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BackgroundNintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC).DesignEORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety.ResultsRAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9–6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0–5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42–0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2–not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3–4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9–8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0–5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16–1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1–24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1–NR) in the placebo arm. Grade 3–4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo.ConclusionThis study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Studies of end-of-life care face difficulties associated with enrollment and attrition. Information and exemplars can help end-of-life care researchers anticipate such difficulties and customize recruitment and retention strategies to achieve planned sample sizes. We analyzed data on recruitment and retention efforts used in a clinical trial of an end-of-life communication intervention that involved African Americans dialysis patients and their chosen surrogate decision makers. Despite the challenges the trial faced (eg, recruiting a minority group of patients who were seriously ill, had a surrogate decision maker willing to join the study, and were willing to join the study, and were willing to engage in end-of-life discussions), the planned sample size was met, and nearly 90% of the participants completed the study. Various strategies were used to sustain accrual during the study. Although a total of 16 contacts per dyad had been planned from enrollment to 3-month data collection, 27 contacts were actually needed. The strategies and procedures used in this study may be pertinent to other studies that involve African Americans with serious illness and require dyadic participation. [ABSTRACT FROM AUTHOR]

The prevalence of and mortality from chronic kidney disease (CKD) are high among African Americans. Interventions to improve knowledge of the likely illness course and the benefits and risks of life-sustaining treatment at the end-of-life are needed for African Americans with CKD and their surrogate decision makers. Nineteen African Americans with stage 5 CKD and their surrogates were randomized to either patient-centered advance care planning (PC-ACP) or usual care. PC-ACP dyads showed greater improvement in congruence in end-of-life treatment preferences (p < .05) and higher perceived quality of communication (p < .05) than do control dyads, but the two groups did not differ on other primary outcomes or acceptability measures, such as perceptions of cultural appropriateness. At posttest, 80% of patients in the intervention group reported that they would choose to continue all life-sustaining treatments in a situation of a low chance of survival, whereas 28.6% of patients in the control group reported that they would make that choice. At posttest, 90% of patients in the intervention group reported that they would choose to undergo cardiopulmonary resuscitation even if the chance of surviving the attempt would be low, whereas 57% of patients in the control group reported that they would make that choice. PC-ACP can be effective in improving patient and surrogate congruence in end-of-life treatment preferences. However, the results suggest a need for further improvements in the intervention to enhance cultural appropriateness for African Americans with CKD. ©2010 Elsevier Inc. All rights reserved.Copyright © 2010 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

A literature review was conducted to identify studies exploring the cost-effectiveness of intensive lipid-lowering regimens compared with a generic low-dose statin for individuals with acute coronary syndrome. Three papers matched the inclusion criteria. All used a Markov model to represent the long-term clinical pathway; two were set in the UK and one was in the USA. While there were substantial differences in the effectiveness data, the definitions of the health states and the numbers of events predicted, all authors found that the intensive regimen was a cost-effective alternative compared with a generic lower dose statin. If the cost of atorvastatin reduces from GBP 368 pounds to 90 pounds per annum when the patent expires in 2011, atorvastatin 80 mg/day would be the most optimal treatment for this patient group. Simvastatin 80 mg/day should not be considered an alternative owing to an adverse safety profile and limited additional benefits. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Based on a stress-coping perspective, the present study was designed to examine links between patients' beliefs (barriers), coping (analgesic use), and quality of life (QOL) outcomes. DESIGN: Not given. SETTING: Outpatient clinic. POPULATION: Participants were outpatients from either a comprehensive cancer center or a private oncology clinic. Inclusion criteria for the parent (intervention) study were diagnosis of metastatic breast or prostate cancer, lung cancer or multiple myeloma. Three hundred sixteen persons were invited to join the study and 240 did so. Of those, 182 reported cancer-related pain; these are the participants involved in this report. Participants were 114 women and 68 men who ranged in age from 31 to 84 years. INTERVENTIONS: Eligible patients were approached by a nurse in the outpatient clinic. After consent, study personnel interviewed the patient to collect data about pain history and recent (past week) analgesic use. The patient was asked to complete the packet of self-report questionnaires while waiting to be seen by a clinician. The Barriers Questionnaire (BQ) is a 27-item instrument designed to measure the extent to which patients have concerns about reporting pain and using analgesics. Three items from the Brief Pain Inventory (BPI) were used to assess pain severity. Coping was operationalized as analgesic use and was measured with a revised version of the Pain Management Index (PMI). The Medication Side-Effect Checklist (MSEC) was used to assess severity of analgesic side-effects. Three facets of impaired QOL were examined. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressed mood. MAIN OUTCOME MEASURE(S): Means for pain severity, barriers, side-effect severity, and interference with life activities were low to moderate. Depression scores were moderate to high. Perceived health varied, with 2 (1%) of the patients viewing their health as very poor, 25 (14%) seeing it as poor, 50 (28%) as fair, 87 (48%) as good, and 17 (9%) as excellent. Coping was inversely associated with pain severity: the more effective the analgesic use the lower was the patient's 'pain now' score. Unexpectedly, coping was not associated with side-effect severity. However, both pain severity and side effects were positively related to impairments in QOL, with the exception that pain severity was not significantly related to depression. RESULTS/CONCLUSIONS: Taken as a whole, the findings point to two areas in which interventions are needed in order to maximize QOL. First, it would be useful to test the impact of informational interventions on beliefs that are barriers to analgesic use. In addition, further attention should be given to refining a measure of coping. As recommended by current practice guidelines (U.S. Department of Health and Human Services, 1994), proactive management of analgesic side effects needs to become a routine facet of pain management. [CINAHL abstract] [ABSTRACT FROM AUTHOR]

