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Introduction: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine., Methods: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months., Results: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups., Conclusions: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies., Trial Registration: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD)., (© 2023. The Author(s).)

Characteristics of an acid soil cultivated with Urochloa brizantha cv. Marandu were evaluated in relation to two types of fertilization: a conventional one, chemical based on nitrogen and potassium, and a biofertilizer, based on microalgae biomass. The results were compared among three treatments, control, conventional, and biological fertilization, with seven replications each. The study evaluated microalgae community, total carbon and nitrogen contents, mineral nitrogen, and enzymatic activity. Chlorella vulgaris showed the highest organism density, which can be explained by its rapid growth and high resistance. The highest species diversity was detected in the control 1,380,938 org cm -3 and biological 1,841,250 org cm -3 treatments, with the latter showing a higher density of cyanobacteria, especially Pseudanabaena limnetica with 394,554 org cm -3 . The soil treated with chemical fertilization showed higher nitrate (9.14 mg NKg -1 NO 3 - -N) and potassium (52.32 mg dm -3 ) contents. The highest levels of sulfur (21.73 mg dm -3 ) and iron (96.46 mgdm -3 ) were detected in the biological treatment. The chemical treatment showed higher activity of the enzymes acid phosphatase, acetylglucosaminidase, and sulfatase, while α-glucosidase and leucine aminopeptidase stood out in the biological treatment. Soil properties were not significantly affected by the treatments. The use of microalgae biomass derived from wastewater treatment from milking parlors was evaluated and presented as a promising biofertilizer for agriculture, following the line of recovering nutrient-rich wastes. In this sense, although many challenges need to be overcome, the results suggest that microalgal-based fertilizers could lead to low-impact agriculture., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The 2019 Coronavirus Disease (COVID-19) pandemic necessitated a mass transition in genetics clinics nationwide from in-person care to virtual care through telehealth. Before the COVID-19 pandemic, there was limited research on the use of telehealth in genetics specialties. Therefore, the COVID-19 pandemic presented a unique opportunity to study this emerging mode of care delivery in the setting of genetics clinics. This study described the scope of telehealth use in genetics clinics nationally and determined how COVID-19 influenced patients' decisions regarding their genetic care. Methods: Two anonymous surveys for patients and providers were developed. The patient survey was offered online to all genetics patients seen through telehealth at a Manhattan-based practice between March and December 2020. The provider survey was distributed through several listservs to genetics providers nationwide. Results: Patients ( n  = 242) and providers ( n  = 150) responded. Telehealth was used in all specialty genetics clinics for both initial and follow-up visits. Telehealth was both effective and satisfactory to patients for both visit types and across specialties; however, Asian and Hispanic/Latino patients had significantly lower mean satisfaction scores compared with White patients ( p  = 0.03 and 0.04, respectively). Patients appreciated telehealth for its convenience and to avoid COVID-19 exposure. Providers across specialties and provider types preferred telehealth for follow-up rather than initial visits. Several clinic initiatives related to telehealth were identified. Discussion: Telehealth was generally well received by both patients and providers, and is expected to become permanent option in genetics clinics. Further studies are needed to identify barriers to accessing telehealth.

Eukaryotic cells' proliferation and growth are controlled by the target of rapamycin kinase (TOR). TOR usually activates in favorable energy and nutritional circumstances. This is challenged by recent research, suggesting that plant cells optimized for nutrient absorption in low nutritional conditions may activate the TOR pathway in a polarized manner., Competing Interests: Declaration of interests We have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Elder mistreatment (EM) harms individuals, families, communities, and society as a whole. Yet research on interventions is lagging, and no rigorous studies demonstrating effective prevention have been published. This pilot study examines whether a first-of-its-kind coaching intervention reduced the experience of EM among older adults with chronic health conditions, including dementia., Methods: We used a double-blind, randomized controlled trial to test a strengths-based person-centered caregiver support intervention, developed from evidence-based approaches used in other types of family violence. Participants (n = 80), family caregivers of older adults who were members of Kaiser Permanente, completed surveys at baseline, post-test, and 3-month follow-up. The primary outcome was caregiver-reported EM; additional proximal outcomes were caregiver burden, quality-of-life, anxiety, and depression. Nonparametric tests (Mann-Whitney U, Fisher's Exact, Wilcoxon Signed Rank, and McNemar's) were used to make comparisons between treatment and control groups and across time points., Results: The treatment group had no EM after intervention completion (assessed at 3-month follow-up), a significantly lower rate than the control group (treatment = 0%, control = 23.1%, p = 0.010)., Conclusions: In this pilot study, we found that the COACH caregiver support intervention successfully reduced EM of persons living with chronic illness, including dementia. Next steps will include: (1) testing the intervention's mechanism in a fully powered RCT and (2) scaling the intervention for testing in a variety of care delivery systems., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta Crop Protection AG submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue level (MRL) for the active substance mandipropamid in radish leaves (classified under the subgroup of kales), based on an intended indoor use on radishes. The residue data in radish leaves submitted in support of the request were found to be sufficient to derive an MRL proposal for this commodity. Adequate analytical methods for enforcement are available to control the residues of mandipropamid on the commodity under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that long-term intake of residues resulting from the use of mandipropamid according to the reported agricultural practice is unlikely to present a risk to consumer health. The reliable end points, appropriate for use in regulatory risk assessment are presented., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

