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The processes that underlie the effectiveness of eye movement desensitization and reprocessing (EMDR) are examined by evaluating the procedural differences between it and exposure therapy. Major factors include the degree of emphasis placed on reliving versus distancing in the therapies and the degree to which clients are encouraged to focus on direct trauma experiences versus experiences associated with the trauma. Research results indicate that, unlike traditional imaginal exposure, reliving responses in EMDR did not correlate with symptom improvement. Instead, consistent with an information processing model, the degree of distancing in EMDR was signifi cantly associated with improvement. A case study is described to highlight these methodological divergences in the respective therapies relating to reliving. Finally, the research regarding the possible sources of the distancing response within EMDR was examined. The results indicate that the distancing process was more likely to be an effect produced by eye movements than by any therapist instructions. Theoretical and research evaluations indicate that the mechanisms underlying EMDR and traditional exposure therapy are different. [ABSTRACT FROM AUTHOR]

A simple tailored version of the California Psychological Inventory (CPI) was derived from the responses of a calibrating sample of 1,190 subjects using an approach based on a one-parameter item-response theory. This tailored version was administered on a microcomputer to a second independent sample. Validity data were obtained separately from the calibrating and second samples. The mean of the correlations of tailored estimates with full-scale scores was .71 for the calibrating sample and .73 for the second sample. These are comparable with reliability coefficients for the inventory. The average reduction in the number of items given with the tailored version was 71%. [ABSTRACT FROM AUTHOR]

Objective: To examine the treatment outcome of an intensive trauma-focused treatment program for post-traumatic stress disorder (PTSD) in older and younger adults. Methods: A non-randomized outcome study was conducted with 62 consecutively admitted older PTSD patients (60–78 years) and 62 younger PTSD patients (19–58 years), matched on gender and availability of follow-up data. Patients participated in an intensive eight-day trauma-focused treatment program consisting of eye movement desensitization and reprocessing (EMDR), prolonged exposure (PE), physical activity, and group psycho-education. PTSD symptom severity (Clinician-Administered PTSD Scale-5 (CAPS-5)) was assessed, at pre- and post-treatment, and for a subsample (n = 31 older; n = 31 younger patients) at six-month follow-up. Results: A repeated-measures ANCOVA (centered CAPS pre-treatment score as covariate) indicated a significant decrease in CAPS-5-scores from pre- to post-treatment for the total sample (partial η2 = 0.808). The treatment outcome was not significantly different across age groups (partial η2 = 0.002). There were no significant differences in treatment response across age groups for the follow-up subsample (pre- to post-treatment partial η2 < 0.001; post-treatment to follow-up partial η2 = 0.006), and the large decrease in CAPS-5 scores from pre- to post-treatment (partial η2 = 0.76) was maintained at follow-up (partial η2 = 0.003). Conclusion: The results suggest that intensive trauma-focused treatment is applicable for older adults with PTSD with a large within-effect size comparable to younger participants. Further research on age-related features is needed to examine whether these results can be replicated in the oldest-old (>80). [ABSTRACT FROM AUTHOR]

The article discusses the aggressive management malignant pleural mesothelioma (MPM) disease. It cites a study which raises concerns over the role of extrapleural pneumonectomy (EPP) in treating patients with MPM. It shows that chemotherapy is associated with a modest survival benefit in fit patients with MPM.

The comparative treatment efficiency of eye movement desensitization and reprocessing (EMDR) therapy and prolonged exposure (PE) therapy for the treatment of posttraumatic stress disorder (PTSD) was tested for 20 participants diagnosed with PTSD. Efficiency was operationalized as the total exposure time to traumatic memories during and between sessions; the number of trauma memories processed over the course of therapy; how many sessions were required to resolve the primary trauma; and lower subjective units of disturbance (SUD) levels after the initial treatment session. Participants were randomized to each condition and received 12 90-minute sessions of therapy over 6 weeks. Symptoms were assessed by treatment-blind assessors at posttreatment, and at 3 and 6 months follow-up. Results demonstrated a significant decrease in symptoms posttreatment for PTSD (d = .64), depression (d = .46), anxiety (d = .52) and stress (d = .57) for both groups, which was maintained at 3 months. At 6 months there was a small increase in symptoms compared to the 3-month time point on the Clinician-Administered PTSD Scale (CAPS) but no significant change in any self-report symptoms EMDR was significantly more efficient than PE. EMDR participants had less total exposure time to traumatic memories when homework hours were included (d = .66), reported lower SUD scores after the first session (d = .45), required fewer sessions for the target memory to decrease to near zero distress levels (d = .84), and processed more traumatic memories. [ABSTRACT FROM AUTHOR]