Cancer-related pain not only affects the patient but the family/caregiver as well. The purpose of this study was to examine concerns about reporting pain and using analgesics in a sample of primary caregivers of cancer patients receiving care from a hospice program. The Barriers Questionnaire (BQ), an instrument designed to measure eight common barriers to adequate management of cancer pain, was administered to 37 persons identified as primary caregivers. Between 62 percent and 100 percent of the caregivers reported having at least some agreement with the various concerns that are barriers to reporting pain and using analgesics, and 3 percent to 43 percent reported having strong agreement. The subscales with the highest means were fear of opioid side effects, fear of addiction, the belief that increasing pain signifies disease progression, and the fear of injections. Caregivers who were older and less educated were more likely to believe that reporting pain may distract the physician from treating or curing the cancer. In addition, caregivers with lower educational levels had higher scores on the overall BQ. Finally, caregivers of patients who reported pain was not a problem on program admission had greater concerns about tolerance and were more likely to believe that 'good' patients do not complain. The caregiver, often, with time and the declining abilities of the patient, becomes the first line decision maker regarding the patient's care and treatment. Understanding caregiver perspectives is important for continued success with managing pain in hospice and, arguably, all settings. [ABSTRACT FROM AUTHOR]

The fact that your patient says he feels satisfied with his pain management doesn't mean he's getting the most therapeutic level of relief available. Here's how a team of nurses helped one patient set -- and meet-- a realistic pain relief goal. [ABSTRACT FROM AUTHOR]

Abstract Background Arsenic is toxic to most living cells. The two soluble inorganic forms of arsenic are arsenite (+3) and arsenate (+5), with arsenite the more toxic. Prokaryotic metabolism of arsenic has been reported in both thermal and moderate environments and has been shown to be involved in the redox cycling of arsenic. No arsenic metabolism (either dissimilatory arsenate reduction or arsenite oxidation) has ever been reported in cold environments (i.e. < 10°C). Results Our study site is located 512 kilometres south of the Arctic Circle in the Northwest Territories, Canada in an inactive gold mine which contains mine waste water in excess of 50 mM arsenic. Several thousand tonnes of arsenic trioxide dust are stored in underground chambers and microbial biofilms grow on the chamber walls below seepage points rich in arsenite-containing solutions. We compared the arsenite oxidisers in two subsamples (which differed in arsenite concentration) collected from one biofilm. 'Species' (sequence) richness did not differ between subsamples, but the relative importance of the three identifiable clades did. An arsenite-oxidising bacterium (designated GM1) was isolated, and was shown to oxidise arsenite in the early exponential growth phase and to grow at a broad range of temperatures (4-25°C). Its arsenite oxidase was constitutively expressed and functioned over a broad temperature range. Conclusions The diversity of arsenite oxidisers does not significantly differ from two subsamples of a microbial biofilm that vary in arsenite concentrations. GM1 is the first psychrotolerant arsenite oxidiser to be isolated with the ability to grow below 10°C. This ability to grow at low temperatures could be harnessed for arsenic bioremediation in moderate to cold climates.

