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Neither the purchase nor the distribution of pharmaceuticals in hospitals and community pharmacies in Mexico is under the care of pharmacists. Some are under control of physicians.This report presents the results of the implementation of somef pharmaceutical services for the Jalisco Pain Relief, and Palliative Care Institute (Palia Institute), under the direction of the Secretary of Health, Government of Jalisco. The services implemented were drug distribution system, Drug Information Service, Pharmacovigilance Program , and home pharmacotherapy follow-up pilot program for patients with advanced illness, with the ultimate using the appropriate medication. The drug distribution system included dispensing of opioid pain medications, antidepressants, anticonvulsants, NSAIDs, anxiolytic drugs, steroid drugs, laxatives, and anti-emetics. The frequently used drugs were morphine sulfate (62%), amitriptyline (6.4%), and dextropropoxyphene (5.8%). The Drug Information Service answered 114 consultations, mainly asked by a physician (71%) concerned with adverse drug reactions and contraindications (21%). The pharmacovigilance program identified 146 suspected adverse drug reactions and classified them reasonably as possible (27%), probable (69%), and certain (4%). These were attributed mainly to pregabalin and tramadol. The home pharmacotherapy follow-up pilot program cared patients with different cancer diagnoses and drug-related problems (DRP), which were identified and classified (according to second Granada Consensus) for pharmaceutical intervention as DRP 1 (5%), DRP 2 (10%), DRP 3 (14%), DRP 4 (19%), DRP 5 (24%), or DRP 6 (28%). This report provides information concerning the accurate use of medication and, above all, an opportunity for Mexican pharmacists to become an part of health teams seeking to resolve drug-related problems.

Background: Higher risk of secondary brain tumor, carotid stenosis and stroke has been reported after conventional sella irradiation for pituitary neuroendocrine tumors (PitNET). Stereotactic radiosurgery (SRS), which is a more focused approach, is now increasingly used instead. The aim was to assess the risk of secondary brain tumor, carotid stenosis/occlusion and stroke after SRS., Methods: In this multicentric retrospective study, 2,254 patients with PitNET were studied, 1,377 in the exposed group and 877 in the control group., Results: There were 9,840.1 patient-years at risk for the SRS and 5,266.5 for the control group. The 15-year cumulative probability of secondary intracranial tumor was 2.3% (95%CI:0.5%, 4.1%) for SRS and 3.7% (95%CI:0%, 8.7%) for the control group (p=0.6), with an incidence rate of 1.32 per 1,000 and 0.95 per 1,000, respectively. SRS was not associated with increased risk of tumorigenesis when stratified by age (HR: 1.59 [95%CI: 0.57, 4.47], p=0.38). The 15-year probability of new carotid stenosis/occlusion was 0.9% (95%CI: 0.2, 1.6) in the SRS and 2% (95%CI: 0, 4.4) in the control group (p=0.8). The 15-year probability of stroke was 2.6% (95%CI: 0.6%, 4.6%) in the SRS and 11.1% (95%CI: 6%, 15.9%) in the control group (p<0.001). In cox multivariate analysis stratified by age, SRS (HR 1.85[95%CI:0.64, 5.35], p=0.26) was not associated with risk of new stroke., Conclusion: No increased risk of long-term secondary brain tumor, new stenosis or occlusion and stroke was demonstrated in SRS group compared to control in this study with imaging surveillance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aim: Increased mortality during the COVID-19 pandemic is not explained exclusively by COVID-19 infection and its complications. We analysed non-COVID-19 causes of mortality in a population analysis based on data from the Spanish National Institute of Statistics., Methods: Using monthly mortality data in Spain (January 2010-December 2020), we analysed deaths associated with cancer, blood, endocrine, mental, nervous, cardiovascular, respiratory and digestive diseases and explored the COVID-19 impact using a difference-in-difference strategy. We calculated monthly interannual variations in mortality and computed percentage change in terms of the log of deaths in month h of year t minus the log of deaths in month h in the previous year t-1 ., Results: In 2020 in Spain, mortality increased 17.9% compared with 2019. COVID-19 was the leading cause of death (n=60 358), followed by ischaemic heart disease (n=29 654). Throughout 2020, monthly interannual variations in cardiovascular mortality showed an average upward trend of 1.7%, while digestive, cancer and blood diseases showed a downward trend., Conclusions: During the COVID-19 pandemic in Spain in 2020, excess mortality was