 0.8. CONCLUSIONS: Inter-rater reliability of ASL and DSC was moderate to good. Agreement between ASL and DSC for determining reperfusion was moderate for each individual rater and increased substantially after consensus. ASL is a noninvasive and practical alternative to DSC for reperfusion assessments in patients with confirmed acute ischemic stroke.

Predictors of mortality after emergency colectomy for Clostridium difficile colitis: an analysis of ACS-NSQIP.

OBJECTIVE: To evaluate clinical factors associated with mortality in emergency colectomies performed for Clostridium difficile colitis. BACKGROUND: The incidence and mortality from C difficile colitis is on the rise. Emergent colectomy performed for C difficile colitis is associated with a high mortality. METHODS: The ACS-NSQIP database from 2005 to 2010 was used to study emergently performed open colectomies for a primary diagnosis of C difficile colitis on the International Classification of Diseases, Ninth Revision. Preoperative, intraoperative, and postoperative factors were noted and compared between survivors and nonsurvivors. We performed multivariate stepwise binomial logistic regression analyses to study clinical factors that may be associated with 30-day mortality. RESULTS: The overall mortality for this cohort was 33% (111/335) with a median time to death of 8 days. On average, survivors were discharged on postoperative day 24. On multivariate analysis, those aged 80 years or older were associated with a ninefold increase in the odds of mortality [95% confidence interval (CI): 3.0-13.0]. Other factors associated with increased mortality were preoperative shock (OR=2.8, 95% CI: 1.6-5.4), preoperative dialysis dependence (OR=2.3, 95% CI: 1.1-4.8), chronic obstructive pulmonary disease (OR=3.7, 95% CI: 2.0-7.1), and wound class III (OR=2.1, 95% CI: 3.0-13). Thrombocytopenia (platelet count < 150×10(3)/mm(3)), coagulopathy (International Normalized Ratio>2.0), and renal insufficiency (blood urea nitrogen>40 mg/dL) were associated with a higher mortality as well. CONCLUSIONS: This is the largest series of colectomies performed for C difficile colitis in the literature. We identified several preoperative clinical risk factors that were associated with increased postoperative mortality. These findings may be useful in selecting appropriate patients for surgical intervention and may help to define a population where surgery may not be beneficial.

The long-term cost-effectiveness of varenicline (12-week standard course and 12 + 12-week extended course) vs. other smoking cessation strategies in Canada.

BACKGROUND: Smoking is the leading risk factor for preventable morbidity and mortality as a result of heart and lung diseases and various forms of cancer. Reimbursement coverage for smoking cessation therapies remains limited in Canada and the United States despite the health and economic benefits of smoking cessation. OBJECTIVES: This study aimed to evaluate the long-term cost-effectiveness of varenicline compared with other smoking cessation interventions in Canada using the Benefits of Smoking Cessation on Outcomes (BENESCO) model. METHODS: Efficacy rates of the standard course (12 weeks) varenicline, extended course (12 + 12 weeks) varenicline, bupropion, nicotine replacement therapy and unaided intervention were derived based on a published mixed treatment comparison methodology and analysed within a Markov cohort model to estimate their cost-effectiveness over the lifetime cycle. Study cohort, smoking rates and prevalence, incidence and mortality of smoking-related diseases were calibrated to represent the Canadian population. RESULTS: Over the subjects' lifetime, both the standard and the extended course of varenicline are shown to dominate (e.g. less costly and more effective) all other alternative smoking cessation interventions considered. Compared with the standard varenicline treatment course, the extended course is highly cost-effective with an incremental cost-effectiveness ratio (ICER) less than $4000 per quality-adjusted life year. Including indirect cost and benefits of smoking cessation interventions further strengthens the result with the extended course of varenicline dominating all other alternatives considered. LIMITATIONS: Evidence from complex smoking cessation models requiring numerous inputs and assumptions should be assessed in conjunction with evidence from other methodologies. CONCLUSIONS: The standard and extended courses of varenicline are decidedly cost-effective treatment regimes compared with alternative smoking cessation interventions and can provide significant cost savings to the healthcare system.

Travelers' thrombosis.

The suggestion that venous thromboembolism (VTE) is associated with air travel has for several decades been the subject of both "media hype" and extensive debate in the medical literature. As emotion and anecdote is often a feature in this debate, it is therefore necessary to separate evidence from anecdote. "Travelers' thrombosis" is a more appropriate term because the evidence suggests that any form of travel involving immobility lasting more than 4 h can predispose to thrombosis. There is no unique factor in the air travel cabin environment that has been shown to have any effect on the coagulation cascade. Prevention of thrombosis in any form of travel, including air travel, requires being aware of the issue and making an adequate risk assessment together with appropriate prophylactic measures.