Childhood maltreatment is relatively common and is related to a range of negative consequences, such as Posttraumatic Stress Disorder (PTSD). There are indications that various maltreatment types are related to PTSD severity, although not all types, such as emotional abuse, meet the PTSD Criterion-A. The aim of the present study was to examine the relationship between 5 types of childhood maltreatment (i.e., sexual, physical, and emotional abuse, and physical and emotional neglect) and the severity of adult PTSD and PTSD symptoms. Adult participants (N = 147) with Childhood-related PTSD (Ch-PTSD) recruited from clinical sites completed the Childhood Trauma Questionnaire-short form (CTQ-sf) and 2 PTSD measures: The Clinician Administered PTSD Scale for DSM-5 (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5). Childhood maltreatment predictors and 2 covariates, age and gender, were analysed in multivariate multilevel models as participants were nested within sites. A model selection procedure, in which all combinations of predictors were examined, was used to select a final set of predictors. The results indicated that emotional abuse was the only trauma type that was significantly related to severity of PTSD and to the severity of specific PTSD symptom clusters (r between 0.130 and 0.338). The final models explained between 6.5% and 16.7% of the variance in PTSD severity. The findings suggest that emotional abuse plays a more important role in Ch-PTSD than hitherto assumed, and that treatment should not neglect processing of childhood emotional abuse. • Childhood maltreatment is very common and several types are related to PTSD. • Only emotional abuse appears to be robustly associated with PTSD severity. • The findings were robust across outcomes and separate PTSD symptom clusters. [ABSTRACT FROM AUTHOR]

Pathogens must efficiently acquire nutrients from host tissue to proliferate, and strategies to block pathogen access therefore hold promise for disease control. In this study, we investigated whether heme biosynthesis is an effective target for ablating the virulence of the phytopathogenic fungus Ustilago maydis on maize plants. We first constructed conditional heme auxotrophs of the fungus by placing the heme biosynthesis gene hem12 encoding uroporphyrinogen decarboxylase (Urod) under the control of nitrogen or carbon source-regulated promoters. These strains were heme auxotrophs under non-permissive conditions and unable to cause disease in maize seedlings, thus demonstrating the inability of the fungus to acquire sufficient heme from host tissue to support proliferation. Subsequent experiments characterized the role of endocytosis in heme uptake, the susceptibility of the fungus to heme toxicity as well as the transcriptional response to exogenous heme. The latter RNA-seq experiments identified a candidate ABC transporter with a role in the response to heme and xenobiotics. Given the importance of heme biosynthesis for U. maydis pathogenesis, we tested the ability of the well-characterized herbicide BroadStar to influence disease. This herbicide contains the active ingredient flumioxazin, an inhibitor of Hem14 in the heme biosynthesis pathway, and we found that it was an effective antifungal agent for blocking disease in maize. Thus, repurposing herbicides for which resistant plants are available may be an effective strategy to control pathogens and achieve crop protection., (© 2024 The Author(s). Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)

The basidiomycete fungus Cryptococcus neoformans is a useful model for investigating mechanisms of fungal pathogenesis in mammalian hosts. This pathogen is the causative agent of cryptococcal meningitis in immunocompromised patients and is in the critical priority group of the World Health Organization fungal priority pathogens list. In this study, we employed a mutant lacking the OPI3 gene encoding a methylene-fatty-acyl-phospholipid synthase to characterize the role of phosphatidylcholine (PC) and lipid homeostasis in the virulence of C. neoformans . We first confirmed that OPI3 was required for growth in nutrient limiting conditions, a phenotype that could be rescued with exogenous choline and PC. Additionally, we established that loss of Opi3 and the lack of PC lead to an accumulation of neutral lipids in lipid droplets and alterations in major lipid classes. The growth defect of the opi3Δ mutant was also rescued by sorbitol and polyethylene glycol (PEG), a result consistent with protection of ER function from the stress caused by lipid imbalance. We then examined the impact of Opi3 on virulence and found that the dependence of PC synthesis on Opi3 caused reduced capsule size and this was accompanied by an increase in shed capsule polysaccharide and changes in cell wall composition. Further tests of virulence demonstrated that survival in alveolar macrophages and the ability to cause disease in mice were not impacted by loss of Opi3 despite the choline auxotrophy of the mutant in vitro . Overall, this work establishes the contribution of lipid balance to virulence factor elaboration by C. neoformans and suggests that host choline is sufficient to support proliferation during disease., Competing Interests: FM is an employee of Springer Nature. The remaining 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., (Copyright © 2024 Lee, Brisland, Qu, Horianopoulos, Hu, Mayer and Kronstad.)