primarily related to cardiovascular mortality while mortality associated with digestive, cancer and blood diseases was reduced., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Free riders, who benefit from collective efforts to mitigate climate change but do not actively contribute, play a key role in shaping behavioral climate action. Using a sample of 2096 registered American voters, we explore the discrepancy between two groups of free riders: cynics, who recognize the significance of environmental issues but do not adopt sustainable behaviors, and doubters, who neither recognize the significance nor engage in such actions. Through statistical analyses, we show these two groups are different. Doubters are predominantly male, younger, with lower income and education, exhibit stronger conspiracy beliefs, lower altruism, and limited environmental knowledge, are more likely to have voted for Trump and lean towards conservative ideology. Cynics are younger, religious, higher in socioeconomic status, environmentally informed, liberal-leaning, and less likely to support Trump. Our research provides insights on who could be most effectively persuaded to make climate-sensitive lifestyle changes and provides recommendations to prompt involvement in individual sustainability behaviors. Our findings suggest that for doubters, incentivizing sustainability through positive incentives, such as financial rewards, may be particularly effective. Conversely, for cynics, we argue that engaging them in more community-driven and social influence initiatives could effectively translate their passive beliefs into active participation., (© 2024. The Author(s).)

Leading up to the 2022 Congressional midterm elections, all predictions pointed to a Republican wave, given factors such as the incumbent president's low approval rate and a struggling national economy. Accordingly, the underwhelming performance of the Republican Party surprised many, resulting in an election that became known as the "asterisk election" due to its unusual and seemingly unpredictable outcome. This study delves into the specifics of the 2022 midterms, exploring factors that may have influenced the results beyond those traditionally considered by political scientists. Our analysis particularly seeks to understand whether a sudden shift in the public salience of specific issues could have influenced voters' preferences, leading them to consider factors they might not have otherwise. To achieve this, we analyzed data from a nationally representative sample of registered voters surveyed immediately after the midterm elections. Our findings reveal that the issue of abortion played a pivotal role during this election. The prominence of abortion was not predestined, as evidenced by a comparative analysis with data from a survey conducted after the 2020 presidential election. Indeed, it seems that the decision by the Supreme Court to overturn Roe v. Wade in June 2022 significantly increased the salience of abortion. This unexpected policy shock had a significant impact on the behavior of voters in the 2022 midterm elections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Conducting hydrogels can be used to fabricate bioelectronic devices that are soft for improved cell- and tissue-interfacing. Those based on conjugated polymers, such as poly(3,4-ethylene-dioxythiophene):polystyrene sulfonate (PEDOT:PSS), can be made simply with solution-based processing techniques, yet the influence of fabrication variables on final gel properties is not fully understood. In this study, we investigated if PEDOT:PSS cross-linking could be manipulated by changing the concentration of a gelling agent, ionic liquid, in the hydrogel precursor mixture. Rheology and gelation kinetics of precursor mixtures were investigated, and aqueous stability, swelling, conductivity, stiffness, and cytocompatibility of formed hydrogels were characterized. Increasing ionic liquid concentration was found to increase cross-linking as measured by decreased swelling, decreased non-network fraction, increased stiffness, and increased conductivity. Such manipulation of IL concentration thus afforded control of final gel properties and was utilized in further investigations of biointerfacing. When cross-linked sufficiently, PEDOT:PSS hydrogels were stable in sterile cell culture conditions for at least 28 days. Additionally, hydrogels supported a viable and proliferating population of human dermal fibroblasts for at least two weeks. Collectively, these characterizations of stability and cytocompatibility illustrate that these PEDOT:PSS hydrogels have significant promise for biointerfacing applications that require soft materials for direct interaction with cells.