Current status of hypertension care and management in the Philippines.

AIMS: In this paper, we discuss the existing data on the burden of hypertension in the Philippines and present the status of management, prevention, and control of hypertension in the country. METHODS: A literature review was conducted to synthesize the status of hypertension care in the Philippines. RESULTS: Hypertension continues to contribute to the country's leading causes of death. Similar to the global trend, almost half of hypertensive Filipinos are still not aware of their condition, and only 27 % have it under control. The prevalence of hypertension has steadily increased from 22 % in 1993 to 25.15 % in 2013. The 2020 Philippine Society for Hypertension clinical practice guideline defines hypertension as an office BP of 140/90 mm Hg or above following the proper standard BP measurement. During the past decade, monotherapy has been the mode of treatment in more than 80 % of Filipino patients. This could also explain why the BP control rates have been low. The most prevalent complications of hypertension in the Philippines were stroke (11.6 %), ischemic heart disease (7.7 %), chronic kidney disease (6.30 %), and hypertensive retinopathy (2.30 %). Hypertension causes economic tolls on patients, from the cost of drugs to hospitalization and complications. Hospitalization from hypertensive complications can easily wipe out the savings of middle-class families and is catastrophic for lower-income Filipinos. CONCLUSION: In this review, we summarize the existing data on the burden of hypertension among Filipinos and the risk factors associated with the disease. We present the current screening tools, diagnostics, treatment, and prevention strategies for hypertension in the Philippines. Lastly, we propose solutions to meet the global targets of hypertension management and help relieve the growing burden of this disease.

Importance of protein quality versus quantity in alternative host plants for a leaf-feeding insect.

The nutritional value of alternative host plants for leaf-feeding insects such as caterpillars is commonly measured in terms of protein quantity. However, nutritional value might also depend on the quality of the foliar protein [i.e., the composition of essential amino acids (EAAs)]. A lack of comparative work on the EAA compositions of herbivores and their host plants has hampered the testing of this hypothesis. We tested the "protein quality hypothesis" using the tree-feeding caterpillars of Lymantria dispar (gypsy moth) and two taxonomically unrelated host plants, red oak (Quercus rubra) and sugar maple (Acer saccharum). Because L. dispar has higher fitness on oak than on maple, support for the hypothesis would be found if protein were of higher quality from oak than from maple. The whole-body EAA composition of L. dispar larvae was measured to estimate its optimum dietary protein composition, which was compared with the EAA compositions of oak and maple leaves. Contrary to the protein quality hypothesis, the EAA compositions of oak and maple were not significantly different in the spring. The growth-limiting EAAs in both tree species were histidine and methionine. Similar results were observed in the summer, with the exception that the histidine composition of oak was between 10 and 15 % greater than in maple leaves. The two main factors that affected the nutritional value of protein from the tree species were the quantities of EAAs, which were consistently higher in oak, and the efficiency of EAA utilization, which decreased from 80 % in May to <50 % in August. We conclude that the relative nutritional value of red oak and sugar maple for L. dispar is more strongly affected by protein quantity than quality. Surveys of many wild herbaceous species also suggest that leaf-feeding insects would be unlikely to specialize on plants based on protein quality.

Allocation of cysteine for glutathione production in caterpillars with different antioxidant defense strategies: a comparison of Lymantria dispar and Malacosoma disstria.

Sulfur amino acids [cysteine (Cys) and methionine (Met)] play two major roles during animal development: protein synthesis for growth and glutathione synthesis for defense. For caterpillars, the levels of sulfur amino acids found in foliar protein can be especially low relative to their nutritional needs. Previous work has measured concentrations of glutathione (GSH; containing Cys) in specific animal tissues, but has not examined whole-body levels to ascertain the costliness of this defense in terms of Cys allocation. This study examined whether the production of GSH varies between species and within individuals in accordance with an insect's need for antioxidant defense. Secondly, we quantified the allocation of total Cys (peptide-bound plus free Cys) to GSH in caterpillars as an estimate of its cost. Two contrasting species were compared: Lymantria dispar (Lymantriidae), a species that is highly defended, and Malacosoma disstria (Lasiocampidae), a species that is less defended. As expected, GSH levels were significantly higher in L. dispar than in M. disstria. Consistent with the function of the midgut as a first line of defense against ingested toxins, GSH levels were significantly higher in these tissues than in the whole bodies of both species. A major finding in this study was that a large fraction of total Cys is used to produce GSH: GSH in the midguts of L. dispar and M. disstria contained 23 and 21%, respectively, of the total Cys in these tissues, and the GSH in their remaining body tissues contained 19 and 17% of the total Cys in these tissues. Levels of total Cys in caterpillar tissues followed the same pattern of distribution as did GSH, producing a strong association between GSH and total Cys (R(2) = 0.794). We conclude that GSH is a costly defense, especially in generalist tree-feeding species such as L. dispar. These results further suggest that the large allocation of Cys to GSH in highly defended species might produce a tradeoff by limiting the amount of Cys available for rapid growth.