Abstract Background We previously identified eight known and novel genes differentially expressed in the small intestines of wild type and W/WV mice, which have greatly reduced populations of the interstitial cells of Cajal, that are responsible for the generation of electrical slow waves, by using a differential gene display method. Methods By using the same method we isolated additional candidate genes that were specifically down- or up-regulated in W/WV mice. Novel transcripts were designated as DDWMEST. Results We isolated seven candidates that were specifically down- or up-regulated in W/WV mice. Two novel transcripts, DDWMEST 1 and -91 were increased in both fed and fasted W/WV mice. Expression of another five genes was suppressed in W/WV mice: ARG2 (Arginase II), ONZIN (encoding leukemia inhibitory factor regulated protein), and three novel transcripts: DDWMEST62, -84, and -100. Together with the previous report, we identified fifteen differentially expressed genes in total in the small intestines of W/WV mice. Eight of these genes were reduced in the jejunums of W/WV mice compared to age matched wild type mice, whereas the other seven genes showed an increase in expression. Differential expression was the same in fasted and fed animals, suggesting that the differences were independent of the dietetic state of the animal. Conclusions Several known and novel genes are differentially expressed in the small intestines of W/WV mice. Differential gene comparison might contribute to our understanding of motility disorders associated with the loss of the interstitial cells of Cajal.

Abstract Background The muscle layers of murine gastric fundus have no interstitial cells of Cajal at the level of the myenteric plexus and only possess intramuscular interstitial cells and this tissue does not generate electric slow waves. The absence of intramuscular interstitial cells in W/WV mutants provides a unique opportunity to study the molecular changes that are associated with the loss of these intercalating cells. Method The gene expression profile of the gastric fundus of wild type and W/WV mice was assayed by murine microarray analysis displaying a total of 8734 elements. Queried genes from the microarray analysis were confirmed by semi-quantitative reverse transcription-polymerase chain reaction. Results Twenty-one genes were differentially expressed in wild type and W/WV mice. Eleven transcripts had 2.0–2.5 fold higher mRNA expression in W/WV gastric fundus when compared to wild type tissues. Ten transcripts had 2.1–3.9 fold lower expression in W/WV mutants in comparison with wild type animals. None of these genes have ever been implicated in any bowel motility function. Conclusions These data provides evidence that several important genes have significantly changed in the murine fundus of W/WV mutants that lack intramuscular interstitial cells of Cajal and have reduced enteric motor neurotransmission.

The purposes of this study were: 1) to compare performance status, mood states, and level of hope between patients with cancer pain and patients without cancer pain; and 2) to determine the relationships of pain intensity and pain interference with daily life to performance status, mood states, and level of hope. A total of 233 Taiwanese cancer patients with pain and 251 without pain participated. The self report instruments consisted of the Chinese version of the Profile of Mood States (POMS) short form, the Chinese version of the Herth Hope Index, the Brief Pain Inventory-Chinese version (BPI-C), the Chinese version of the Karnorfsy Performance Scale (KPS), and a demographic questionnaire. The major findings of this study were that cancer patients with pain reported significantly lower levels of performance status and higher levels of total mood disturbance than did cancer patients who did not experience pain after controlling for sex, disease stage, and recruitment site. In addition, patients with cancer pain experienced significantly more anger, fatigue, depression, confusion, and lethargy than did patients without pain after controlling for sex, disease stage, and recruitment site. Among patients with pain, pain intensity was significantly correlated with performance status and mood state, but not with level of hope. Pain interference with daily life was significantly correlated both with performance status, mood state, and level of hope. Pain intensity and pain interference were significantly correlated with each mood state as well as with total mood disturbance. This study has demonstrated the effect of cancer pain on patients' physical, psychological, and spiritual life and has supported the multidimensional notion of the cancer pain experience in Taiwanese patients. [ABSTRACT FROM AUTHOR]

Following a High-Throughput Screening campaign to discover inhibitors of acid ceramidase, we report the novel and extremely potent covalent inhibitor, 1 . Following resynthesis and stability monitoring, we discovered that 1 is chemically unstable and reacts with DMSO at room temperature. This mode of decomposition is likely general for this class of compound, and we urge caution for their use in drug discovery research.