Objective: To evaluate the prognostic value of tumor volume on preoperative MRI in endometrial cancer (EC) patients and its association with adverse prognostic factors and survival., Methods: A retrospective observational study with 127 consecutive patients with endometrioid EC was carried out between 2016 and 2021 at Juan Ramón Jiménez University Hospital, Huelva (Spain). All patients underwent preoperative magnetic resonance imaging (MRI) for local staging. The tumor volume was analyzed on MRI by two different methods: by measuring the three maximum diameters of the tumor according to an ellipse formula and by manual region of interest in different sections; the ratio between tumor volume and uterus volume was also calculated as a third tool. The relationships between volume, prognostic factors, and survival were analyzed., Results: A total of 127 patients with endometroid EC underwent preoperative MRI and were included in the study. Tumor volume was significantly higher for deep myometrial invasion, cervical stromal involvement, infiltrated serosa, lymph node metastases, high-grade EC, and lymphovascular space involvement, advanced FIGO stage, and High Recurrence Risk Group (P < 0.001). ROC curves showed that tumor volume greater than 25 cm 3 predicts lymph node metastases. Volume index greater than 17 cm 3 was associated with reduced disease-free survival (P < 0.001) and overall survival (P < 0.003). Multivariate analysis showed that the greatest tumor volume had an independent impact on recurrence (odds ratio [OR]1.019, 95% confidence interval [CI] 1.005-1.032) and survival (OR 1.027, 95% CI 1.009-1.046)., Conclusions: This study shows an important correlation between tumor volume on MRI and poor prognostic factors. Preoperative tumor volume on MRI is a valuable biomarker to be considered for management of EC., (© 2023 International Federation of Gynecology and Obstetrics.)

At Lalonde we know that the determinants that most influence the health of the population are lifestyle, genetics and the environment. Health represents only 10% and is the determinant that consumes the most resources. It has been shown that a salutogenic approach focused on the social determinants of health and the support of public policies to improve the environment are more efficient in the long term than medicine focused on hospitals, technology and super-specialization. Primary Care (PC) that has an approach centered on the person and families with a community vision, is the ideal level to provide health care, and to influence lifestyles. However it is not invested in PC. In this article we review the socioeconomic and political factors that globally influence the lack of interest in the development of PC., (Copyright © 2023 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Geoengineering techniques such as solar radiation management (SRM) could be part of a future technology portfolio to limit global temperature change. However, there is public opposition to research and deployment of SRM technologies. We use 814,924 English-language tweets containing #geoengineering globally over 13 years (2009-2021) to explore public emotions, perceptions, and attitudes toward SRM using natural language processing, deep learning, and network analysis. We find that specific conspiracy theories influence public reactions toward geoengineering, especially regarding "chemtrails" (whereby airplanes allegedly spray poison or modify weather through contrails). Furthermore, conspiracies tend to spillover, shaping regional debates in the UK, USA, India, and Sweden and connecting with broader political considerations. We also find that positive emotions rise on both the global and country scales following events related to SRM governance, and negative and neutral emotions increase following SRM projects and announcements of experiments. Finally, we also find that online toxicity shapes the breadth of spillover effects, further influencing anti-SRM views., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Identifying drivers of climate misinformation on social media is crucial to climate action. Misinformation comes in various forms; however, subtler strategies, such as emphasizing favorable interpretations of events or data or reframing conversations to fit preferred narratives, have received little attention. This data-driven paper examines online climate and sustainability communication behavior over 7 years (2014-2021) across three influential stakeholder groups consisting of eight fossil fuel firms (industry), 14 non-governmental organizations (NGOs), and eight inter-governmental organizations (IGOs). We examine historical Twitter interaction data ( n  = 668,826) using machine learning-driven joint-sentiment topic modeling and vector autoregression to measure online interactions and influences amongst these groups. We report three key findings. First, we find that the stakeholders in our sample are responsive to one another online, especially over topics in their respective areas of domain expertise. Second, the industry is more likely to respond to IGOs' and NGOs' online messaging changes, especially regarding environmental justice and climate action topics. The fossil fuel industry is more likely to discuss public relations, advertising, and corporate sustainability topics. Third, we find that climate change-driven extreme weather events and stock market performance do not significantly affect the patterns of communication among these firms and organizations. In conclusion, we provide a data-driven foundation for understanding the influence of powerful stakeholder groups on shaping the online climate and sustainability information ecosystem around climate change., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