Small GTPases of the Rab family coordinate multiple membrane fusion and trafficking events in eukaryotes. In fungi, the Rab GTPase, Ypt7, plays a critical role in late endosomal trafficking, and is required for homotypic fusion events in vacuole biogenesis and inheritance. In this study, we identified a putative YPT7 homologue in Cryptococcus neoformans , a fungal pathogen causing life threatening meningoencephalitis in immunocompromised individuals. As part of an ongoing effort to understand mechanisms of iron acquisition in C. neoformans , we established a role for Ypt7 in growth on heme as the sole iron source. Deletion of YPT7 also caused abnormal vacuolar morphology, defective endocytic trafficking and autophagy, and mislocalization of Aph1, a secreted vacuolar acid phosphatase. Ypt7 localized to the vacuolar membrane and membrane contact sites between the vacuole and mitochondria (vCLAMPs), and loss of the protein impaired growth on inhibitors of the electron transport chain. Additionally, Ypt7 was required for robust growth at 39°C, a phenotype likely involving the calcineurin signaling pathway because ypt7 mutants displayed increased susceptibility to the calcineurin-specific inhibitors, FK506 and cyclosporin A; the mutants also had impaired growth in either limiting or high levels of calcium. Finally, Ypt7 was required for survival during interactions with macrophages, and ypt7 mutants were attenuated for virulence in a mouse inhalation model thus demonstrating the importance of membrane trafficking functions in cryptococcosis., 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 author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hu, Qu, Bhalla, Xue, Bakkeren, Lee and Kronstad.)

Mitochondrial functions are critical for the ability of the fungal pathogen Cryptococcus neoformans to cause disease. However, mechanistic connections between key functions such as the mitochondrial electron transport chain (ETC) and virulence factor elaboration have yet to be thoroughly characterized. Here, we observed that inhibition of ETC complex III suppressed melanin formation, a major virulence factor. This inhibition was partially overcome by defects in Cir1 or HapX, two transcription factors that regulate iron acquisition and use. In this regard, loss of Cir1 derepresses the expression of laccase genes as a potential mechanism to restore melanin, while HapX may condition melanin formation by controlling oxidative stress. We hypothesize that ETC dysfunction alters redox homeostasis to influence melanin formation. Consistent with this idea, inhibition of growth by hydrogen peroxide was exacerbated in the presence of the melanin substrate L-DOPA. In addition, loss of the mitochondrial chaperone Mrj1, which influences the activity of ETC complex III and reduces ROS accumulation, also partially overcame antimycin A inhibition of melanin. The phenotypic impact of mitochondrial dysfunction was consistent with RNA-Seq analyses of WT cells treated with antimycin A or L-DOPA, or cells lacking Cir1 that revealed influences on transcripts encoding mitochondrial functions (e.g., ETC components and proteins for Fe-S cluster assembly). Overall, these findings reveal mitochondria-nuclear communication via ROS and iron regulators to control virulence factor production in C. neoformans .IMPORTANCEThere is a growing appreciation of the importance of mitochondrial functions and iron homeostasis in the ability of fungal pathogens to sense the vertebrate host environment and cause disease. Many mitochondrial functions such as heme and iron-sulfur cluster biosynthesis, and the electron transport chain (ETC), are dependent on iron. Connections between factors that regulate iron homeostasis and mitochondrial activities are known in model yeasts and are emerging for fungal pathogens. In this study, we identified connections between iron regulatory transcription factors (e.g., Cir1 and HapX) and the activity of complex III of the ETC that influence the formation of melanin, a key virulence factor in the pathogenic fungus Cryptococcus neoformans . This fungus causes meningoencephalitis in immunocompromised people and is a major threat to the HIV/AIDS population. Thus, understanding how mitochondrial functions influence virulence may support new therapeutic approaches to combat diseases caused by C. neoformans and other fungi., Competing Interests: The authors declare no conflict of interest.