According to Article 12 of Regulation (EC) No 396/2005, EFSA has reviewed the maximum residue levels (MRLs) currently established at European level for the pesticide active substance zoxamide. To assess the occurrence of zoxamide residues in plants, processed commodities, rotational crops and livestock, EFSA considered the conclusions derived in the framework of Regulation (EC) No 1107/2009, the MRLs established by the Codex Alimentarius Commission and the European authorisations reported by Member States and the UK (including the supporting residues data). Based on the assessment of the available data, MRL proposals were derived, and a consumer risk assessment was carried out. Although no apparent risk to consumers was identified, some information required by the regulatory framework was missing. Hence, the consumer risk assessment is considered indicative only and some MRL proposals derived by EFSA still require further consideration by risk managers. Furthermore, in accordance with Article 6 of Regulation (EC) No 396/2005, the Applicant Gowan Crop Protection Ltd, submitted a request to the competent national authority in Latvia to set an import tolerance for zoxamide in onions (extrapolated to garlic and shallots) based on the use authorised in USA. The data submitted in support of the request were found to be sufficient to derive MRL proposals for all crops under assessment. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of zoxamide according to the agricultural practices on onions, garlic and shallots is unlikely to present a risk to consumer health., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Objective: Two phase 3 galcanezumab trials were conducted in Europe and North America to analyze the reduction of weekly cluster headache (CH) attack frequency in populations with episodic and chronic CH. The current study aims to illustrate prospectively recorded baseline clinical data from these trials and to identify possible predictors of response., Methods: Patients (aged 18-65 years) met The International Classification of Headache Disorders 3rd edition-beta criteria for CH. Attacks were evaluated using an electronic headache diary for 7-day (episodic) or 14-day (chronic) eligibility assessments before patients were randomized 1:1 to monthly subcutaneous galcanezumab 300 mg or placebo., Results: Data were collected from 106 patients with episodic and 237 with chronic CH. Overall, the mean age [standard deviation] was 45.4 [11.0] years; patients were predominantly White (84.5%), male (75.8%), and European (77.6%). Patients with episodic CH reported 17.5 [10.0] attacks/week; patients with chronic CH reported 18.8 [10.2] attacks/week. The average pain severity score (range 0-4) was 2.5 [0.7] for episodic CH and 2.7 [0.7] for chronic CH. Higher attack frequency was a possible predictor of response to galcanezumab; potential negative predictors of response were greater attack severity and duration., Conclusion: This large dataset of patients with CH provides reliable systematically and prospectively collected information on disease characteristics. The analysis in episodic CH underscores potential predictors of response worth considering for future CH trial design., Clinical Trial Registration: ClinicalTrials.gov, identifiers: NCT02397473 and NCT02438826., Competing Interests: RJ reports speaker's fees from Novartis, ATI, Lundbeck, TEVA, and Allergan and institutional payments for clinical trials with Eli Lilly and Company, Lundbeck, and ATI. CT reports fees for advisory boards or speaker's fees for Allergan/AbbVie, Eli Lilly and Company, Dompé, Lundbeck, Novartis, and TEVA and institutional payments for clinical trials with Allergan/AbbVie, Eli Lilly and Company, Lundbeck, Novartis, and TEVA. TM, JB, CZ, YD, and JM are full-time employees of Eli Lilly and Company and/or one of its subsidiaries and are minority holders of company stock. SA reports no commercial or financial relationships that could be construed as a potential conflict of interest. At the time the study was conducted, SA was a full-time employee of Eli Lilly and Company, Indianapolis, IN, USA, and was a minority holder of company stock., (Copyright © 2023 Jensen, Tassorelli, Myers Oakes, Bardos, Zhou, Dong, Aurora and Martinez.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Gowan Crop Protection Limited submitted a request to the competent national authority in Greece to set an import tolerance for the active substance fenazaquin in hops imported from the United States of America. The data submitted in support of the request were found to be sufficient to derive an maximum residue limit (MRL) proposal for hops. An adequate analytical method for enforcement is available to control the residues of fenazaquin in the plant matrix under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues of fenazaquin and its toxicologically relevant plant metabolite TBPE resulting from the use of fenazaquin on imported hops from United States according to the reported agricultural practice is unlikely to present a risk to consumer health., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG, Crop Science Division submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue levels (MRL) and to set import tolerances for flupyradifurone and its metabolite difluoroacetic acid (DFA) in various plant commodities. The data submitted in support of the request were found to be sufficient to derive MRL proposals for flupyradifurone and DFA in avocados, mangoes, papayas, asparagus, sesame seeds, sunflower seeds, sugar beet roots and chicory roots. Adequate analytical methods for enforcement are available to control the residues of flupyradifurone and DFA in plant matrices under consideration at the validated limits of quantification (LOQs) of 0.01 and 0.007 mg/kg, respectively. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of flupyradifurone and DFA residues resulting from the use of flupyradifurone according to the reported agricultural practices is unlikely to present a risk to consumer health., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Objective: To describe clinical characteristics and regional treatment patterns of episodic cluster headache (CH)., Methods: A point-in-time survey of physicians and their patients with CH was conducted in the United States, United Kingdom and Germany in 2017., Results: Overall, 1012 patients with episodic CH were analyzed. Demographic and clinical findings were generally consistent across regions. Most patients were men (66.6%) and the mean age was 40.9 years. The greatest proportion of patients (38.3%) had ≤1 attack per day. The mean number of attacks per day (APD) was 2.4 and mean number of cluster periods per year was 2.6; the mean cluster period duration was 30.8 days. Most patients (69.3%) did not report a specific or predicable time when cluster periods occurred. Acute treatment was prescribed for 47.6% of patients, 10.3% of patients received preventive treatment, and 37.9% of patients received combined acute and preventive treatment; 4.2% of patients were not receiving treatment. Frequently prescribed acute treatments were sumatriptan, oxygen, and zolmitriptan; oxygen use varied considerably across countries and was prescribed least often in the United States. Frequently prescribed preventive treatments were verapamil, topiramate, and lithium. Lack of efficacy and tolerability were the most common reasons for discontinuing preventive treatment., Conclusions: We observed high use of acute treatments, but only half of patients used preventive treatments despite experiencing several cluster periods per year with multiple cluster APD. Further studies about the need for and benefits of preventive treatment for episodic CH are warranted.