The demand for cloud computing has drastically increased recently, but this paradigm has several issues due to its inherent complications, such as non-reliability, latency, lesser mobility support, and location-aware services. Fog computing can resolve these issues to some extent, yet it is still in its infancy. Despite several existing works, these works lack fault-tolerant fog computing, which necessitates further research. Fault tolerance enables the performing and provisioning of services despite failures and maintains anti-fragility and resiliency. Fog computing is highly diverse in terms of failures as compared to cloud computing and requires wide research and investigation. From this perspective, this study primarily focuses on the provision of uninterrupted services through fog computing. A framework has been designed to provide uninterrupted services while maintaining resiliency. The geographical information system (GIS) services have been deployed as a test bed which requires high computation, requires intensive resources in terms of CPU and memory, and requires low latency. Keeping different types of failures at different levels and their impacts on service failure and greater response time in mind, the framework was made anti-fragile and resilient at different levels. Experimental results indicate that during service interruption, the user state remains unaffected.

Background: The optimal management of asymptomatic, presumed WHO grade I meningiomas remains controversial., Objective: To define the safety and efficacy of stereotactic radiosurgery (SRS) compared with active surveillance for the management of patients with asymptomatic parafalcine/parasagittal (PFPS) meningiomas., Methods: Data from SRS-treated patients from 14 centers and patients managed conservatively for an asymptomatic, PFPS meningioma were compared. Local tumor control rate and new neurological deficits development were evaluated in the active surveillance and the SRS-treated cohorts., Results: There were 173 SRS-treated patients and 98 patients managed conservatively in the unmatched cohorts. After matching for patient age and tumor volume, there were 98 patients in each cohort. The median radiological follow-up period was 43 months for the SRS cohort and 36 months for the active surveillance cohort (P = .04). The median clinical follow-up for the SRS and active surveillance cohorts were 44 and 36 months, respectively. Meningioma control was noted in all SRS-treated patients and in 61.2% of patients managed with active surveillance (P < .001). SRS-related neurological deficits occurred in 3.1% of the patients (n = 3), which were all transient. In the active surveillance cohort, 2% of patients (n = 2) developed neurological symptoms because of tumor progression (P = 1.0), resulting in death of 1 patient (1%)., Conclusion: Up-front SRS affords superior radiological PFPS meningioma control as compared with active surveillance and may lower the risk of meningioma-related permanent neurological deficit and/or death., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Purpose: The aim of the present study is to investigate the prognostic significance of nutritional risk factors and sarcopenia on the outcome of patients with recurrent gynaecological malignancies treated by pelvic exenteration., Methods: We retrospectively evaluated muscle body composite measurements based on pre-operative CT scans, nutritional risk factors as assessed by a validated pre-operative questionnaire, and clinical-pathological parameters in 65 consecutive patients with recurrent gynaecological malignancies, excluding ovarian cancer, treated by pelvic exenteration at the Royal Marsden Hospital London. Predictive value for postoperative morbidity was investigated by logistic regression analyses. Relevant parameters were included in uni- and multivariate survival analyses., Results: We found only (1) low muscle attenuation (MA)-an established factor for muscle depletion-and (2) moderate risk for malnutrition to be independently associated with shorter overall survival (p = 0.006 and p = 0.008, respectively). MA was significantly lower in overweight and obese patients (p = 0.04). Muscle body composite measurements were not predictive for post-operative morbidity., Conclusion: The study suggests that pre-operative low MA and moderate risk for malnutrition are associated with shorter survival in patients with recurrent gynaecological malignancies treated with pelvic exenteration. Further studies are needed to validate these findings in larger cohorts., (© 2021. The Author(s).)

