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BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophy- delaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS; In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 Suppledays, and the primary safety outcome was death from any cause at 90 days. Mul- tiplicity-adjusted key secondary outcomes were ventilator-associated pneumonia, Clostridioides dificile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.096) receiving pantoprazole and in 84 of 2377 patients (3.5°/0) receiving placebo (hazard ratio, 0.30; 95% confidence interval ICI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.196) in the pantoprazole group and in 734 of 2379 patients (30.9°/o) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P=0.25). Patient-important bleeding was reduced with pantoprazole; all other key secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. [ABSTRACT FROM AUTHOR]

The AVATAR I Trial demonstrated that oligoprogressive luminal (ER positive, HER2 negative) advanced breast cancer patients undergoing established first-line systemic therapy for metastatic disease benefited from SRT as second-line therapy along with their original systemic treatment. A modified PFS, defined as a disease progression not amenable to SRT treatment, was reported as 10.4 months. Given this result, this trial in progress seeks to assess if SRT combined with systemic therapy CDK4/6 inhibitor and Aromatase Inhibitor (CDK4/6+AI) can improve the Quality of Life (QoL) for this cohort of patients. AVATAR II is a Phase 2 randomized control trial that enrolls patients with advanced luminal breast cancer who have received first-line systemic treatment in the metastatic setting with a CDK4/6+AI. Patients require at least 1 extracranial oligoprogressing lesion amenable to SRT. Patients who had chemotherapy for metastatic disease, leptomeningeal disease, or prior radiotherapy to an oligoprogressing lesion were excluded. Patients were randomized to Arm A; SRT to all oligoprogressing lesions and continue CDK4/6+AI systemic therapy or Arm B; no SRT and review to assess if a change in systemic therapy is required. If a patient subsequently progresses, further SRT was permitted to delay a change in systemic therapy in patients who had received SRT as part of the trial. At 3-monthly reviews, patient reported outcomes are measured using the EORTC QLQ C30 and FACT-B forms. The trial is expected to recruit 74 patients. The primary endpoint is the area under the curve (AUC) of the Quality of Life/Global Health Status score from the EORTC QLQ-C30 from baseline to the 12-month follow-up visit. The secondary endpoints are to determine Progression-free Survival (PFS) and PFS 2, defined as the time from randomization to the date of first and second evidence of progression, respectively. Other secondary endpoints include ST-PFS, defined as randomization to the first evidence of progression requiring change in systemic therapy, Overall Survival, treatment-related toxicity and further QoL assessment using AUC of the FACT-B Total score from baseline to 12 months. TBD. Assessing quality of life (QoL) is integral to evaluating the overall impact of cancer treatment. AVATAR II aims to demonstrate that by delaying a change in systemic therapy and potentially more potent side effects, receiving SRT at this stage in a patient's treatment paradigm will have a more positive impact on patients' QoL. [ABSTRACT FROM AUTHOR]

Background/objectives: No erythrocyte elution method developed is uniformly successful or allows elution/phenotyping together. We previously developed an elution method using deionised formamide. We modified it to be universal for various cell types and call it modified formamide-method (Fm-method). It also preserves cells for phenotyping after elution., Materials and Methods: Fm-method reagent contains deionised formamide, buffered high salt, EDTA, TE. Elution-reagent is removed by column centrifugation. Blood samples were used for development and validation. Results compared to commercial/common antibody elution/phenotyping methods., Results: Fm-method eluted antibodies, complement, other proteins, and nucleic acids and works with erythrocytes, leukocytes, other cells. It worked better than commercial kits used for elution/phenotyping with no false positives/negatives. It did not denature Kell and Lewis antigens and could be repeated as needed on samples to recover more antibodies and clean cells for phenotyping. Western blotting, PAGE and FCM demonstrated eluted proteins were not degraded and cells remained intact., Conclusion: Fm-method is excellent for elution and phenotyping and permits elution and phenotyping with one method and sample. It is useful for studies of various bound molecules and cell surface structures. It should be possible to elute various simple and complex carbohydrates as well. The Fm-method is efficient, inexpensive, scalable, uses common reagents. It should have excellent applications in various clinical, research, commercial settings., (Published 2025. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: A patient with major depressive disorder (MDD) was receiving transcranial magnetic stimulation (TMS). A little over halfway through the course the patient was bereaved and experienced normal sadness. Our objective is to describe the tracking and outcome of this common emotionally distressing event., Method: Routine assessments conducted at the centre include the six-item Hamiton depression rating (HAMD6) scale, the Clinical Global Impression-Severity (CGI-S) scale, and the Subjective Depression Scale (SDS6). In addition, the Daily Sadness Scale (DSS) is applied at each treatment day; this is a single question asking how much sadness/depression is being experienced., Results: On the 19th treatment day, the patient was bereaved and experienced appropriate sadness. The pathological state (MDD) resolved, as reflected by changes in the psychometric tools. Following the death, normal sadness emerged and lessened over a few weeks., Conclusion: This case illustrates that while TMS can effectively treat MDD, it does not prevent the emergence of sadness in uncomplicated bereavement., (Copyright © 1964–2025 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Objective: To report the outcomes of transcranial magnetic stimulation (TMS) treatment of patients with acute major depressive disorder (MDD), with particular attention to the performance of the individual assessment tools, including two new subjective mood scales., Methods: Patients with MDD were treated with up to 35 daily TMS sessions. Objective quantification of mood utilised the Hamilton Depression Rating Scale (HAM-D6) and the Clinical Global Impression-Severity scale (CGI-S). Subjective quantification was made using the Subjective Depression Scale (SDS6) and a new Daily Emotion Score (DES) - a single question which is asked daily., Results: Ninety consecutive patients (58 females; 64.4%) with a mean age of 46.9 years were included. Using HAM-D6 criteria, 51 patients (56.7%) achieved remission. Scores obtained using the different tools correlated well at the same time point, especially at the conclusion of TMS therapy. The only statistically significant independent predictors of remission were the percentage improvement at session 10 (relative to baseline) in the SDS6 ( p = .0026) and in the DES ( p = .043)., Conclusion: The SDS6 was confirmed as a valuable companion for the HAM-D6. The DES correlated with the other subjective tool (SDS6); the latter, in particular, may also have utility in predicting treatment outcome., Competing Interests: DisclosureThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Uncertainty remains regarding the role of diet in colorectal cancer development. We examined associations of 97 dietary factors with colorectal cancer risk in 542,778 Million Women Study participants (12,251 incident cases over 16.6 years), and conducted a targeted genetic analysis in the ColoRectal Transdisciplinary Study, Colon Cancer Family Registry, and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Alcohol (relative risk per 20 g/day=1.15, 95% confidence interval 1.09-1.20) and calcium (per 300 mg/day=0.83, 0.77-0.89) intakes had the strongest associations, followed by six dairy-related factors associated with calcium. We showed a positive association with red and processed meat intake and weaker inverse associations with breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C. Genetically predicted milk consumption was inversely associated with risk of colorectal, colon, and rectal cancers. We conclude that dairy products help protect against colorectal cancer, and that this is driven largely or wholly by calcium., Competing Interests: Competing interests: UP was a consultant with AbbVie and her husband is holding individual stocks for the following companies: BioNTech SE – ADR, Amazon, CureVac BV, NanoString Technologies, Google/Alphabet Inc Class C, NVIDIA Corp, Microsoft Corp. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Objective: This clinical trial sought to evaluate the safety and preliminary efficacy of psilocybin and MBSR for frontline healthcare providers with symptoms of depression and burnout related to the COVID-19 pandemic., Methods: This was a randomized controlled trial that enrolled physicians and nurses with frontline clinical work during the COVID-19 pandemic and symptoms of depression and burnout. Participants were randomized in a 1:1 ratio to either an 8-week MBSR curriculum alone or an 8-week MBSR curriculum plus group psilocybin-assisted psychotherapy (PAP) with 25mg psilocybin. Symptoms of depression and burnout were assessed at baseline, and 2-weeks and 6-months post intervention utilizing the Quick Inventory of Depressive Symptoms (QIDS-SR-16) and Maslach Burnout Inventory Human Services Survey for Medical Professionals (MBI-HSS-MP), respectively. Secondary outcome measures included the Demoralization Scale (DS-II) and the Watt's Connectedness Scale (WCS). Adverse events and suicidality were assessed through 6-month follow-up., Results: 25 participants were enrolled and randomized. There were 12 study-related AEs recorded that were Grade 1-2 and no serious AEs. There was larger decrease in QIDS score for the MBSR+PAP arm compared to MBSR-only from baseline to 2-weeks post-intervention and significant between-group differences favoring MBSR+PAP on subscales of the MBI-HSS-MP as well as the DS-II and WCS., Conclusions: Group psilocybin-assisted therapy plus MBSR was associated with clinically significant improvement in depressive symptoms without serious adverse events and with greater reduction in symptoms than MBSR alone. Study findings suggest that integrating psilocybin with mindfulness training may represent a promising treatment for depression and burnout among physicians and nurses.