Objectives: To characterize pregnant women admitted to Irene Neto Maternity Hospital, Lubango city, Huíla province, and their pregnancy outcomes., Methods: We conducted a descriptive cross-sectional facility-based survey between October 2016 and September 2017, involving 500 pregnant women, followed from admission in labor until the end of delivery. Mean (SD) was computed for quantitative variables, while relative and absolute frequencies were determined for categorical variables. Additionally, confidence intervals were estimated., Results: Among pregnant women 18.3% were adolescents (≤ 19 years) and 14.5% had advanced maternal age (≥ 35 years). Illiteracy was reported by 8.2%. One in three (33.6%) had a short stature (< 1.55 m). Malaria was the most frequent infection during pregnancy (16.3%). Upon admission, 18.1% were anemic (Hb < 11 g/dl) and 36.0% had hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg), contrasting with the few cases reported of chronic hypertension and pregnancy-induced hypertension. There were 15 twin pregnancies. Cesarean section was performed in 25.2% of the women, although there was no medical indication for 23.0% of women having cesareans. Two maternal deaths occurred in our sample. Among live births from singleton pregnancies (97.1%), birth asphyxia (Apgar < 7 at 5 min) was observed in 22.7% and 10.3% had low birth weight (< 2.5 kg)., Conclusions: There are very few studies reporting pregnancy outcomes in Angola. This analysis presents data from Huíla province, the second most populous province. We identified characteristics for higher risk of adverse pregnancy outcomes: adolescence, illiteracy, and short stature. Among newborn outcomes, birth asphyxia and low birth weight demand special attention. Further research is needed to explore the non-medical indications for cesarean section and to better understand the twinning rate in Lubango., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1-12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1-17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, C max and area under the curve in the 2-week dosing interval, AUC 2W ), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC 2W ) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA., (© 2023. The Author(s).)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG Crop Science Division submitted a request to the competent national authority in Greece to modify the existing maximum residue level (MRL) for the active substance propamocarb in honey. The data submitted in support of the request were found to be sufficient to derive MRL proposals for honey. Adequate analytical methods for enforcement are available to control the residues of propamocarb on the commodity under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of propamocarb according to the reported agricultural practice is unlikely to present a risk to consumer health., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Background: Malaria is transmitted by different Anopheles species. In Brazil, the disease is concentrated in the Amazon region. Rivers play an important role in the life cycle of malaria since the vector reproduces in aquatic environments. The waters of the rivers in the Amazon have distinct chemical characteristics, which affect the colour of the water and therefore, the study analysed whether the colour of the waters of the rivers have an on influence the distribution of malaria. The goal of the study was to correlate the different colourations of the water (black, white and mixed water) and the malaria incidence in 50 municipalities of the Amazonas state, Brazil, and then test hypotheses about the characteristics of the colour of the rivers and disease incidence., Methods: This study was conducted for a period of seventeen years (2003-2019) in 50 municipalities in the state of Amazonas, Brazil. A conditionally Gaussian dynamic linear model was developed to analyse the association of malaria incidence and three types of river colour: white, black and mixed., Results: The analyses indicate that the distribution of malaria is related to the colouration of the rivers. The results showed that places located near black-water rivers have a higher malaria incidence when compared to places on the banks of white-water rivers., Conclusions: Historically, the hydrological regime has played an important role in the dynamics of malaria in the Amazon, but little is known about the relationship between river colours and the incidence of the disease. This research was carried out in a region with hydrographic characteristics that were heterogeneous enough to allow an analysis that contrasted different colours of the rivers and covered almost the whole of the state of Amazonas. The results help to identify the places with the highest risk of malaria transmission and it is believed that they will be able to contribute to more precise planning of actions aimed at controlling the disease in the region., (© 2023. The Author(s).)

For faculty members, job satisfaction, compensation, and career advancement hinge on achieving 'critical' career milestones (e.g., external funding, tenure). Faculty face unique barriers to achieving career milestones (Bagley et al., 2018), and therefore must employ tailored strategies to overcome challenges. The current project extends research on barriers to career milestones (Soller et al., 2022) to examine strategies faculty employ to overcome barriers in the pursuit of critical career milestones. Thirty-seven faculty members participated across eight US academic institutions, including 22 under-represented minorities in science (URM-S; women or racial/ ethnic minorities). Respondents identified critical career milestones they achieved or will pursue within the next 24 months and then discussed strategies used and suggestions for achieving milestones during semi-structured qualitative interviews. The research team conducted a thematic, qualitative, descriptive analysis of qualitative data using NVivo software in a systematic, interactive, team-based process. Four key strategies emerged for navigating barriers in the pursuit of critical career milestones: 1) Careful engagement of mentors and allies; 2) Collaborate and network; 3) Set boundaries and prioritize; and 4) Reflect on values and use personal strengths. Administrators should aim to remove structural barriers, particularly those that reduce equity (Davis et al., 2022). Identifying strategies that faculty employ to overcome challenges can enhance mentoring by helping mentors understand how mentees overcome unique challenges, particularly those that are not easily addressed through structural interventions.

Background: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors?, Methods: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ., Results: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii)., Conclusions: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants., Impact: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477., (©2023 American Association for Cancer Research.)