Meningioma is a common incidental finding, and clinical course varies based on anatomical location. The aim of this sub-analysis of the IMPASSE study was to compare the outcomes of patients with an incidental frontobasal meningioma who underwent active surveillance to those who underwent upfront stereotactic radiosurgery (SRS). Data were retrospectively collected from 14 centres. The active surveillance (n = 28) and SRS (n = 84) cohorts were compared unmatched and matched for age, sex, and duration of follow-up (n = 25 each). The study endpoints included tumor progression, new symptom development, and need for further intervention. Tumor progression occurred in 52.0% and 0% of the matched active surveillance and SRS cohorts, respectively (p < 0.001). Five patients (6.0%) treated with SRS developed treatment related symptoms compared to none in the active monitoring cohort (p = 0.329). No patients in the matched cohorts developed symptoms attributable to treatment. Three patients managed with active surveillance (10.7%, unmatched; 12.0%, matched) underwent an intervention for tumor growth with no persistent side effects after treatment. No patients subject to SRS underwent further treatment. Active monitoring and SRS confer a similarly low risk of symptom development. Upfront treatment with SRS improves imaging-defined tumor control. Active surveillance and SRS are acceptable treatment options for incidental frontobasal meningioma.

Background: The optimal treatment strategy of asymptomatic, convexity meningiomas, remains unclear., Objective: The purpose of this study was to define the safety and efficacy of stereotactic radiosurgery (SRS) in the management of patients with asymptomatic convexity meningiomas., Methods: Data of SRS-treated patients from 14 participating centers and patients managed conservatively for an asymptomatic, convexity-located meningioma were compared. Local tumor control rate and development of new neurologic deficits were evaluated in the active surveillance and in the SRS-treated cohorts., Results: In the unmatched cohorts, there were 99 SRS-treated patients and 140 patients managed conservatively for an asymptomatic, convexity meningioma. Following propensity score matching for age, there were 98 patients in each cohort. In the matched cohorts, tumor control was achieved in 99% of SRS-treated, and in 69.4% of conservatively managed patients (p < 0.001). New neurological deficits occurred in 2.0% of patients in each of the matched cohorts (p = 1.00). Increasing age was predictive of tumor growth [(OR 1.1; 95% CI (1.04 - 1.2), (p < 0.001)]., Conclusion: This is one of the first reports to suggest that SRS is a low risk and effective treatment strategy for asymptomatic incidentally discovered convexity meningiomas. In this study, tumor control was achieved in significantly more patients after radiosurgery compared to those managed with active surveillance. SRS may be offered at diagnosis of an asymptomatic convexity meningioma and should be recommended when meningioma growth is noted on follow-up., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance., Methods: This retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed., Results: The combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up., Conclusions: SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The initial management of asymptomatic, incidentally discovered, cavernous sinus (CS) meningiomas remains incompletely defined. This study evaluated the safety and efficacy of stereotactic radiosurgery (SRS) for patients presenting with an asymptomatic CS meningioma., Methods: This is an international, retrospective study included patients treated with upfront SRS for an asymptomatic CS meningioma. Local tumor control, tumor and SRS-related complications, and the development of new neurologic deficits after SRS were evaluated., Results: A total of 37 patients (29 men; mean ± SD age: 55.05 ± 11.56 years) treated with upfront SRS for an asymptomatic, CS meningioma were included in the study. The mean ± SD margin dose was 12.27 ± 2.3 Gy. The median clinical and radiological follow-up periods were 66 (IQR 84) and 72 (IQR 84) months, respectively. At the last follow-up, tumor regression and stability were noted in 19 (51.35%) and 18 (48.65%) of CS meningiomas, respectively. SRS-related complications occurred in 2 patients (5.4%) and were managed conservatively., Conclusions: Upfront SRS is a safe and effective treatment option for asymptomatic CS meningiomas. SRS may be considered at the time of initial diagnosis of a CS meningioma. If observation is the initial management chosen, SRS should be recommended when CS meningioma