We studied the mechanisms of eye movement desensitization and reprocessing (EMDR) and imagery rescripting (ImRs). We hypothesized that EMDR works via changes in memory vividness, that ImRs works via changes in encapsulated beliefs (EB), and that both treatments work via changes in memory distress. Patients (N = 155) with childhood-related posttraumatic stress disorder (Ch-PTSD) received 12 sessions of EMDR or ImRs. The vividness, distress, and EB related to the index trauma were measured with the Imagery Interview. PTSD severity was assessed with the Impact of Events Scale-Revised and the Clinician-Administered PTSD Scale for DSM-5. We conducted mixed regressions and Granger causality analyses. EMDR led to initially stronger changes in all predictors, but only for distress this was retained until the last assessment. No evidence for vividness as a predictive variable was found. However, changes in distress and EB predicted changes in PTSD severity during ImRs. These findings partially support the hypothesized mechanisms of ImRs, while no support was found for the hypothesized mechanisms of EMDR. Differences in the timing of addressing the index trauma during treatment and the timing of assessments could have influenced the findings. This study provides insight into the relative effectiveness and working mechanisms of these treatments., Competing Interests: Declaration of competing interest A. Arntz publishes scientific articles and book chapters about ImRs, and occasionally gives workshops. The financial remuneration received go to the university to support research. C. W. Lee reports grants and receives personal fees from Psychology Training. E. Fassbinder gives workshops and lectures on ImRs and PTSD treatment and received personal fees and grants. There are no other conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The relationship between trauma-related negative cognitions and post-traumatic stress disorder (PTSD) symptoms has been studied frequently. Several studies found a mediating effect of trauma-related negative cognitions on symptom reduction in studies on different psychotherapeutic treatments, however, this relationship has never been studied in imagery rescripting (ImRs) or eye movement desensitization and reprocessing (EMDR). Objective: To analyse the role of trauma-related negative cognitions in the treatment of PTSD due to childhood trauma with EMDR and ImRs. Method: N  = 155 patients with PTSD due to childhood trauma aged between 18 and 65 ( M  = 38.54) participated in a randomized clinical trial and were treated with either EMDR or ImRs in Australia, Germany, and the Netherlands between October 2014 and June 2019. We analysed the relationship between PTSD symptoms (Clinician-administered PTSD Scale for DSM-5, CAPS-5 and Impact of Event Scale revised; IES-R, completed twice for index trauma and for all other traumas) and trauma-related negative cognitions (Post-Traumatic Cognitions Inventory, PTCI) using Granger Causality analyses with linear mixed models on person-centered variables. Assessments were conducted pre-treatment, post-treatment (12 sessions in 6 weeks), eight weeks post-treatment, and one year after the pre-treatment assessment. Results: Changes in negative cognitions (PTCI) preceded changes in PTSD symptoms (unidirectional) as measured by the CAPS and the IES-R for index trauma. For the IES-R related to all other traumas, a unidirectional relationship was found in which changes in PTSD symptoms preceded changes in negative cognitions. No moderating effect of treatment was found. On the level of PTCI subscales only changes in cognitions about oneself preceeded changes in PTSD symptoms. Conclusions: The results support the idea of a general role of trauma-related negative cognitions in the treatment of PTSD. The analyses should be replicated with a higher frequency of assessments.