The applicant Syngenta Crop Protection AG submitted a request to the competent national authority in Germany to evaluate the confirmatory data that were identified for S-metolachlor in the framework of the maximum residue level (MRL) review under Article 12 of Regulation (EC) No 396/2005 as not available. To address the data gaps, a new freezer storage stability study for S-metolachlor in commodities with high acid content was submitted. However, the data gap on storage stability was considered only partially addressed for strawberries because, in the absence of information on the storage time interval of the samples of the residue trials performed on strawberries, no conclusion on the validity of these trials could be drawn. The data gap on the lack of trials to support the good agricultural practice (GAP) on pineapples was not addressed. Consequently, the existing tentative MRLs for strawberries and pineapple cannot be confirmed and EFSA recommends lowering these MRLs to the enforcement limit of quantification (LOQ). Since a new lower LOQ for enforcement in high acid content commodities of 0.01 mg/kg has been validated, it is proposed to change the existing MRL value from 0.05* to 0.01* mg/kg for these two commodities., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Background: Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach., Methods: The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software., Results: Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions., Conclusions: A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability., Competing Interests: G. Tuffal, G. Tiraboschi, F. Hurbin, RP, J.-M. Martinez, and D. Fabre are employees at Sanofi. P. Boittet is an employee at Altran. This study was sponsored by Sanofi. The remaining author declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Background: The complex process of liver graft assessment is one point for improvement in liver transplantation. The main objective of this study is to develop a tool that supports the surgeon who is responsible for liver donation in the decision-making process whether to accept a graft or not using the initial variables available to it., Material and Method: Liver graft samples candidate for liver transplantation after donor brain death were studied. All of them were evaluated " in situ " for transplantation, and those discarded after the " in situ " evaluation were considered as no transplantable liver grafts, while those grafts transplanted after " in situ " evaluation were considered as transplantable liver grafts. First, a single-center, retrospective and cohort study identifying the risk factors associated with the no transplantable group was performed. Then, a prediction model decision support system based on machine learning, and using a tree ensemble boosting classifier that is capable of helping to decide whether to accept or decline a donor liver graft, was developed., Results: A total of 350 liver grafts that were evaluated for liver transplantation were studied. Steatosis was the most frequent reason for classifying grafts as no transplantable, and the main risk factors identified in the univariant study were age, dyslipidemia, personal medical history, personal surgical history, bilirubinemia, and the result of previous liver ultrasound ( p  < 0.05). When studying the developed model, we observe that the best performance reordering in terms of accuracy corresponds to 76.29% with an area under the curve of 0.79. Furthermore, the model provides a classification together with a confidence index of reliability, for most cases in our data, with the probability of success in the prediction being above 0.85., Conclusion: The tool presented in this study obtains a high accuracy in predicting whether a liver graft will be transplanted or deemed non-transplantable based on the initial variables assigned to it. The inherent capacity for improvement in the system causes the rate of correct predictions to increase as new data are entered. Therefore, we believe it is a tool that can help optimize the graft pool for liver transplantation., 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., (© 2023 Pontes Balanza, Castillo Tuñón, Mateos García, Padillo Ruiz, Riquelme Santos, Álamo Martinez, Bernal-Bellido, Suarez Artacho, Cepeda Franco, Gomez Bravo and Marin Gome.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant BASF Agro B.V. Arnhem (NL) Freienbach Branch submitted a request to the competent national authority in Austria to modify the existing maximum residue levels (MRLs) for the active substance mefentrifluconazole in various crops and swine liver and other swine products. The data submitted in support of the request were found to be sufficient to derive MRL proposals. Adequate analytical methods for enforcement are available to control the residues of mefentrifluconazole in the plant commodities under consideration and in animal matrices at the validated limit of quantification (LOQ) of 0.01 mg/kg. New data relevant to the data gaps on storage stability and feeding studies of triazole derivative metabolites (TDMs), that were identified during the peer review of confirmatory data of the TDMs, were submitted in support of the present MRL application. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of mefentrifluconazole according to the reported agricultural practices is unlikely to present a risk to consumer health. EFSA noted a narrow safety margin with regard to acute exposure to mefentrifluconazole residues from the intake of spinaches if residues occur at the level of the proposed MRL. EFSA also performed an indicative risk assessment for the TDMs based on uses of mefentrifluconazole only. The estimated exposure for TDMs did not exceed the toxicological reference values., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Wheelchair users are often perceived as someone ill and who will be limited in performing daily activities. This paradigm can be changed if instead to focus on limits, we start to think about the new possibilities that could be explored from their current mobility and technology. We present a novel dancing wheelchair with augmented mobility named Volting. Our novel wheelchair was designed to tilt the seat laterally up to 14°. This inclination is performed proportionally to the inclination of the user by a mechanism based on passive suspensions. Our system was analyzed as a double inverted pendulum and a mathematical model was developed using Euler-Lagrange equations. This analysis was used to calculate the ideal stiffness. Thus, we performed experiments with three distinct stiffness values and varying the weight of participants to analyze the behavior of our mechanism. Our results show that lateral inclinations in our wheelchair can be unstable, low sensitivity or linear tendency. The latter behavior, which is the most appropriate, was obtained using the suspension whose stiffness was close to the ideal value, thus validating our mathematical approach. Moreover, this behavior was maintained even if the user weight varies up to 10kg above the estimated value, ensuring a good performance for varying morphologies. Finally, our device was tested by a professional wheelchair dancer who shows the new possibilities of Volting in terms of mobility.

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Ascenza Agro S.A. submitted a request to the competent national authority in Greece to modify the existing maximum residue levels (MRL) for the active substance pyrimethanil in table grapes, garlic and honey. The data submitted in support of the request were found to be sufficient to derive MRL proposals for table grapes, garlic and honey. Adequate analytical methods for enforcement are available to control the residues of pyrimethanil in the commodities under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the long-term intake of residues resulting from the use of pyrimethanil according to the reported agricultural practice is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant BASF SE submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue levels (MRLs) for the active substance metazachlor in leeks and honey. The data submitted in support of the request were found to be sufficient to derive MRL proposals. Adequate analytical methods for enforcement are available to control the residues of metazachlor metabolites 479 M04, 479 M08 and 479 M16 in plant matrices and honey at the validated limit of quantification (LOQ) of 0.01 and 0.02 mg/kg for each analyte. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of metazachlor according to the reported agricultural practice is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta Crop Protection AG submitted an application to the competent national authority in Germany (evaluating Member State, EMS) to modify the existing maximum residue levels (MRLs) for the active substance difenoconazole in wheat and rye grain. The data submitted in support of the request were found sufficient to derive MRL proposals for wheat and rye grain. Adequate analytical methods for enforcement are available to control the residues of difenoconazole in plant matrices under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. The submitted data indicate no need to modify the EU MRLs in animal commodities for the existing enforcement residue definition. EFSA concluded that the dietary exposure to difenoconazole residues from the intake of wheat and rye grain is low, noting that the impact of intended uses on the residues in animal commodities and the consumer exposure could not be properly addressed. Overall, the present risk assessment confirms a very narrow margin of safety for the overall chronic exposure and is considered provisional, pending the submission of confirmatory data on possible preferential metabolism/degradation of the four stereo isomers of difenoconazole in plants and animals and the impact of isomerisation on the toxicity of difenoconazole. The assessment is also affected by uncertainties related to the toxicological profile of animal metabolite CGA205375 and, additionally, it does not take into consideration triazole derivative metabolites (TDMs)., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