One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. Staphylococcus aureus ( S. aureus ) DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria. Crystal structures of uncleaved DNA with a gepotidacin precursor (2.1 Å GSK2999423) or with doubly cleaved DNA and zoliflodacin (or with its progenitor QPT-1) have been solved in the same P6 1 space-group (a = b ≈ 93 Å, c ≈ 412 Å). This suggests that it may be possible to observe the two DNA cleavage steps (and two DNA-religation steps) in this P6 1 space-group. Here, a 2.58 Å anomalous manganese dataset in this crystal form is solved, and four previous crystal structures (1.98 Å, 2.1 Å, 2.5 Å and 2.65 Å) in this crystal form are re-refined to clarify crystal contacts. The structures clearly suggest a single moving metal mechanism-presented in an accompanying (second) paper. A previously published 2.98 Å structure of a yeast topoisomerase II, which has static disorder around a crystallographic twofold axis, was published as containing two metals at one active site. Re-refined coordinates of this 2.98 Å yeast structure are consistent with other type IIA topoisomerase structures in only having one metal ion at each of the two different active sites.

Purpose: Dislocation remains 1 of the leading causes of revision after primary total hip arthroplasty (THA) and there is clear evidence the dual-mobility (DM) is used more frequently to minimise this. But in smaller cups, whether the use of DM with smaller 22-mm heads imparts any increased stability compared to standard bearing is unknown; especially when those smaller cups now allow for large single-bearing (SB) heads., Methods: 3 primary cup sizes (48 mm, 50 mm, 52 mm) were chosen a priori for modelling. Head sizes trialled for the standard bearing (SB) constructs group were 28-0 mm, 32-0 mm and 36-0 mm against neutral polyethylene liners. In the modular sub-hemispheric DM constructs the inner head sizes for the DM constructs were altered where appropriate (22-0 mm vs. 28-0 mm). Cup position, stem offset, and stem size were standardised., Results: Both DM constructs outperformed all SB constructs because of a statistically significant jump distance increase ( p  < 0.001). However, there was no difference in range of motion (ROM) or jump distances between the 22-mm and 28-mm DM inner heads.The ROM angle before impingement between the DM (with 22-mm or 28-mm heads) and SB (with different head sizes where appropriate) showed no statistically significant difference. However, DM constructs presented significantly larger jump distances than SB constructs for both provocative dislocation tests across all 3 cup sizes.Of interest, for 50-mm and 52-mm cup sizes (for which this particular DM construct design can accommodate both 22-mm and 28-mm inner heads), there were no differences in ROM or jump distance between 22-mm versus 28-mm inner heads., Conclusions: In this computer-modelling study, DM constructs are advantageous over SB constructs for improving jump distances in clinically provocative positions, but not range of motion angles. Inner head diameter of DM has no effect on stability., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK: and AA: receive consulting fees from Smith+Nephew and Zimmer Biomet; educational support from Smith+Nephew and Zimmer Biomet.DR: and AN: employees of Smith+Nephew.All other authors declare that there is no conflict of interest.

Purpose: There is variable and suboptimal use of fascia iliaca compartment nerve blocks (FICBs) in hip fracture care. Our objective was to use an evidence-based and theory-informed implementation science approach to analyze barriers and facilitators to timely administration of FICB and select evidence-based interventions to enhance uptake., Methods: We conducted a qualitative study at a single centre using semistructured interviews and site observations. We interviewed 35 stakeholders including health care providers, managers, patients, and caregivers. We mapped barriers and facilitators to the Theoretical Domains Framework (TDF) and Consolidated Framework for Implementation Research (CFIR). We compared the rate and timeliness of FICB administration before and after evidence-based implementation strategies were applied., Results: The study identified 18 barriers and 11 facilitators within seven themes of influences of FICB use: interpersonal relationships between health care professionals; clinician knowledge and skills related to FICB; roles, responsibilities, and processes for delivering FICB; perceptions on using FICB for pain; patient and caregiver perceptions on using FICB for pain; communication of hip fracture care between departments; and resources for delivering FICBs. We mapped the behaviour change domains to eight implementation strategies: restructure the environment, create and distribute educational materials, prepare patients to be active participants, perform audits and give feedback, use local opinion leaders, use champions, train staff on FICB procedures, and mandate change. We observed an increase in the rates of FICBs administered (48% vs 65%) and a decrease in the median time to administration (1.63 vs 0.81 days)., Conclusion: Our study explains why FICBs are underused and shows that the TDF and CFIR provide a framework to identify barriers and facilitators to FICB implementation. The mapped implementation strategies can guide institutions to improve use of FICB in hip fracture care., (© 2023. Canadian Anesthesiologists' Society.)