Background: Previous prediction models for adiposity gain have not yet achieved sufficient predictive ability for clinical relevance. We investigated whether traditional and genetic factors accurately predict adiposity gain., Methods: A 5-year gain of ≥5% in body mass index (BMI) and waist-to-hip ratio (WHR) from baseline were predicted in mid-late adulthood individuals (median of 55 years old at baseline). Proportional hazards models were fitted in 245,699 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to identify robust environmental predictors. Polygenic risk scores (PRS) of 5 proxies of adiposity [BMI, WHR, and three body shape phenotypes (PCs)] were computed using genetic weights from an independent cohort (UK Biobank). Environmental and genetic models were validated in 29,953 EPIC participants., Findings: Environmental models presented a remarkable predictive ability (AUC BMI : 0.69, 95% CI: 0.68-0.70; AUC WHR : 0.75, 95% CI: 0.74-0.77). The genetic geographic distribution for WHR and PC1 (overall adiposity) showed higher predisposition in North than South Europe. Predictive ability of PRSs was null (AUC: ∼0.52) and did not improve when combined with environmental models. However, PRSs of BMI and PC1 showed some prediction ability for BMI gain from self-reported BMI at 20 years old to baseline observation (early adulthood) (AUC: 0.60-0.62)., Interpretation: Our study indicates that environmental models to discriminate European individuals at higher risk of adiposity gain can be integrated in standard prevention protocols. PRSs may play a robust role in predicting adiposity gain at early rather than mid-late adulthood suggesting a more important role of genetic factors in this life period., Funding: French National Cancer Institute (INCA&#95;N°2019-176) 1220, German Research Foundation (BA 5459/2-1), Instituto de Salud Carlos III (Miguel Servet Program CP21/00058)., Competing Interests: Declaration of interests L.M. discloses that an immediate family member holds stocks in Novo Nordisk. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Pathogen reduction (PR) may be used as an alternative to gamma or x-ray irradiation (I) to prevent transfusion associated graft versus host disease (TA-GVHD) if the pathogen reduction technology has been shown to inactivate residual lymphocytes. However, as I is considered the gold standard for reducing the risk of TA-GVHD, some centers continue to perform I in addition to PR. This study investigated the effect of concurrent pathogen reduction and irradiation (PR/I) on the biochemical characteristics of apheresis platelets at day 1, 5, and 7 of storage at room temperature., Methods: We compared in vitro characteristics of apheresis platelets (PLTs), PR PLTs, I PLTs, and PR/I PLTs at storage day 1, 5, and 7. PLTs from six healthy volunteers were suspended in 65% PAS-3/35% plasma prior to splitting and treatment with PR, I, or PR/I. Parameters measured were: PLT loss, mean PLT volume (MPV), pH, glucose consumption, lactate production, CD62P, annexin V binding, PLT aggregation, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS)., Results: PR/I PLTs did not show significant changes in measured parameters when compared to PR PLTs. However, when compared to control PLTs, PR and PR/I PLTs showed significant declines in PLT content, pH, MMP, aggregation and significant increases in MPV, CD62P, annexin V binding, and ROS production, mostly on day 7 of storage. Irradiation did not cause significant changes in measured parameters in comparison to control PLTs., Conclusions/summary: While PR impacts PLTs' biochemical characteristics and function, irradiation of PR PLTs did not cause additional significant changes., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background:  Circulating tumor cells and clusters (CTC) from soft-tissue sarcoma (STS) that become entrapped in the lung can form micro-metastases and lead to pulmonary metastatic disease. Many patients with localized high-risk STS later develop metastases. Radiation is effective at reducing local recurrence by eradicating microscopic infiltration and satellites in the reactive zone surrounding the primary tumor. Prophylactic lung irradiation for patients with high-risk STS is a novel concept to potentially reduce the appearance of macroscopic metastases and improve survival. A proof-of-principle study was performed based on a novel approach: prophylactic lung radiation after resection of the primary tumor to address microscopic pulmonary deposits from CTC., Methods:  Immunocompromised mice and luciferase-expressing human fibrosarcoma (HT-1080-Luc) cell lines were used. In phase 1, HT-1080-Luc cells were injected into the tail vein to simulate CTC for the development of pulmonary metastases. Whole-lung irradiation (WLI) was then performed in the treated mice prior to the appearance of macroscopic metastases. In phase 2, a flank tumor was established to simulate a primary STS, followed by a tail-vein injection of HT-1080-Luc cells. Treatment groups included surgical removal of the primary STS and hemithoracic irradiation (HTI). Body weight and bioluminescence data were obtained and the mice were euthanized on Day 31 (phase 1) and Day 15 (phase 2) or when they reached 20% weight loss., Results:  In phase 1, prophylactic WLI increased survival and decreased pulmonary metastases. In phase 2, prophylactic HTI (left lung) decreased pulmonary metastases compared to controls. Lung histology showed dramatically decreased growth and number of established metastases with HTI. Resection of the primary tumor did not affect the growth of metastases., Conclusion:  Prophylactic WLI after resection of the primary tumor to inhibit the growth of pulmonary metastases from previously entrapped CTCs may be a promising approach to improve survival for patients with localized high-risk STS., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Animal subjects: University of Maryland, Baltimore, Institutional Animal Care and Use Committee (IACUC) Issued protocol number 1021001. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ruditsky et al.)

Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear., Methods: Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association., Results: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated-suggestive of a potential mediating role-most strongly for the BMI-overall CRC association in women., Conclusion: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women., (© The Author(s) 2025. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Chickpea (Cicer arietinum L.) is the second most widely grown legume crop after soybean. Here, we measured the macronutrients and performed proteome profiling of eight chickpea cultivars using two complementary protein extraction solvents. The total protein, starch, and soluble sugar contents significantly differ between cultivars, and we quantified 2434 and 1809 proteins, respectively, from urea- and water-based extraction solvents using a data-independent acquisition approach. The proteome-level differences can vary from 9-25% for the urea-extracted proteins, and the storage protein abundances significantly differed between the cultivars, where legumin content was detected as the highest, followed by vicilin and albumin. Fifty common allergens were detected from two extraction solvents, primarily overrepresented in chromosomes 3, 4, and 5. Integrated analysis revealed distinct subclusters of proteins and their associated pathways for total protein, lipids, and starch content. Overall, we established chickpea pan-proteome resources and provided insights into the key pathways that define the genotypes.