The applicant Corteva Agrosciences submitted a request to the competent national authority in Slovenia to evaluate the confirmatory data that were identified for fenbuconazole in the framework of the MRL review under Article 12 of Regulation (EC) No 396/2005 as not available. To address the Article 12 confirmatory data gaps, new residue trials analysing triazole derivative metabolites (TDMs) were submitted on grapefruits, lemons, apples, pears, peaches, cherries and blueberries. Following the assessment of submitted data, EFSA concluded that Article 12 confirmatory data gaps are considered addressed for grapefruits, oranges, lemons, limes, pome fruits, peaches, cherries and blueberries. The calculated livestock dietary burdens indicated that for the individual TDMs, the trigger value of 0.004 mg/kg bw day is not exceed from the intake of apple pomace and citrus dried pulp. The new information provided required the assessment of consumer exposure to TDMs, which identified no consumer intake concerns for the crops under consideration. No data were submitted to address the Article 12 confirmatory data gaps for tree nuts, apricots, plums, table grapes, wine grapes, cranberries, bananas, sweet peppers/bell peppers, cucurbits with edible/inedible peel, peanuts/groundnuts, sunflower seeds and rapeseeds/canola seeds, barley, rye and wheat. For these commodities, the existing EU MRL could be lowered to the enforcement LOQ., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta Crop Protection AG submitted a request to the competent national authority in Germany to modify the existing maximum residue level (MRL) for the active substance azoxystrobin in hops. The data submitted in support of the request were found to be sufficient to derive an MRL proposal for hops. Adequate analytical methods for enforcement are available to control the residues of azoxystrobin on the commodity under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, noting that an acute risk assessment was not deemed necessary for azoxystrobin, EFSA concluded that the long-term intake of residues resulting from the use of azoxystrobin according to the reported agricultural practice is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant DLR-Rheinpfalz submitted a request to the competent national authority in Germany to modify the existing maximum residue levels (MRLs) for the active substance flonicamid in Chinese cabbages, kales and kohlrabies. The data submitted in support of the request were found to be sufficient to derive MRL proposals for the commodities under assessment. Adequate analytical methods for enforcement are available to control the residues of flonicamid, 4-trifluoromethylnicotinic acid (TFNA) and N -(4-trifluoromethylnicotinoyl) glycine (TFNG) (sum expressed as flonicamid) in the commodities under consideration at the validated combined limit of quantification (LOQ) of 0.03 mg/kg and the residues of flonicamid and TFNA-AM in animal matrices at the validated combined LOQ of 0.02 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of flonicamid according to the reported agricultural practices is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer CropScience Deutschland GmbH submitted a request to the competent national authority in Germany to modify the existing maximum residue levels (MRLs) for the active substance prothioconazole in sugar beet roots and chicory roots. The data submitted in support of the request were found to be sufficient to derive MRL proposals for sugar beet roots and chicory root. Adequate analytical methods for enforcement are available to control the residues of prothioconazole on the commodities under consideration at the validated limit of quantification (LOQ) of 0.02 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of prothioconazole according to the reported agricultural practices is unlikely to present a risk to consumer health. An indicative exposure assessment to triazole derivative metabolites from the intended uses of prothioconazole did not indicate consumer intake concerns., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant ISK Biosciences Europe N.V. submitted a request to the competent national authority in Belgium to modify the existing maximum residue levels (MRLs) for the active substance isofetamid in certain salad plants. The data submitted in support of the request were found to be sufficient to derive MRL proposals for lamb's lettuces/corn salads, escaroles/broad leaved endives, cresses and other sprouts and shoots, land cresses, Roman rocket/rucola, red mustards, baby leaf crops (including brassica species) and other lettuces and salad plants. An adequate analytical method for enforcement is available to enforce the residues of isofetamid on the commodities under consideration at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the uses of isofetamid according to the reported agricultural practices is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta Crop Protection AG submitted a request to the competent national authority in Italy to modify the existing maximum residue levels (MRLs) for the active substance acibenzolar-S-methyl in grapes. The data submitted in support of the request were found to be sufficient to derive MRL proposals for table and wine grapes. Adequate analytical methods for enforcement are available to control the residues of acibenzolar-S-methyl residues and of the metabolite acibenzolar acid (free and conjugated) in plant matrices at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of acibenzolar-S-methyl according to the reported agricultural practices is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer AG Crop Science Division submitted a request to the competent national authority in the Netherlands to set a maximum residue level (MRL) for the active substance trifloxystrobin in honey. The data submitted in support of the request were found to be sufficient to derive an MRL proposal for the commodity under assessment. An adequate analytical method for enforcement is available to control the residues of trifloxystrobin in honey at the validated limit of quantification (LOQ) of 0.01 mg/kg. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the potential transfer of residues into honey assessed in the present MRL application of trifloxystrobin is unlikely to present a risk to consumer health. The consumer risk assessment shall be regarded as indicative and affected by uncertainties., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Dormfresh limited submitted a request to the competent national authority in the Netherlands to modify the existing maximum residue level (MRL) for the active substance 1,4-dimethylnaphthalene in potatoes. The data submitted in support of the request were found to be sufficient to derive an MRL proposal. Adequate analytical methods for enforcement are available to control the residues of 1,4-dimethylnaphthalene in potatoes and residues of 1,4-dimethylnaphthalene, M23 and M23 conjugates in animal matrices. The data gaps identified during the MRL review relevant to the identity of metabolites found at significant levels in the processing studies and the analytical methods for enforcement in animal matrices were considered satisfactorily addressed. Based on the risk assessment results, EFSA concluded that the short-term and long-term intake of residues resulting from the use of 1,4-dimethylnaphthalene according to the reported agricultural practice is unlikely to present a risk to consumer health., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