Background: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma., Methods: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m 2 ] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m 2 , every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual., Findings: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group., Interpretation: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma., Funding: The Canadian Cancer Society and Merck & Co., Competing Interests: Declaration of interests MP has received grants for research to institution from AstraZeneca and Roche; payment for educational events from Astellas, Pfizer, and AstraZeneca; and received drugs for research from Roche and AstraZeneca. GLR received consulting fees from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received support for attending meetings or travel from Roche, MSD, BMS, and Amgen; has participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; and has other financial or non-financial interests from MSD, BMS, AstraZeneca, Roche, Novartis, Amgen, Sanofi, Pfizer, Takeda, and GSK. YL holds stock or stock options from Merck. SL received consulting fees from Lilly, MSD, Sanofi, and AbbVie and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca. AS received grants or contracts (payments to institution) from MSD, BMS, AstraZeneca, Roche, and Amphera; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, MSD, and Roche; received support for attending meetings or travel from AstraZeneca, BMS, MSD, and Roche; and participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BMS, MSD, and Roche. MF received consulting fees from AstraZeneca, BMS, and Takeda and received honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, and Takeda. SAL has participated on a Data Safety Monitoring Board or Advisory Board for Sanofi and Bayer. JRG received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and BMS. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck and participated on a Data Safety Monitoring Board or Advisory Board for Mirati and AbbVie. NL has received editorial support from EMD Serono; received grants to institute (unrelated) from Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Guardant Health, Inivata, Janssen, Merck/MSD, Novartis, Pfizer, Roche, and Takeda; received honoraria or travel funding for CME lectures (unrelated) from AstraZeneca, Beigene, BMS, Janssen, Merck, Novartis, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Mirati, Helsinn, and Daichii Sankyo. LS has received grants or contracts to institution to support clinical trial from AstraZeneca, Merck, Bayer, Novartis, Repare, GSK, and Janssen and holds stock or stock options from AstraZeneca. DED has received research grants from CIHR, CancerCare Manitoba Foundation, and AstraZeneca; received research grants and salary awards from Manitoba Medical Services Foundation; received payment for educational events from Roche, Boehringer Ingelheim, and BMS; served on an advisory board for Merck, AstraZeneca, Pfizer, Jazz Pharmaceuticals, and Novartis; has acted in a leadership or fiduciary role in a board, society, committee or advocacy group, paid or unpaid for Lung Cancer Canada (Medical Advisory Committee), Canadian Association of Medical Oncologists (Chair, Fellowship Committee), and Canadian Cancer Trials Group (Chair, Small Cell Lung Cancer Working Group); and received equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca (Medical writing assistance on a small-cell lung cancer paper). QC has received grants to institution from Alkermes, Amgen, Apollomics, Astellas, AstraZeneca, Bicycle, BMS, Conjupro, Decipher, Eli Lilly, Esperas, Exactis, GSK, iTEOS, Kelun, Merck, Mirati, Nuvalent, Ocellaris, Pfizer, Rvolution Medicines, Roche, SeaGen, Spectrum, and Treadwell; received consulting fees from Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; received payment for speaking or presentations from AstraZeneca; acted on an advisory board for Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; acted on a Data Safety Monitoring Committee for Merck and KGaA; and occupied a leadership or fiduciary role in a board, society, committee, or advocacy group, paid or unpaid for Lung Cancer Canada and Canadian Mesothelioma Foundation. CWL has served as a member of the Board of Directors for Canadian Mesothelioma Foundation. LG received grants or contracts to institution from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received support for attending meetings or travel from Pfizer, MSD, AstraZeneca, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Inhatarget Therapeutics. XQ received support for attending meetings or travel from Pfizer (ESMO 2022), Janssen (ASCO 2022), and Sanofi (ASCO 2023). VW received consulting fees from Amgen; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Sanofi; received support for attending meetings or travel from AstraZeneca, Bristol Myers Squibb, Janssen, MSD, Roche, and Sanofi; and participated on a Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, and Ipsen. GZ received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Inventiva Pharma, Lilly, MSD Oncology, Pfizer, and Roche; acted in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Da Volterra, Inventiva Pharma, MSD Oncology, Pfizer, and Roche; received research funding from AstraZeneca, Bristol-Myers Squibb, Pfizer, Roche, and Takeda; and received travel, accommodations, and expenses from AbbVie, AstraZeneca, Bristol-Myers Squibb, Lilly, Pfizer, and Roche. MLS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and support for attending meetings or travel from Pfizer (ESMO 2022). AM received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, AstraZeneca, BMS, MSD, Pfizer, Takeda, Boehringer, Sanofi, Lilly, Novartis, and Italfarmaco and participated on a Data Safety Monitoring Board or Advisory Board for Roche, AstraZeneca, Pfizer, MSD, and Takeda. FG received consulting fees from Novocure, BMS, Novartis, PharmaMar, Pierre Fabre, and MSD; received payment for speaker bureau from Novocure; received support for attending meetings or travel from Novartis, MSD, BMS, PharmaMar, and Pierre Fabre. SD received payment for presentations from Novartis, Pierre-Fabre, and BMS and travel and accommodation support during meetings from Istituto Gentili, Novartis, Pierre-Fabre, and BMS. GLC received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novocure and BMS and participated on a Data Safety Monitoring Board or Advisory Board for Novocure. PAZ received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; received support for attending meetings or travel from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; and participated on a Data Safety Monitoring Board or Advisory Board for Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer. MM received support for attending meetings or travel from Roche, Pfizer, and Novartis. FLC received consulting fees from Takeda, Amgen, Novartis, AstraZeneca, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Amgen, Novartis, AstraZeneca, and Roche; and received support for attending meetings or travel from Takeda and Amgen. CG received consulting fees from Karyopharm, Menarini, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaux, manuscript writing, or educational events from MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer, AstraZeneca, and Pfizer; and participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer Ingelheim, AstraZeneca, and Pfizer. FP received partial funding to institution and experimental study drug from Pfizer; received financial support to institution from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, and Merck; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The corn smut fungus, Ustilago maydis , is an excellent model for studying biotrophic plant-pathogen interactions, including nutritional adaptation to the host environment. Iron acquisition during host colonization is a key aspect of microbial pathogenesis yet less is known about this process for fungal pathogens of plants. Monothiol glutaredoxins are central regulators of key cellular functions in fungi, including iron homeostasis, cell wall integrity, and redox status via interactions with transcription factors, iron-sulfur clusters, and glutathione. In this study, the roles of the monothiol glutaredoxin Grx4 in the biology of U. maydis were investigated by constructing strains expressing a conditional allele of grx4 under the control of the arabinose-inducible, glucose-repressible promoter P crg 1 . The use of conditional expression was necessary because Grx4 appeared to be essential for U. maydis. Transcriptome and genetic analyses with strains depleted in Grx4 revealed that the protein participates in the regulation of iron acquisition functions and is necessary for the ability of U. maydis to cause disease on maize seedlings. Taken together, this study supports the growing appreciation of monothiol glutaredoxins as key regulators of virulence-related phenotypes in pathogenic fungi.