"Functional speech" by 5 years of age is widely established as increasing the probability of long-term positive outcomes across a range of domains for autistic individuals. While terms such as "functional" or "useful" speech are often used, what defines these terms is not well established. Furthermore, most research focusing on language development has emphasized the transition from little or no language to use of single words, but much less is known about the transition from single words to phrase speech, which could be equally important. The verb lexicon is foundational to the development of simple, generative phrases and has been linked to prosocial behaviors and general developmental outcomes including better social communication skills, socioemotional reciprocity, and nonverbal communication in autistic children. The current systematic review synthesized information from 20 independent samples to characterize autistic children who transitioned from single words to phrase speech. On average, 48% of the pooled sample transitioned to phrase speech during the study periods. Results were highly variable across studies. Participants under the age of 5 years were more likely to transition to phrases than participants over the age of 5. Though average standard scores were above 50, children who transitioned to phrases generally demonstrated below average adaptive and cognitive skills and moderate-high ASD symptomatology. Variable measures of cognition made it difficult to ascertain patterns in cognitive skills; nonetheless, nonverbal IQ emerged as a salient predictor of the transition to phrases across studies. More research is needed to better understand who transitions beyond single words, clinical benchmarks on the way to generative phrase speech and the factors that predict this transition. Such information can be used to inform clinical decision making and develop or improve targeted interventions based on individual communication profiles. This could make the use of phrases more likely for a greater number of autistic individuals, increasing the likelihood that these individuals communicate independently and effectively with others., Competing Interests: Declarations. Conflict of interest: KB, KS, and CL have no relevant non-financial interests to disclose. Ethical approval: Ethics approval was not required for this systematic review. All research was conducted in accordance with ethical standards., (© 2024. The Author(s).)

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policies, or views of the International Agency for Research on Cancer/World Health Organization. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Informed consent was obtained for all participants included in the discovery and validation sets. Ethical approvals were obtained from Local and Federal Research Ethics Committees, and from the IARC Ethics Committee (IEC Project 17-10A4). For the TCGA datasets, also used as validation set, the enrolling, collection, clinical and genomic data processing and distributions are subject to 45-CFR-46 (the “Common Rule”) governing protection of human research subjects. Under the revised TCGA consent policy, re-consent of still-living participants is no longer a programme-imposed requirement. The Project Team described the best practices for informed consent for participating in TCGA in this memo ( http://cancergenome.nih.gov/abouttcga/policies/informedconsent )., (© 2024. World Health Organization.)

Background: Inflammation influences tumour progression and cancer prognosis, but its role preceding breast cancer (BC) and its prognostic implications remain inconclusive., Methods: We studied pre-diagnostic plasma inflammatory biomarkers in 1538 women with BC from the EPIC study. Cox proportional hazards models assessed their relationship with all-cause and BC-specific mortality, adjusting for tumour characteristics and lifestyle factors., Results: Over a 7-year follow-up after diagnosis, 229 women died, 163 from BC. Elevated IL-6 levels were associated with increased all-cause mortality risk (HR 1-SD 1.25, 95% CI 1.07-1.47). Among postmenopausal, IL-6 was associated with higher all-cause (HR 1-SD 1.41, 95% CI 1.18-1.69) and BC-specific mortality (HR 1-SD 1.31, 95% CI 1.03-1.66), (P Heterogeneity (pre/postmenopausal)  < 0.05 for both), while IL-10 and TNFα were associated with all-cause mortality only (HR 1-SD 1.19, 95% CI 1.02-1.40 and HR 1-SD 1.28, 95% CI 1.06-1.56). Among ER+PR+, IL-10 was associated with all-cause and BC-specific mortality (HR 1-SD 1.35, 95% CI 1.10-1.65 and HR 1-SD 1.42 95% CI 1.08-1.86), while TNF-α was associated with all-cause mortality in HER2- (HR 1-SD 1.31, 95% CI 1.07-1.61). An inflammatory score predicted higher all-cause mortality, especially in postmenopausal women (HR 1-SD 1.30, 95% CI 1.07-1.58)., Conclusions: Higher pre-diagnosis IL-6 levels suggest poorer long-term survival among BC survivors. In postmenopausal survivors, elevated IL-6, IL-10, and TNFα and inflammatory scores seem to predict all-cause mortality., (© 2024. The Author(s).)