ATM is an apical kinase of the DNA damage response involved in the repair of DNA double-strand breaks. Germline ATM variants (gATM) have been associated with an increased risk of developing lung adenocarcinoma (LUAD), and approximately 9% of LUAD tumors harbor somatic ATM mutations (sATM). Biallelic carriers of pathogenic gATM exhibit a plethora of immunological abnormalities, but few studies have evaluated the contribution of immune dysfunction to lung cancer susceptibility. Indeed, little is known about the clinicopathological characteristics of lung cancer patients with sATM or gATM alterations. The introduction of targeted therapies and immunotherapies, and the increasing number of clinical trials evaluating treatment combinations, warrants a careful reexamination of the benefits and harms that different therapeutic approaches have had in lung cancer patients with sATM or gATM. This review will discuss the role of ATM in the pathogenesis of lung cancer, highlighting potential therapeutic approaches to manage ATM-deficient lung cancers., Competing Interests: Declaration of Competing Interest Oscar Arrieta reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees. Oscar Arrieta reports a relationship with AstraZeneca PLC that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Oscar Arrieta reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Oscar Arrieta reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees and travel reimbursement. Oscar Arrieta reports a relationship with Merck & Co Inc that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Oscar Arrieta reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Oscar Arrieta reports a relationship with Roche that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Left bundle branch area pacing (LBBAP) for cardiac resynchronization therapy (CRT) is an alternative to biventricular pacing (BiVp)., Objectives: The purpose of this study was to compare the outcomes between LBBAP and BiVp as an initial implant strategy for CRT., Methods: In this prospective multicenter, observational, nonrandomized study, first-time CRT implant recipients with LBBAP or BiVp were included. The primary efficacy outcome was a composite of heart failure (HF)-related hospitalization and all-cause mortality. The primary safety outcomes were acute and long-term complications. Secondary outcomes included postprocedural New York Heart Association functional class and electrocardiographic and echocardiographic parameters., Results: A total of 371 patients (median follow-up of 340 days [IQR: 206-477 days]) were included. The primary efficacy outcome occurred in 24.2% in the LBBAP vs 42.4% in the BiVp (HR: 0.621 [95% CI: 0.415-0.93]; P = 0.021) group, driven by a reduction in HF-related hospitalizations (22.6% vs 39.5%; HR: 0.607 [95% CI: 0.397-0.927]; P = 0.021) without significant difference in all-cause mortality (5.5% vs 11.9%; P = 0.19) or differences in long-term complications (LBBAP: 9.4% vs BiVp: 15.2%; P = 0.146). LBBAP resulted in shorter procedural (95 minutes [IQR: 65-120 minutes] vs 129 minutes [IQR: 103-162 minutes]; P < 0.001) and fluoroscopy times (12 minutes [IQR: 7.4-21.1 minutes] vs 21.7 minutes [IQR: 14.3-30 minutes]; P < 0.001), shorter QRS duration (123.7 ± 18 milliseconds vs 149.3 ± 29.1 milliseconds; P < 0.001), and higher postprocedural left ventricular ejection fraction (34.1% ± 12.5% vs 31.4% ± 10.8%; P = 0.041)., Conclusions: LBBAP as an initial CRT strategy resulted in a lower risk of HF-related hospitalizations compared to BiVp. A reduction in procedural and fluoroscopy times, shorter paced QRS duration, and improvements in left ventricular ejection fraction compared with BiVp were observed., Competing Interests: Funding Support and Author Disclosures Dr Diaz has received speaker honoraria and is a proctor for Medtronic for conduction system pacing. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The applicant UPL Europe Ltd submitted a request to the competent national authority in Slovenia to evaluate the confirmatory data that were identified for napropamide in the framework of the maximum residue levels (MRLs) review under Article 12 of Regulation (EC) No 396/2005 as not available. To address the data gaps, a new storage stability study on grapes (high acid content commodity) was submitted while a metabolism study in fruit crops following foliar treatment, residue trials on fresh herbs and edible flowers and an analytical method for matrices difficult to analyse were not submitted. Therefore, only the data gap for storage stability was satisfactorily addressed. The new information provided required a revision of the tentative MRLs for commodities where confirmatory data were indicated. An update of the consumer risk assessment for napropamide was performed considering the new data submitted and it did not indicate any consumer intake concerns in relation to the chronic exposure., (© 2023 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Background and Objectives: Person-centered care (PCC) applied to elder mistreatment interventions is an approach to include victim priorities. Although PCC may improve outcomes by supporting choice, victim preferences are often difficult to support, especially in high-risk situations. We studied the adaptation of PCC structures and process to a pilot intervention, aimed at including client preferences in a multidisciplinary team's plans to address complex elder mistreatment., Research Design and Methods: Case study analysis was used to examine the process of integrating client priorities into a risk-reduction plan. A well-being framework was used to understand the relationship between safety and preferences. Purposive sampling identified a case study of a high-risk victim with history of refusing help who agreed to work with the Service Advocate, a member of a multidisciplinary team., Results: PCC required a relationship of trust, honed over several weeks by prioritizing the clients' perspective. Client preferences included remaining at home, continuing the relationship with the abuser, and maintaining a sense of mastery. Individualized definitions of "safety" were unrelated to elder mistreatment risk. Assistance included working with the suspected perpetrator, which is not offered by most elder mistreatment interventions, and resulted in some risk reduction. Reasons for refusing help were a desire for control and fear of loss of well-being assets., Discussion and Implications: Individualized definitions of well-being should be considered in measuring intervention success. Future research could determine guidelines on what levels of elder mistreatment risk are acceptable, and how to monitor clients for safety while supporting autonomy., (Published by Oxford University Press on behalf of The Gerontological Society of America 2022.)