Despite unequivocal roles in disease, transcription factors (TFs) remain largely untapped as pharmacologic targets due to the challenges in targeting protein-protein and protein-DNA interactions. Here we report a chemical strategy to generate modular synthetic transcriptional repressors (STRs) derived from the bHLH domain of MAX. Our synthetic approach yields chemically stabilized tertiary domain mimetics that cooperatively bind the MYC/MAX consensus E-box motif with nanomolar affinity, exhibit specificity that is equivalent to or beyond that of full-length TFs and directly compete with MYC/MAX protein for DNA binding. A lead STR directly inhibits MYC binding in cells, downregulates MYC-dependent expression programs at the proteome level and inhibits MYC-dependent cell proliferation. Co-crystallization and structure determination of a STR:E-box DNA complex confirms retention of DNA recognition in a near identical manner as full-length bHLH TFs. We additionally demonstrate structure-blind design of STRs derived from alternative bHLH-TFs, confirming that STRs can be used to develop highly specific mimetics of TFs targeting other gene regulatory elements., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Although life-history trade-offs are central to life-history evolution, their mechanistic basis is often unclear. Traditionally, trade-offs are understood in terms of competition for limited resources among traits within an organism, which could be mediated by signal transduction pathways at the level of cellular metabolism. Nevertheless, trade-offs are also thought to be produced as a consequence of the performance of one activity generating negative consequences for other traits, or the result of genes or pathways that simultaneously regulate two life-history traits in opposite directions (antagonistic pleiotropy), independent of resource allocation. Yet examples of genes with antagonistic effects on life-history traits are limited. This study provides direct evidence for a gene- RLS1 , that is involved in increasing survival in nutrient-limiting environments at a cost to immediate reproduction in the single-celled photosynthetic alga, Chlamydomonas reinhardtii . Specifically, we show that RLS1 mutants are unable to properly suppress their reproduction in phosphate-deprived conditions. Although these mutants have an immediate reproductive advantage relative to the parental strain, their long-term survival is negatively affected. Our data suggest that RLS1 is a bona fide life-history trade-off gene that suppresses immediate reproduction and ensures survival by downregulating photosynthesis in limiting environments, as part of the general acclimation response to nutrient deprivation in photosynthetic organisms.

Background: Trauma-focused treatments for posttraumatic stress disorder (PTSD) are commonly delivered either once or twice a week. Initial evidence suggests that session frequency affects treatment response, but very few trials have investigated the effect of session frequency. The present study's aim is to compare treatment outcomes of twice-weekly versus once-weekly sessions of two treatments for PTSD related to childhood trauma, imagery rescripting (ImRs) and eye movement desensitization and reprocessing (EMDR). We hypothesize that both treatments will be more effective when delivered twice than once a week. How session frequency impacts treatment response, whether treatment type moderates the frequency effect, and which treatment type and frequency works best for whom will also be investigated., Methods: The IREM-Freq trial is an international multicenter randomized clinical trial conducted in mental healthcare centers across Australia, Germany, and the Netherlands. We aim to recruit 220 participants, who will be randomized to one of four conditions: (1) EMDR once a week, (2) EMDR twice a week, (3) ImRs once a week, or (4) ImRs twice a week. Treatment consists of 12 sessions. Data are collected at baseline until one-year follow-up. The primary outcome measure is clinician-rated PTSD symptom severity. Secondary outcome measures include self-reported PTSD symptom severity, complex PTSD symptoms, trauma-related cognitions and emotions, depressive symptoms, dissociation, quality of life, and functioning. Process measures include memory, learning, therapeutic alliance, motivation, reluctance, and avoidance. Additional investigations will focus on predictors of treatment outcome and PTSD severity, change mechanisms of EMDR and ImRs, the role of emotions, cognitions, and memory, the optimization of treatment selection, learned helplessness, perspectives of patients and therapists, the network structure of PTSD symptoms, and sudden treatment gains., Discussion: This study will extend our knowledge on trauma-focused treatments for PTSD related to childhood trauma and, more specifically, the importance of session frequency. More insight into the optimal session frequency could lead to improved treatment outcomes and less dropout, and in turn, to a reduction of healthcare costs. Moreover, the additional investigations will broaden our understanding of how the treatments work and variables that affect treatment outcome., Trial Registration: Netherlands Trial Register NL6965, registered 25/04/2018., (© 2021. The Author(s).)