Deficits in positive emotion regulation skills may be an important factor in the development and maintenance of anxiety and mood disorders. A treatment, which includes strategies to build and strengthen positive emotion regulation skills has been provided to patients primarily diagnosed with an anxiety and or mood disorder in an adult mental health outpatient service setting. To study the effects on positive and negative emotion, emotion regulation skills, emotional disorder symptoms, quality of life, and wellbeing during a new developed treatment. An exploratory clinical trial was used to conduct a preliminary assessment of a novel intervention. The intervention was provided in a group format over a 6-week period and independent practice over an 8-week period. Outcome variables were assessed pre- and post-treatment and at a 2-month follow up. Life quality, subjective wellbeing ratings, depressive and anxiety symptoms improved at follow up. The data suggests that the intervention may have the potential to produce desired change in positive emotion regulation. Preliminary findings suggest the intervention can have beneficial effects. These findings are promising and support the possibility that disturbances in positive emotion regulation may be a generative target for treatment research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Atherosclerosis in more than 1 vs. 1 arterial bed is associated with increased risk for major adverse cardiovascular events (MACE). This study aimed to determine whether the risk of post percutaneous coronary intervention (PCI) MACE associated with polyvascular disease (PVD) differs by sex., Methods: We analyzed 18,721 patients undergoing PCI at a tertiary-care center between 2012 and 2019. Polyvascular disease was defined as history of peripheral artery and/or cerebrovascular disease. The primary endpoint was MACE, a composite of all-cause death, myocardial infarction, or stroke at 1 year. Multivariate Cox regression was used to adjust for differences in baseline risk between patients with PVD vs. coronary artery disease (CAD) alone and interaction testing was used to assess risk modification by sex., Results: Women represented 29.2% (N = 5,467) of the cohort and were more likely to have PVD than men (21.7% vs. 16.1%; P < .001). Among both sexes, patients with PVD were older with higher prevalence of comorbidities and cardiovascular risk factors. Women with PVD had the highest MACE rate (10.0%), followed by men with PVD (7.2%), women with CAD alone (5.0%), and men with CAD alone (3.6%). Adjusted analyses revealed similar relative MACE risk associated with PVD vs. CAD alone in women and men (adjusted hazard ratio [aHR] 1.54, 95% confidence interval [CI] 1.20-1.99; P < .001 and aHR 1.31, 95% CI 1.06-1.62; P = .014, respectively; p-interaction = 0.460)., Conclusion: Women and men derive similar excess risk of MACE from PVD after PCI. The heightened risk associated with PVD needs to be addressed with maximized use of secondary prevention in both sexes., Competing Interests: Conflict of Interest Dr. Spirito received a research grant from the Swiss National Science Foundation. Dr. Dangas has received consulting fees and advisory board fees from AstraZeneca; has received consulting fees from Biosensors; and previously held stock in Medtronic. Dr. Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia, I-Laser, Janssen, Magenta, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Transverse Medical, Inc., Vivasure, Zoll; personal fees from AstraZeneca, Ionis Pharmaceuticals, J-CalC, Mediasphere, Novartis, Novo Nordisk, Vectura, WebMD; Equity, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To report an observational case series study of sustained, once-weekly continuation transcranial magnetic stimulation (TMS) provided with the aim of maintaining remission in patients with major depressive disorder (MDD)., Methods: Once-weekly TMS treatments were provided to 7 patients (median age of 54 years) with chronic relapsing MDD: 4 of these patients entered the study in remission according to the six-item Hamilton depression rating scale (HAM-D6) and were followed for more than 12 months, and 3 patients entered the study in HAM-D6 partial remission/relapse and were followed for more than 6 months., Results: All patients remained clinically well throughout the study. The 4 patients who entered in remission were maintained in HAM-D6 remission or partial remission. The 3 patients who entered the study in HAM-D6 partial remission/relapse were maintained free of clinical depression., Conclusions: Seven patients with a history of relapsing MDD were provided with once-weekly continuation TMS and remained free of clinical relapse for more than 6 or 12 months. While the study had a small sample size, the clear, real-world outcomes warrant further investigation.