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf.

Mirizzi syndrome is a rare complication of chronic calculous cholecystitis. Preoperative diagnosis is challenging due to the absence of pathognomonic signs and symptoms and low sensitivity rates of imaging tests. Historically, laparotomy has been the preferred choice of surgical management. Endoscopic and laparoscopic approaches have been increasingly described as diagnostic and therapeutic options for Mirizzi type I and II, but data is limited regarding the management of more complex cases. We describe a staged endoscopic and laparoscopic approach for the management of type IV Mirizzi syndrome and review the management options.

In 2019, the Brumadinho dam rupture released a massive amount of iron ore mining tailings into the Paraopeba River. Up to now, it remains a public health issue for the local and downstream populations. The present study aims to assess the behavior and fate of metal contamination following the disaster. Using new sampling strategies and up-to-date geochemistry tools, we show that the dissolved metal concentrations (< 0.22 µm cutoff filtration) remained low in the Paraopeba River. Although the tailings present high metal concentrations (Fe, Mn, Cd, and As), the high local background contents of metals and other previous anthropogenic contamination hamper tracing the sediment source based only on the geochemical signature. The Pb isotopic composition coupled with the metals enrichment factor of sediments and Suspended Particulate Matter (SPM) constitutes accurate proxies that trace the fate and dispersion of tailing particles downstream of the dam collapse. This approach shows that 1) The influence of the released tailing was restricted to the Paraopeba River and the Retiro Baixo reservoir, located upstream of the São Francisco River; 2) The tailings' contribution to particulate load ranged from 17 % to 88 % in the Paraopeba River; 3) Other regional anthropogenic activities also contribute to water and sediment contamination of the Paraopeba river., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

G protein-coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β 2 -adrenergic receptor (β 2 AR) stimulation induced the nuclear export of phosphodiesterase 4D5 (PDE4D5), an enzyme that degrades the second messenger cAMP, to enable memory consolidation. We demonstrated that the endocytosis of β 2 AR phosphorylated by GPCR kinases (GRKs) mediated arrestin3-dependent nuclear export of PDE4D5, which was critical for promoting nuclear cAMP signaling and gene expression in hippocampal neurons for memory consolidation. Inhibition of the arrestin3-PDE4D5 association prevented β 2 AR-induced nuclear cAMP signaling without affecting receptor endocytosis. Direct PDE4 inhibition rescued β 2 AR-induced nuclear cAMP signaling and ameliorated memory deficits in mice expressing a form of the β 2 AR that could not be phosphorylated by GRKs. These data reveal how β 2 AR phosphorylated by endosomal GRK promotes the nuclear export of PDE4D5, leading to nuclear cAMP signaling, changes in gene expression, and memory consolidation. This study also highlights the translocation of PDEs as a mechanism to promote cAMP signaling in specific subcellular locations downstream of GPCR activation.

Objective Injuries resulting from trauma or tumor resection may cause length alterations in the bones of the upper extremities (UE) requiring reconstruction. Direct contralateral bone is often used to determine the appropriate length for reconstruction but fails to account for potential asymmetry. Given the paucity of data assessing asymmetry in living populations and the need for accurate length approximation, we developed a study evaluating UE long bone asymmetry using radiographic imaging in living subjects. Methods Bilateral X-ray images previously obtained for traumatic injury or chronic osseous conditions were retrospectively collected for adult subjects (ages 18-81). After screening, 61 patients met the inclusion criteria: 28 radii, 29 ulnae, and 19 humeri. Three serial measurements were taken, and the median was used for subsequent analysis. Wilcoxon signed-rank tests were performed to assess differences in contralateral bone lengths. Bootstrapping was utilized to obtain sample sizes of 200, 500, and 1000 for each bone. Results The difference in mean absolute length was 27.0 mm for the humerus, 8.6 mm for the radius, and 7.5 mm for the ulna. Neither the left side nor the right side was significantly longer for any bone. In 57.9% (11/19) of patients, the right humerus was longer than the left; in 60.7% (17/28), the right radius was longer than the left; and in 48.3% (14/29), the right ulna was longer than the left. All other measurements showed the left was longer than the right. Wilcoxon signed-rank tests did not find significant differences between contralateral pairs in any direct measurement group. In bootstrap samples, significant differences in length (p ≤ 0.05) were seen in all samples (n = 200, 500, and 1000) for both humerus and radius but only the 1000 sample group for the ulna. Conclusions Direct contralateral measure may be an appropriate method of length estimation for the humerus, radius, and ulna in post-industrial humans., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kharbat et al.)