The Young Schema Questionnaire (YSQ) was developed to measure Early Maladaptive Schemas (EMS), a construct central to Schema Therapy (ST). Traditionally YSQ items were placed in a grouped format for each schema but in recent versions of the questionnaire, items are presented in a random order. This study investigates the effect of item placement on the psychometric properties of the questionnaire. On different occasions, participants completed two versions of the YSQ short form, one with items grouped according to schemas and another where items were placed in a random order. Responses were analysed using the polytomous Rasch model of measurement (partial credit parameterization). Results show that the two versions are not psychometrically equivalent. There were greater differences between the clinical and non-clinical group means for the grouped format than the random format and greater person separation. There was more response dependence between items in the grouped format which has been linked to inflated reliability indices.

Introduction: During mass-casualty incidents (MCIs), patient volume often overwhelms available Emergency Medical Services (EMS) personnel. First responders are expected to triage, treat, and transport patients in a timely fashion. If other responders could triage accurately, prehospital EMS resources could be focused more directly on patients that require immediate medical attention and transport., Hypothesis: Triage accuracy, error patterns, and time to triage completion are similar between second-year primary care paramedic (PCP) and fire science (FS) students participating in a simulated MCI using the Sort, Assess, Life-saving interventions, Treatment/Transport (SALT) triage algorithm., Methods: All students in the second-year PCP program and FS program at two separate community colleges were invited to participate in this study. Immediately following a 30-minute didactic session on SALT, participants were given a standardized briefing and asked to triage an eight-victim, mock MCI using SALT. The scenario consisted of a four-car motor vehicle collision with each victim portrayed by volunteer actors given appropriate moulage and symptom coaching for their pattern of injury. The total number and acuity of victims were unknown to participants prior to arrival to the mock scenario., Results: Thirty-eight PCP and 29 FS students completed the simulation. Overall triage accuracy was 79.9% for PCP and 72.0% for FS (∆ 7.9%; 95% CI, 1.2-14.7) students. No significant difference was found between the groups regarding types of triage errors. Over-triage, under-triage, and critical errors occurred in 10.2%, 7.6%, and 2.3% of PCP triage assignments, respectively. Fire science students had a similar pattern with 15.2% over-triaged, 8.7% under-triaged, and 4.3% critical errors. The median [IQR] time to triage completion for PCPs and FSs were 142.1 [52.6] seconds and 159.0 [40.5] seconds, respectively (P=.19; Mann-Whitney Test)., Conclusions: Primary care paramedics performed MCI triage more accurately than FS students after brief SALT training, but no difference was found regarding types of error or time to triage completion. The clinical importance of this difference in triage accuracy likely is minimal, suggesting that fire services personnel could be considered for MCI triage depending on the availability of prehospital medical resources and appropriate training.

Appropriate fluid resuscitation has been a major focus of critical care medicine since its inception. Currently, the most accurate method to guide fluid administration decisions uses "dynamic" measures that estimate the change in cardiac output that would occur in response to a fluid bolus. Unfortunately, their use remains limited due to required technical expertise, costly equipment, or applicability in only a subset of patients. Alternatively, point-of-care ultrasound (POCUS) has become widely used as a tool to help clinicians prescribe fluid therapy. Common POCUS applications that serve as guides to fluid administration rely on assessments of the inferior vena cava to estimate preload and lung ultrasound to identify the early presence of extravascular lung water and avoid fluid overresuscitation. Although application of these POCUS measures has multiple limitations that are commonly misunderstood, current evidence suggests that they can be used in combination to sort patients among 3 fluid management categories: (1) fluid resuscitate, (2) fluid test, and (3) fluid restrict. This article reviews the pertinent literature describing the use of inferior vena cava and lung ultrasound for fluid responsiveness and presents an evidence-informed algorithm using these measures to guide fluid resuscitation decisions in the critically ill., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: We used nationally representative data to investigate health disparities associated with sexual minority status among adults in the United States., Methods: We analyzed data from 11,114 adults who participated in the 2001 to 2010 waves of the National Health and Nutrition Examination Survey. Using multiple logistic regressions, we examined the prevalence of HIV, sexually transmitted infections, mental health problems, cigarette smoking, and alcohol and illicit drug use in sexual minorities and heterosexual adults., Results: After adjusting for sociodemographic characteristics, sexual minority men had greater odds of mental health problems, testing positive for HIV and herpes simplex virus type 2 and self-reported gonorrhea and chlamydia. Sexual minority women had greater odds of mental health problems, testing positive for hepatitis C, smoking, heavy drinking, and illicit drug use., Conclusions: Numerous health disparities continue to face sexual minority men and women in the United States. Notably, health disparities persisted beyond the role of sociodemographic factors, including access to insurance and primary care, suggesting that further research is warranted to identify the determinants of health inequity for sexual minorities.