Context: Whether a largescale disaster alters people's previous decisions about their end-of-life care is unknown., Objectives: We examined the effects of a disaster, the COVID-19 pandemic, on stability of end-of-life care preferences among dialysis patients and on patient-surrogate goals-of-care congruence., Methods: We used a natural experimental design to examine goals-of-care preferences pre- and postexposure to the pandemic during a pragmatic trial testing SPIRIT (sharing patient's illness representations to increase trust), an evidence-based advance care planning (ACP) intervention. There were 151 patient-surrogate dyads who prior to the pandemic lockdown had completed baseline (T1) and postintervention assessments (T2) regarding their goals-of-care preferences in two end-of-life scenarios. Of those 151 dyads, 59 intervention, and 51 usual care dyads consented to be in the present study and completed the goals-of-care tool two additional times, at enrollment (T3) and six months later (T4), along with the COVID stress scale (CSS). Dyad congruence was ascertained by comparing patient and surrogate responses to the goals-of-care tool., Results: There were no changes over time in the proportions of patients who chose comfort-care-only in the goals-of-care tool. The proportion of patients who chose comfort-care-only and dyad congruence were higher in SPIRIT compared to usual care, but there was no interaction between that treatment effect and exposure to the pandemic. CSS was associated with neither patients' preferences nor dyad congruence., Conclusions: The pandemic alone did not appear to influence patients' goals-of-care preferences or dyad congruence. This finding supports the stability of value-based end-of-life preferences in general, even during a disaster., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Reliable and valid measures are critical in accurately assessing outcomes of advance care planning interventions (ACP) for end-of-life (EOL) decision-making., Objectives: To develop measures of preparedness for EOL decision-making for patients with end-stage renal disease and their surrogates (an exemplar population)., Methods: In this 3-phase study, Phases 1 and 2 included a cross-discipline concept analysis of the preparedness construct, item generation for patient and surrogate scales (82 items), evaluation of content validity and readability, cognitive interviewing, and item reduction. In phase 3, the retained 26 patient and 25 surrogate items were administered to 426 patients and 426 surrogates during a multisite trial of an ACP intervention versus care-as-usual and evaluated internal consistency, 2-week test-retest reliability, and construct validity., Results: Scales were reduced to 20 patient and 19 surrogate items during phase 3. Cronbach's alphas were 0.86 (patient) and 0.90 (surrogate). There was a strong correlation between preparedness at baseline and two weeks for both scales (r = 0.66-0.69, P < 0.001). Confirmatory factor analysis and item-response analyses suggested unidimensionality. A significant correlation was shown between patient preparedness and patient decisional conflict (r = -0.53, P < 0.001), and surrogate preparedness and surrogate decision-making confidence (r = 0.44, P < 0.001). Among those who received the ACP intervention, the effect size of change was medium: Cohen's d = 0.54, P < 0.001 for patients and d = 0.57, P < 0.001 for surrogates., Conclusions: The preparedness scales demonstrated strong psychometric properties. Future studies should examine scale performance in other populations., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases., Competing Interests: Declaration of competing interest The authors declare no financial competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The green peach aphid, Myzus persicae (Sulzer) (Homoptera: Aphididae), is a major pest of brassica plants, with the ability to transmit > 100 viruses. Although the adoption of Integrated Pest Management is increasing, chemical treatment remains the predominant method used to control M. persicae globally. Insecticide seed treatments, typically with neonicotinoid active ingredients, have become commonplace in canola crops, and are viewed as a "softer" alternative to foliar sprays but may nevertheless impact natural enemies of M. persicae. In this study, the effects of canola seed treatments, containing imidacloprid, thiamethoxam, and a mixture of thiamethoxam + lambda-cyhalothrin, were investigated on the parasitoid wasp, Aphidius colemani Viereck (Hymenoptera: Braconidae) and the green lacewing, Mallada signatus (Schneider) (Neuroptera: Chrysopidae), both important natural enemies of M. persicae. Laboratory trials were undertaken using whole plants, with lethal and sublethal effects assessed by measuring several traits. Compared with untreated plants, more aphid mummies were produced and more A. colemani were reared on plants treated with thiamethoxam + lambda-cyhalothrin and more aphid mummies were produced on imidacloprid plants. Imidacloprid reduced the time A. colemani spent searching for M. persicae and thiamethoxam reduced its cleaning time. However, after A. colemani were removed from treated plants, there were no such effects observed, suggesting these impacts were relatively short-lived. We found no significant effects of seed treatments on M. signatus. These results point to the complexity of ecotoxicology studies involving multiple trophic levels and indicate that seed treatments may have variable impacts on key fitness traits of natural enemies., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Evidence of effectiveness of advance care planning (ACP) strategies for patients receiving dialysis and their families is needed., Objectives: To test the effectiveness of an ACP intervention to prepare patients and their surrogates for end-of-life (EOL) decision-making and to improve surrogate bereavement outcomes., Design, Setting, and Participants: This cluster randomized clinical trial, An Effectiveness-Implementation Trial of SPIRIT (Sharing Patients' Illness Representations to Increase Trust) in ESRD, was conducted from December 2017 to March 2023 and included 42 dialysis clinics in 5 US states (Georgia, New Mexico, North Carolina, Pennsylvania, and Virginia) randomized to provide intervention or usual care. Recruitment was from February 15, 2018, to January 31, 2022, and patient-surrogate dyads were followed up for 21 months (until January 17, 2023) or until patient death., Intervention: Each clinic selected 1 or 2 health care workers (eg, nurse practitioner, registered nurse, or social worker) to conduct 45- to 60-minute ACP discussions with dyads in the clinic or remotely. After March 13, 2020 (commencement of the COVID-19 emergency declaration), all discussions were conducted remotely. An ACP summary was placed in patients' medical records., Main Outcomes and Measures: The primary, 2-week preparedness outcomes were dyad congruence on EOL goals of care, patient decisional conflict, surrogate decision-making confidence, and a composite of dyad congruence and surrogate decision-making confidence. Secondary bereavement outcomes were anxiety, depression, and posttraumatic distress 3 months after patient death. To adjust for COVID-19 pandemic effects on bereavement outcomes, a variable to indicate the timing of baseline and 3-month assessment relative to the COVID-19 emergency declaration was created., Results: Of the 426 dyads enrolled, 231 were in the intervention clinics, and 195 were in the control clinics. Among all dyads, the mean (SD) patient age was 61.9 (12.7) years, and the mean (SD) surrogate age was 53.7 (15.4) years. At 2 weeks, after adjusting for baseline values, dyad congruence (odds ratio [OR], 1.61; 95% CI, 1.12-2.31; P = .001), decisional conflict scores (β, -0.10; 95% CI, -0.13 to -0.07; P < .001), and the composite (OR, 1.57; 95% CI, 1.06-2.34; P = .03) were higher in the intervention group than in the control group. Surrogate decision-making confidence was similar between groups (β, 0.06; 95% CI, -0.01 to 0.13; P = .12). Among 77 bereaved surrogates, after adjusting for baseline values and assessment timing, intervention group anxiety was lower than control group anxiety (β, -1.55; 95% CI, -3.08 to -0.01; P = .05); however, depression (β, -0.18; 95% CI, -2.09 to 1.73; P = .84) and posttraumatic distress (β, -0.96; 95% CI, -7.39 to 5.46; P = .75) were similar., Conclusions and Relevance: In this randomized clinical trial, the ACP intervention implemented by health care workers at dialysis centers improved preparation for EOL decision-making but showed mixed effectiveness on bereavement outcomes. The ACP intervention implemented in dialysis centers may be an effective strategy to the dyad preparation for end-of-life care as opposed to the current focus on advance directives., Trial Registration: ClinicalTrials.gov Identifier: NCT03138564.