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs., Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs., Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67 + regulatory T cells (Tregs) and Ki-67 + CD8 + T cells is also likely to be associated with increased risk of irAEs., Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs., Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen., Competing Interests: Declaration of interests L.F. has/had advisory roles for Novartis, Sanofi, Philogen, and Bristol-Myers Squibb, all which took place outside the submitted work. P.A.A. has/had consultant/advisory roles for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, Bio-Al Health, and ValoTx; he also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, Sanofi, and Pfizer, as well as travel support from Merck Sharp & Dhome and Pfizer, all which was outside the submitted work. T.A. served as consultant to Bristol-Myers Squibb, Novartis, and CeCaVa; received travel support from Bristol-Myers Squibb and Novartis; received speaker fees from Novartis, Bristol-Myers Squibb, Pierre Fabre, and CeCaVa; received institutional funding from Neracare, Novartis, Sanofi, and SkylineDX; and received institutional research grants from Novartis outside the submitted work. R.D. has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME, all which took place outside the submitted work. W.v.d.V. declares research support from the Novartis research foundation and the PROMEDICA Stiftung and serves as a consultant for Mabylon outside the submitted work. S.U. declares research support from Bristol-Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre outside the submitted work. L.Z. declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; research support from Novartis; and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma, and Novartis outside the submitted work. F.D. receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, and Sun Pharma outside the submitted work. L.H. declares research support from Therakos and speakers and advisory board honoraria from Amgen, BiomeDx, Bristol-Myers Squibb, Curevac, Merck, Merck Sharp & Dohme, Myoncare, Novartis, Pierre Fabre, Sanofi, SUN, and Roche, outside the submitted work. M.E. declares honoraria and travel support from Bristol-Myers Squibb, Immunocore, and Novartis outside the submitted work. R.K. declares travel support from Pierre Fabre and Sun Pharma outside the submitted work. M.J. declares advisory roles (institutional) for Novartis, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol-Myers Squibb, Debiopharm, Merck Sharp & Dhome, Roche, and Sanofi; research funding from Swiss Cancer Research; and travel grants from Roche, Sanofi, and Takeda. D.S. has/had consultant/advisory roles in the last 3 years for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pfizer, Pierre Fabre, Sun Pharma, Sanofi, Regeneron, Ultimovacs, Sandoz, Immunocore, 4SC, Neracare, Nektar, Daiichi Sankyo, Oncosec, Amgen, BioCon, Immatics, InFlarX, Innovent, Labcorp, Replimune, and Haystack; his institution also received research funding from Bristol-Myers Squibb, Roche-Genentech, Array, and Merck Sharp & Dhome, all of which took place outside the submitted work. N.K. received personal fees, travel costs, and speaker’s honoraria from Astellas, Novartis, Ipsen, and Photocure, all of which took place outside the submitted work. M.P.L. has received project-specific research funding from Roche, Novartis, Molecular Partners, and Oncobit., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Most studies evaluating factors associated with the survival of patients with brain metastases (BM) have focused on patients with newly diagnosed BM. This study aimed to identify prognostic factors associated with survival after brain re-irradiation in order to develop a new prognostic index., Methods: This 5-year retrospective study included patients treated with repeat-radiotherapy for recurrent BM at the "Instituto Nacional de Cancerología" of Mexico between 2015 and 2019. Significant variables in the multivariate Cox regression analysis were used to create the brain re-irradiation index (BRI). Survival and group comparisons were performed using the Kaplan-Meier method and the log-rank test., Results: Fifty-seven patients receiving brain re-irradiation were identified. Most patients were women (75.4%) with a mean age at BM diagnosis of 51.4 years. Lung and breast cancer were the most prevalent neoplasms (43.9% each). Independent prognostic factors for shorter survival after re-irradiation were: Age >50 years (hazard ratio [HR]:2.5 [95% confidence interval [CI], 1.1-5.8]; p = 0.026), uncontrolled primary tumor (HR:5.5 [95% CI, 2.2-13.5]; p < 0.001), lesion size >20 mm (4.6 [95% CI, 1.7-12.2]; p = 0.002), and an interval <12 months between radiation treatments (HR:4.3 [95% CI, 1.7-10.6]; p = 0.001). Median survival (MS) after re-irradiation was 14.6 months (95% CI, 8.2-20.9).MS of patients stratified according to the BRI score was 17.38, 10.34, and 2.82 months, with significant differences between all groups., Conclusions: The new BRI can be easily implemented for the prognostic classification of cancer patients with progressive or recurrent BM from extracranial solid tumors., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Persistent barriers exist to engage rural providers in research and training. Provider shortages exacerbate these challenges, leading to a scarcity of time and limiting motivation to participate in research. We present application of an innovative engagement model to increase rural primary care provider participation in research. Using our Community Engagement and Research Core, we demonstrate that fundamental principles of training and expertise, attention to efficiency and multitasking, and commitment to community are important for addressing provider recruitment barriers. We encourage other Clinical and Translational Science Centers to provide similar services to their local investigators to enhance provider engagement in research., (© The Author(s) 2022.)

Water and sediment discharges can change rapidly, and low-frequency measurement devices might not be sufficient to elucidate existing dynamics. As such, above-water radiometry might enhance monitoring of suspended particulate matter (SPM) dynamics in inland waters. However, it has been barely applied for continuous monitoring, especially under partially cloudy sky conditions. In this study, an in situ, high-frequency (30 s timestep), above-water radiometric dataset, collected over 18 days in a tropical reservoir, is analyzed for the purpose of continuous monitoring of SPM concentration. Different modalities to retrieve reflectance spectra, as well as SPM inversion algorithms, were applied and evaluated. We propose a sequence of processing that achieved an average unsigned percent difference (UPD) of 10.4% during cloudy conditions and 4.6% during clear-sky conditions for Rrs (665 nm), compared to the respective UPD values of 88.23% and 13.17% when using a simple calculation approach. SPM retrieval methods were also evaluated and, depending on the methods used, we show that the coefficient of variation (CV) of the SPM concentration varied from 69.5% down to 2.7% when using a semi-analytical approach. As such, the proposed processing approach is effective at reducing unwanted variability in the resulting SPM concentration assessed from above-water radiometry, and our work paves the way towards the use of this noninvasive technique for high-frequency monitoring of SPM concentrations in streams and lakes.

This study aims to explore and compare the reaction of long-term care staff towards situations of sexual intercourse in which one or both partners have dementia. Participants were 538 staff members at 28 Portuguese long-term care facilities. Data were collected using a printed questionnaire with seven vignettes with situations related to the sexuality of LTCF residents. In this study, three of these vignettes were analysed with situations in which residents were having relationships in their bedrooms: (1) one male resident and one female resident; (2) two residents with dementia; (3) two residents, one of them with dementia. For each of the vignettes, participants are asked what they think their 'colleagues' would do in each vignette, i.e. 'What do you think most of your colleagues would do?' The results revealed that when sexual relationships involved both partners living with dementia, the most selected reaction was 'Comment on what happened with supervision or direction', which may suggest that the situation was perceived as difficult or problematic. The most restrictive reactions were most often chosen when only one partner had dementia. This study suggests the need to improve and provide training, so that staff have knowledge and strategies that allow people living with dementia to preserve their sexual rights in long-term care facilities., (© 2022 John Wiley & Sons Ltd.)