Feasibility of volumetric modulated arc therapy (VMAT) for partial breast irradiation (PBI) with simultaneous integrated boost (SIB) to tumour bed was investigated. Four plans were created for 10 patients: 30 Gy/5 fractions, 26 Gy/5 fractions with 30 Gy SIB, 40.05 Gy/15 fractions, and 40.05 Gy/15 fractions with 48 Gy SIB. SIB in the 5 fraction arm had reduced ipsilateral breast dose relative to uniform dose. SIB in the 15 fraction arm had noninferior conformity compared to uniform dose. Addition of SIB did not increase other organ-at-risk doses or plan complexity. VMAT PBI with SIB was feasible for both fractionation regimens., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Objective: Self-efficacy for leisure-time or health-promoting physical activity (SEPA) is a psychosocial determinant of physical activity. The socioecological model can provide a robust perspective of SEPA. The objective of this study was to synthesize the evidence on multilevel correlates of SEPA among individuals with chronic musculoskeletal pain. The second aim examined the extent to which socioecological disparities are associated with SEPA among individuals with chronic musculoskeletal pain., Methods: An integrative review was conducted. Included studies needed to investigate the relationship between SEPA and socioecological factors at the interpersonal, institutional, community, and/or macrosystem level among adults with chronic musculoskeletal pain (≥3 months). Searches in PubMed, EMBASE, PsycINFO, and CINAHL were performed (December 30, 2020, and October 12, 2022), yielding 4047 records after duplicates were removed. Two independent reviewers completed screening, full-text reviews, and data extraction. After title and abstract screening and full-text reviews, 17 studies were included. The constant comparison method included: data reduction, data display, data comparison, and conclusion drawing/verification. Quality of evidence was assessed using the Joanna Briggs Institute appraisal tools., Results: Five themes emerged with respect to relationships between SEPA and socioecological factors: social relations, social comparisons, patient-provider relationship, organizational resources, and accessibility to physical activity. Relationships between interpersonal factors and SEPA were most prominently studied. One study examined and addressed potential disparities in SEPA at the macrosystem level., Conclusion: A spectrum of relationships from supporting to straining SEPA were found at the interpersonal level. Relationships between institutional, community, and macrosystem factors and SEPA were comparably sparse. Gaps in the literature were identified regarding how health disparities present across the socioecological model with respect to SEPA., Impact: Clinicians can use this review to evaluate how SEPA can be supported or threatened by factors across the socioecological model. This may be a preliminary step towards examining and addressing health disparities in SEPA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Physical Therapy Association.)

Background: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes., Methods: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984)., Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively)., Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes., (© 2024. The Author(s).)

Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk., Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted., Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004)., Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer., Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers., (©2024 American Association for Cancer Research.)

Study Design: Retrospective cohort study., Objective: To evaluate intensive postoperative nutritional supplementation on wound healing complications and outcomes after spinal fusion surgery., Background: Poor nutritional status leads to inferior postoperative outcomes by increasing mortality and predisposing patients to infection and wound healing complications. While perioperative nutritional supplementation has shown promise in mitigating these risks, there is a paucity of literature regarding specific nutritional routines in spinal fusion surgery., Methods: A retrospective analysis was conducted on patients who underwent spinal fusion surgery between 2019 and 2022. Demographic and nutritional data, including preoperative prealbumin levels (PAB) and postoperative supplemental diet, were examined. Primary endpoints included wound complications, with secondary outcomes assessing Oswestry Disability Index (ODI) and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Health (PH) scores. Statistical analyses included unpaired t-tests and Chi-squared/Fischer's exact tests with significance set at P<0.05., Results: Patients receiving the supplemental diet (n=229) demonstrated fewer wound complications (7% vs. 21%, P=0.004) and reoperations (3% vs. 11%, P=0.016) compared to those without supplementation (n=56). No significant differences were observed in preoperative or postoperative PROMIS PH or ODI scores. Patients with normal preoperative PAB had more wound complications without the supplemental diet (5% vs. 