Background: Mass-casualty incidents (MCIs) present a unique challenge with regards to triage as patient volume often outweighs the number of available Emergency Medical Services (EMS) providers. A possible strategy to optimize existing triage systems includes the use of other first responder groups, namely fire and police, to decrease the triage time during MCIs, allowing for more rapid initiation of life-saving treatment and prioritization of patient transport. Hypothesis First-year primary care paramedic (PCP), fire, and police trainees can apply with similar accuracy an internationally recognized MCI triage tool, Sort, Assess, Life-saving interventions, Treatment/transport (SALT), immediately following a brief training session, and again three months later., Methods: All students enrolled in the PCP, fire, and police foundation programs at two community colleges were invited to participate in a 30-minute didactic session on SALT. Immediately following this session, a 17-item, paper-based test was administered to assess the students' ability to understand and apply SALT. Three months later, the same test was given to assess knowledge retention., Results: Of the 464 trainees who completed the initial test, 364 (78.4%) completed the three month follow-up test. Initial test scores were higher (P<.05) for PCPs (87.0%) compared to fire (80.2%) and police (68.0%) trainees. The mean test score for all respondents was higher following the initial didactic session compared to the three month follow-up test (75% vs 64.7%; Δ 10.3%; 95% CI, 8.0%-12.6%). Three month test scores for PCPs (75.4%) were similar to fire (71.4%) students (Δ 4.0%; 95% CI, -2.1% to 10.1%). Both PCP and fire trainees significantly outperformed police (57.8%) trainees. Over-triage errors were the most common, followed by under-triage and then critical errors, for both the initial and follow-up tests., Conclusions: Amongst first responder trainees, PCPs were able to apply the SALT triage tool with the most accuracy, followed by fire, then police. Over-triage was the most frequent error, while critical errors were rare.

Background and Objectives: Physicians frequently search bibliographic databases, such as MEDLINE via PubMed, for best evidence for patient care. The objective of this study was to develop and test search filters to help physicians efficiently retrieve literature related to dialysis (hemodialysis or peritoneal dialysis) from all other articles indexed in PubMed, Ovid MEDLINE, and Embase., Design, Setting, Participants, & Measurements: A diagnostic test assessment framework was used to develop and test robust dialysis filters. The reference standard was a manual review of the full texts of 22,992 articles from 39 journals to determine whether each article contained dialysis information. Next, 1,623,728 unique search filters were developed, and their ability to retrieve relevant articles was evaluated., Results: The high-performance dialysis filters consisted of up to 65 search terms in combination. These terms included the words "dialy" (truncated), "uremic," "catheters," and "renal transplant wait list." These filters reached peak sensitivities of 98.6% and specificities of 98.5%. The filters' performance remained robust in an independent validation subset of articles., Conclusions: These empirically derived and validated high-performance search filters should enable physicians to effectively retrieve dialysis information from PubMed, Ovid MEDLINE, and Embase.

Background: Tools to enhance physician searches of Medline and other bibliographic databases have potential to improve the application of new knowledge in patient care. This is particularly true for articles about glomerular disease, which are published across multiple disciplines and are often difficult to track down. Our objective was to develop and test search filters for PubMed, Ovid Medline, and Embase that allow physicians to search within a subset of the database to retrieve articles relevant to glomerular disease., Methods: We used a diagnostic test assessment framework with development and validation phases. We read a total of 22,992 full text articles for relevance and assigned them to the development or validation set to define the reference standard. We then used combinations of search terms to develop 997,298 unique glomerular disease filters. Outcome measures for each filter included sensitivity, specificity, precision, and accuracy. We selected optimal sensitive and specific search filters for each database and applied them to the validation set to test performance., Results: High performance filters achieved at least 93.8% sensitivity and specificity in the development set. Filters optimized for sensitivity reached at least 96.7% sensitivity and filters optimized for specificity reached at least 98.4% specificity. Performance of these filters was consistent in the validation set and similar among all three databases., Conclusions: PubMed, Ovid Medline, and Embase can be filtered for articles relevant to glomerular disease in a reliable manner. These filters can now be used to facilitate physician searching.