The styryl dye FM1-43 is widely used to study endocytosis but behaves as a permeant blocker of the mechano-electrical transducer (MET) channel in sensory hair cells, loading rapidly and specifically into the cytoplasm of hair cells in a MET channel-dependent manner. Patch clamp recordings of mouse outer hair cells (OHCs) were used to determine how a series of structural modifications of FM1-43 affect MET channel block. Fluorescence microscopy was used to assess how the modifications influence hair-cell loading in mouse cochlear cultures and zebrafish neuromasts. Cochlear cultures were also used to evaluate otoprotective potential of the modified FM1-43 derivatives. Structure-activity relationships reveal that the lipophilic tail and the cationic head group of FM1-43 are both required for MET channel block in mouse cochlear OHCs; neither moiety alone is sufficient. The extent of MET channel block is augmented by increasing the lipophilicity/bulkiness of the tail, by reducing the number of positive charges in the head group from two to one, or by increasing the distance between the two charged head groups. Loading assays with zebrafish neuromasts and mouse cochlear cultures are broadly in accordance with these observations but reveal a loss of hair-cell specific labelling with increasing lipophilicity. Although FM1-43 and many of its derivatives are generally cytotoxic when tested on cochlear cultures in the presence of an equimolar concentration of the ototoxic antibiotic gentamicin (5 µM), at a 10-fold lower concentration (0.5 µM), two of the derivatives protect OHCs from cell death caused by 48 h-exposure to 5 µM gentamicin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AB declared a shared affiliation with the author SK to the handling editor at the time of review., (Copyright © 2023 Derudas, O’Reilly, Kirkwood, Kenyon, Grimsey, Kitcher, Workman, Bull, Ward, Kros and Richardson.)