Spider Bite Wound Care and Review of Traditional and Advanced Treatment Options.

Background: Approaches to chronic wound care are worlds apart: In developing nations, the care of chronic wounds often involves traditional management with local products (eg, honey, boiled potato peels, aloe vera gel, banana leaves); whereas in developed nations, more expensive and technologically advanced products are available (eg, wound vacuum, saline wound chamber, hyperbaric oxygen therapy, antibacterial foam). The cost for wound care plays a significant role in total health care costs, and that cost is expected to rise dramatically. Case Presentation: A healthy, 60-year-old man presented after being bitten by a spider 6 days earlier. He was treated and prescribed clindamycin 300 mg 4 times daily for 14 days. Despite treatment, the wound continued to enlarge, and the patient showed symptoms of septicemia. The patient was admitted to the hospital and remained for 3 days. On discharge the patient was given a prescription for doxycycline 100 mg twice a day for 10 days and instructed to use iodoform gauze to pack the wound during daily dressing changes. However, the gauze was ineffective. The patient's dressing was switched to an antibacterial foam dressing impregnated with gentian violet and methylene blue. Conclusions: There is a disparity in available wound care product availability. Modern products may yield faster healing times with fewer adverse effects than traditional products. Products used by local healers can produce satisfactory results when more modern products are unavailable and at a fraction of the cost.

Evaluating an ACT-Based Brief Intervention for Educators Treatment Package on Reported Well-Being and ACT-Consistent Language in the Classroom.

Educators continue to experience stress and burnout, both of which have been negatively impacted by the COVID-19 pandemic, and there continues to be a need to develop interventions that support not only educators' well-being, but a climate within school buildings that fosters psychological well-being for students and school staff alike. Acceptance and Commitment Therapy (ACT) is one promising approach to interventions for both educator and student psychological well-being. The present study sought to evaluate the effect of a low-dosage, online, and remotely delivered ACT intervention for educators on self-reported burnout, psychological flexibility, ACT knowledge, and frequency of use of ACT-consistent language while teaching in an alternative educational setting. The ACT-based intervention targeted the development of educator psychological flexibility, but the analysis provided an evaluation of non-targeted participants' use of ACT-consistent language in the classroom, as well. Results suggest an overall improvement in participants' self-reported burnout and psychological flexibility, an increase in participants' ACT knowledge following each phase of the study, and an increase in the frequency of ACT-consistent language for all participants following the onset of a feedback component. We discuss potential implications of practical ACT-based interventions for educators in an applied setting and related increases in ACT-consistent verbal stimuli within the classroom setting.

Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners.

Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.

Pseudocontinuous arterial spin labeling quantifies relative cerebral blood flow in acute stroke.

BACKGROUND AND PURPOSE: The aim of this study was to test whether arterial spin labeling (ASL) can detect significant differences in relative cerebral blood flow (rCBF) in the core, mismatch, and reverse-mismatch regions, and whether rCBF values measured by ASL in those areas differ from values obtained using dynamic susceptibility contrast (DSC) MRI. METHODS: Acute stroke patients were imaged with diffusion-weighted imaging (DWI) and perfusion-weighted imaging (ASL and DSC) MRI. An expert reader segmented the ischemic lesion on DWI and the DSC time-to-peak (TTP) maps. Three regions were defined: core (DWI+, TTP+), mismatch (DWI-, TTP+), and reverse-mismatch (DWI+, TTP-). For both ASL and DSC, rCBF maps were created with commercially available software, and the ratio was calculated as the mean signal intensity measured on the side of the lesion to that of the homologous region in the contralateral hemisphere. Values obtained from core, mismatch, and reverse-mismatch were used for paired comparison. RESULTS: Twenty-eight patients were included in the study. The mean age was 65.6 (16.9) years, with a median baseline National Institutes of Health Stroke Scale score of 10 (interquartile range, 4-17). Median time from last known normal to MRI was 5.7 hours (interquartile range, 2.9-22.6). Mean rCBF ratios were significantly higher in the mismatch 0.53 (0.23) versus the core 0.39 (0.33) and reverse-mismatch 0.68 (0.49) versus the core 0.38 (0.35). Differences in rCBF measured with DSC and ASL were not significant. CONCLUSIONS: ASL allows for the measurement of rCBF in the core and mismatch regions. Values in the mismatch were significantly higher than in the core, suggesting there is potential salvageable tissue.