growth is documented on follow-up imaging., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present our experience with Gamma Knife surgery (GKS) and refractory glossopharyngeal neuralgia (GPN), analyzing its usefulness and safety in patients with or without previous surgeries, another concomitant neuralgia, or retreats. In addition, we study some factors that could condition the outcome of this technique. According to our review, our follow-up is the longest in the literature. We performed the prospective study of 8 patients submitted to GKS between 2008 and 2020. We employed the Leksell radiosurgery Gamma Knife system. The cases were evaluated before and after surgery (3, 6, 12 months and then annually). The VAS (Visual Analogue Scale) and BNI (Barrow Neurological Institute) scale were used. The data were assessed with SPSS25. Our series was composed of 6 (75%) women and 2 (25%) men, with an average age of 59.5 ± 14.04 years. Six patients (75%) had one or more than one previous surgeries. The median follow-up time was 7.22 ± 3.66 years (1.08-12.5 years). In the short-term postoperative period (1 year), eight patients (100%) experienced significant pain relief (VAS, p = 0.012; BNI I-IIIb). After the last interview, 5 patients felt pain relief (62.5%) (BNI grade I = 3; BNI grade IIIa = 2); 3 patients (37.5%) (BNI grade IV) were retreated (MVD, 2; GKS, 1). We found no association between patients with long evolution time of disease (p = 0.356), previous surgeries (p = 0.206), or vascular contact (p = 0.673) and worse clinical results after GKS. Both morbidity and mortality were 0%. Our results suggest that GKS for treating drug-resistant GPN with high initial doses is both a minimally invasive and useful and effective therapeutic strategy, without permanent complications. It presents good results even in patients with one or more previous surgical interventions. These findings encourage us to use this non-invasive technique as initial therapy against the invasive options., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The optimal management of patients with incidental meningiomas remains unclear. The aim of this study was to characterize the radiologic and neurological outcomes of expectant and stereotactic radiosurgery (SRS) management of asymptomatic meningioma patients., Methods: Using data from 14 centers across 10 countries, the study compares SRS outcomes to active surveillance of asymptomatic meningiomas. Local tumor control of asymptomatic meningiomas and development of new neurological deficits attributable to the tumor were evaluated in the SRS and conservatively managed groups., Results: In the unmatched cohorts, 727 meningioma patients underwent SRS and were followed for a mean of 57.2 months. In the conservatively managed cohort, 388 patients were followed for a mean of 43.5 months. Tumor control was 99.0% of SRS and 64.2% of conservatively managed patients (P < .001; OR 56.860 [95% CI 26.253-123.150]). New neurological deficits were 2.5% in the SRS and 2.8% of conservatively managed patients (P = .764; OR 0.890 [95% CI 0.416-1.904]). After 1:1 propensity matching for patient age, tumor volume, location, and imaging follow-up, tumor control in the SRS and conservatively managed cohorts was 99.4% and 62.1%, respectively (P < .001; OR 94.461 [95% CI 23.082-386.568]). In matched cohorts, new neurological deficits were noted in 2.3% of SRS-treated and 3.2% of conservatively managed patients (P = .475; OR 0.700 [95% CI 0.263-1.863])., Conclusions: SRS affords superior radiologic tumor control compared to active surveillance without increasing the risk of neurological deficits in asymptomatic meningioma patients. While SRS and active surveillance are reasonable options, SRS appears to alter the natural history of asymptomatic meningiomas including tumor progression in the majority of patients treated., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option., Objective: To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli., Design, Setting, and Participants: This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021., Interventions: Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or parenteral ertapenem for the comparator group after 4 days., Main Outcomes and Measures: The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered., Results: Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to ∞ percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI, -∞ to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01)., Conclusions and Relevance: This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections., Trial Registration: ClinicalTrials.gov Identifier: NCT02142751.