A common practice used to restore and maintain biodiversity in grasslands is to stop or decrease the use of fertilizers as they are a major cause of biodiversity loss. This practice is problematic for farmers who need fertilizers to increase forage and meet the nutritional needs of livestock. Evidence is needed that helps identify optimal fertilizer regimes that could benefit biodiversity and livestock production simultaneously over the long-term. Here, we evaluated the impact of different fertilizer regimes on indicators related to both biodiversity (plant, pollinator, leaf miners and parasitoid Shannon-Weiner diversity, bumblebee abundance, nectar productivity and forb species richness), and forage production (ash, crude protein, ruminant metabolizable energy and dry matter). To this end, we used data from a grassland restoration experiment managed under four nutrient inputs schemes for 27 years: farmyard manure (FYM; 72 kg N ha-1 yr-1), artificial nitrogen-phosphorus and potassium (NPK; 25 kg N ha-1 yr-1), FYM + NPK (97 kg N ha-1 yr-1) and no-fertilizer. Results showed strong trade-offs between biodiversity and forage production under all treatments even in applications lower than the critical load in the EU. Overall, farmyard manure was the fertilizer that optimized production and biodiversity while 97 kg N ha-1 yr-1 of fertilizer addition (FYM+NPK) had the most negative impact on biodiversity. Finally, forage from places where no fertilizer has been added for 27 years did not meet the nutritional requirements of cattle, but it did for sheep. Rethinking typical approaches of nutrient addition could lead to land management solutions suitable for biological conservation and agriculture., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Villa-Galaviz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk -knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8 + T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8 + T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy., Competing Interests: The authors declare no competing interests that pertain to this work except the following declaration. J.Z., and A.S.L.C. hold a related US Provisional Patent (Application No: 63/528,199)., (© 2023 The Authors.)

Three polyphagous pest Liriomyza spp. (Diptera: Agromyzidae) have recently invaded Australia and are damaging horticultural crops. Parasitic wasps are recognized as effective natural enemies of leafmining species globally and are expected to become important biocontrol agents in Australia. However, the hymenopteran parasitoid complex of agromyzids in Australia is poorly known and its use hindered due to taxonomic challenges when based on morphological characters. Here, we identified 14 parasitoid species of leafminers based on molecular and morphological data. We linked DNA barcodes (5' end cytochrome c oxidase subunit I (COI) sequences) to five adventive eulophid wasp species ( Chrysocharis pubicornis (Zetterstedt), Diglyphus isaea (Walker), Hemiptarsenus varicornis (Girault), Neochrysocharis formosa (Westwood), and Neochrysocharis okazakii Kamijo) and two braconid species ( Dacnusa areolaris (Nees) and Opius cinerariae Fischer). We also provide the first DNA barcodes (5' end COI sequences) with linked morphological characters for seven wasp species, with three identified to species level ( Closterocerus mirabilis Edwards & La Salle, Trigonogastrella parasitica (Girault), and Zagrammosoma latilineatum Ubaidillah) and four identified to genus ( Aprostocetus sp., Asecodes sp., Opius sp. 1, and Opius sp. 2). Phylogenetic analyses suggest C. pubicornis , D. isaea , H. varicornis, and O. cinerariae are likely cryptic species complexes. Neochrysocharis formosa and Aprostocetus sp. specimens were infected with Rickettsia . Five other species ( Cl. mirabilis , D. isaea, H. varicornis, Opius sp. 1, and Opius sp. 2) were infected with Wolbachia , while two endosymbionts ( Rickettsia and Wolbachia ) co-infected N. okazakii. These findings provide background information about the parasitoid fauna expected to help control the leafminers.