18%, P=0.025). A similar trend was seen in the patients with low preoperative PAB (12% vs. 26%, P=0.12)., Conclusion: Postoperative nutritional supplementation significantly reduces wound complications after spinal fusion surgery in a cost-effective manner. This study underscores the modifiability of certain perioperative risk factors and suggests that nutritional strategies can mitigate potential complications., Competing Interests: Conflicts of Interest and Sources of Funding: None., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Scope: Edible insect proteins are increasingly introduced as an alternative sustainable food source to address the world's need to feed the growing population. Tropomyosin is the main insect allergen; however, additional potential allergens are not well characterized and the impact of extraction procedures on immunological reactivity is unknown., Methods and Results: Proteins from different commercial food products derived from cricket (Acheta domesticus) and black soldier fly (BSF) (Hermetia illucens) are extracted using five different extraction buffers. The proteins are analyzed by SDS-PAGE and immunoblotting using allergen-specific antibodies and crustacean allergic patient sera. IgE binding bands are analyzed by mass spectrometry as well as the complete allergen profile of all 30 extracts. Urea-based buffers are most efficient in extracting insect allergens. Shrimp-specific antibody cross-reactivity to tropomyosin from cricket and BSF indicates high sequence and structural similarity between shrimp and insects. Additional unique allergens are identified in both species, including hemocyanin, vitellogenin, HSP20, apolipophorin-III, and chitin-binding protein., Conclusions: Identifying potential allergenic proteins and their isoforms in cricket and BSF requires specific extraction approaches using urea-based methods. While tropomyosin is the most abundant and immunoreactive allergen, seven unique allergens are identified, highlighting the need for insect species-specific allergen detection in food products., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Objective . To fabricate and validate a novel focused collimator designed to spare normal tissue in a murine hemithoracic irradiation model using 250 MeV protons delivered at ultra-high dose rates (UHDRs) for preclinical FLASH radiation therapy (FLASH-RT) studies. Approach . A brass collimator was developed to shape 250 MeV UHDR protons from our Varian ProBeam. Six 13 mm apertures, of equivalent size to kV x-ray fields historically used to perform hemithorax irradiations, were precisely machined to match beam divergence, allowing concurrent hemithoracic irradiation of six mice while sparing the contralateral lung and abdominal organs. The collimated field profiles were characterized by film dosimetry, and a radiation survey of neutron activation was performed to ensure the safety of staff positioning animals. Main results . The brass collimator produced 1.2 mm penumbrae radiation fields comparable to kV x-rays used in preclinical studies. The penumbrae in the six apertures are similar, with full-width half-maxima of 13.3 mm and 13.5 mm for the central and peripheral apertures, respectively. The collimator delivered a similar dose at an average rate of 52 Gy s -1 for all apertures. While neutron activation produces a high (0.2 mSv h -1 ) initial ambient equivalent dose rate, a parallel work-flow in which imaging and setup are performed without the collimator ensures safety to staff. Significance . Scanned protons have the greatest potential for future translation of FLASH-RT in clinical treatments due to their ability to treat deep-seated tumors with high conformality. However, the Gaussian distribution of dose in proton spots produces wider lateral penumbrae compared to other modalities. This presents a challenge in small animal pre-clinical studies, where millimeter-scale penumbrae are required to precisely target the intended volume. Offering high-throughput irradiation of mice with sharp penumbrae, our novel collimator-based platform serves as an important benchmark for enabling large-scale, cost-effective radiobiological studies of the FLASH effect in murine models., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention., Methods: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets., Findings: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions., Interpretation: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer., Funding: This work was supported by Cancer Research UK (grant no. C8221/A29017)., Competing Interests: Declaration of interests This work was supported by Cancer Research UK (grant no. C8221/A29017). Anders Mälarstig, Åsa Hedman, and Marios Dimitriou are employees of Pfizer Inc. Anders Mälarstig declares stock options for Pfizer Inc. Alastair D. Lamb is Section Editor for Prostate Cancer and Web, British Journal of Urology International., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk., Methods: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics., Results: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade., Conclusions: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk., (© 2024. The Author(s).)