Background: The optimal management of asymptomatic, petroclival meningiomas remains incompletely defined. The purpose of this study was to evaluate the safety and efficacy of upfront stereotactic radiosurgery (SRS) for patients with asymptomatic, petroclival region meningiomas., Methods: This retrospective, international, multicenter study involved patients treated with SRS for an asymptomatic, petroclival region meningioma. Study endpoints included local tumor control rate, procedural complications, and the emergence of new neurological deficits., Results: There were 72 patients (22 males, mean age 59.53 years (SD ± 11.9)) with an asymptomatic meningioma located in the petroclival region who were treated with upfront SRS. Mean margin dose and maximum dose were 13.26 (SD ± 2.72) Gy and 26.14 (SD ± 6.75) Gy respectively. Median radiological and clinical follow-up periods post-SRS were 52.5 (IQR 61.75) and 47.5 months (IQR 69.75) respectively. At last follow-up, tumor control was achieved in all patients. SRS-related complications occurred in 6 (8.33%) patients, with 3 of them (4.17%) exhibiting new neurological deficits., Conclusions: Upfront SRS for asymptomatic, petroclival region meningiomas affords excellent local tumor control and does so with a relatively low risk of SRS-related complications. SRS can be considered at diagnosis of an asymptomatic petroclival region meningioma. If active surveillance is initially chosen, SRS should be recommended when growth is noted during radiological follow-up., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2- d ]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2- d ]pyrimidine MCXs, which led to the discovery of IBL-302 ( 31 ), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35 - 37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Background: Stereotactic radiosurgery (SRS) is increasingly considered for selected olfactory groove meningiomas (OGMs)., Objective: To investigate the safety and efficacy of SRS for OGMs., Methods: From 20 institutions participating in the International Radiosurgery Research Foundation, we pooled patients who underwent SRS for histologically confirmed or radiologically suspected WHO grade I OGMs and were followed for 6 mo or more after the SRS., Results: In total, 278 (median age 57 yr) patients underwent SRS for histologically confirmed (29%) or radiologically suspected (71%) WHO grade I OGMs Median treatment volume was 4.60 cm3 (range: 0.12-27.3 cm3), median prescription dose was 12 Gy, and median dose to the olfactory nerve was 11.20 Gy. During median post-SRS imaging follow-up of 39 mo (range: 6-240 mo), 43% of patients had partial or marginal response, 54% of patients had stable disease, and 3% of patients experienced progression. During median post-SRS clinical follow-up of 51 mo (range: 6-240 mo), 36 (13%) patients experienced clinical and/or radiological adverse radiation events (AREs). Elevated risk of AREs was associated with larger OGM volume (P = .009) and pre-SRS peritumoral T2/fluid-attenuated inversion-recovery signal abnormalities (P < .001). After the SRS, olfaction remained stable, improved, or deteriorated in 90%, 8%, and 2% of patients, respectively. Complete post-SRS anosmia was predicted by partial/complete anosmia before the SRS (odds ratio [OR] = 83.125; 95% CI [24.589-281.01], P < .001) and prior resection of OGM (OR = 3.919; 95% CI [1.713-8.970], P = .001)., Conclusion: SRS is associated with durable local control of the majority of OGM patients with acceptable safety profile. SRS allows preservation or improvement of olfactory function in the majority of OGM patients., (© Congress of Neurological Surgeons 2021.)

Background: ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees., Methodology: National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used., Results: National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system., Conclusion: Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

When SARS-CoV-2 emerged at the end of 2019, no approved therapeutics or vaccines were available. An urgent need for countermeasures during this crisis challenges the current paradigm of traditional drug discovery and development, which usually takes years from start to finish. Approaches that accelerate this process need to be considered. Here we propose the minimum data package required to move a compound into clinical development safely. We further define the additional data that should be collected in parallel without impacting the rapid path to clinical development. Accelerated paths for antivirals, immunomodulators, anticoagulants, and other agents have been developed and can serve as "roadmaps" to support prioritization of compounds for clinical testing. These accelerated paths are fueled by a skewed risk-benefit ratio and are necessary to advance therapeutic agents into human trials rapidly and safely for COVID-19. Such paths are adaptable to other potential future pandemics., Competing Interests: Declaration of interests Authors of the manuscript are members of ACTIV Preclinical Working group. Jay A Grobler is a shareholder in Merck. Annaliesa S Anderson is an employee of Pfizer, receives a salary from Pfizer and may own Pfizer stock; she is also a non-salaried member of the Contrafect Scientific Advisory Board. Michael S. Diamond is a consultant for Inbios, Vir Biotechnology, and NGM Biopharmaceuticals and is on the Scientific Advisory Board of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. John A.T. Young is an employee and shareholder of F.Hoffmann-La Roche, Ltd. Kara Carter is on the Scientific Advisory Board for the Alabama Drug Discovery and Development Consortium and owns stock in Evotec and Celldex Therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Modern psychological theories postulate that individual differences in prejudice are determined by social and ideological attitudes instead of personality. For example, the dual-process motivational (DPM) model argues that personality does not directly associate with prejudice when controlling for the attitudinal variables that capture the authoritarian-conservatism motivation and the dominance motivation. Previous studies testing the DPM model largely relied on convenience samples and/or European samples, and have produced inconsistent results. Here we examined the extent to which anti-black prejudice was associated with the Big Five personality traits and social and ideological attitudes (authoritarianism, social dominance orientation, political party affiliation) in two large probability samples of the general population (N1 = 3,132; N2 = 2,483) from the American National Election Studies (ANES). We performed structural equation modeling (SEM) to test the causal assumptions between the latent variables and used survey weights to generate estimates that were representative of the population. Different from prior theories, across both datasets we found that two personality traits, agreeableness and conscientiousness, were directly associated with anti-black prejudice when controlling for authoritarianism, social dominance orientation, and political party affiliation. We also found that a substantial part of the associations between personality traits and anti-black prejudice were mediated through those social and ideological attitudes, which might serve as candidates for prejudice-reduction interventions in the real world., Competing Interests: The authors have declared that no competing interests exist.

Introduction: The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β) receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 antibody blocking programmed death-ligand 1 (PD-L1), was evaluated in patients with advanced NSCLC., Methods: This expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR)., Results: A total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 19.6-74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1-positive and PD-L1-high (≥80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively. Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred., Conclusions: Bintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum., (Copyright © 2020. Published by Elsevier Inc.)

Background: Fibroblast Growth Factor 21 (FGF21) serum levels are associated with insulin resistance and metabolic syndrome in HIV patients., Objective: To quantify FGF21 levels in HIV patients using antiretroviral therapy (ART) and to analyze a possible association between serum FGF21 levels and lipid profile, levels of proinflammatory cytokines, and atherogenic risk factors., Materials and Methods: Twenty patients with HIV infection, who received ART in a scheme consisting of Tenofovir/Emtricitabine+Lopinavir/Ritonavir, were enrolled in this study. The serum levels of FGF21, inflammatory parameters (IL-6 and IL-1β), glucose, cholesterol, triglycerides, and insulin were determined at baseline and after 36 weeks of treatment. The homeostatic model assessment for insulin resistance (HOMA-IR) and the atherogenic risk factor were also calculated., Results: After 36 weeks, serum FGF21 levels decreased significantly (p=0.011), whereas IL-6 levels (r=0.821, p=0.0001) and the CD4+ T cell count (r=0.446, p=0.048), showed a positive correlation with the decrease in FGF21 levels. There was an increase in total cholesterol (r=-0.483, p=0.031), LDL (r=-0.496, p=0.026), VLDL (r=-0.320, p=0.045), and the atherogenic index factor (r=-0.539, p=0.014), these values showed a negative correlation with FGF21 levels., Conclusion: The decrease of serum FGF21 levels due to ART is associated with the alteration in lipid profile and an increased risk for cardiovascular diseases. These variations are predictors of inflammatory status in HIV patients using antiretroviral therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

BACKGROUND VIPomas are rare neuroendocrine tumors typically located in the pancreas. The majority of cases autonomously secret vasoactive intestinal polypeptide (VIP), which can result in profuse, refractory, watery diarrhea. The fluid and electrolyte imbalance can progress to dehydration and profound hypokalemia, resulting in the watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome. One previous case of a pancreatic VIPoma progressing to hypokalemic rhabdomyolysis has been described. CASE REPORT A 33-year-old woman presented with 3 months of progressive, refractory diarrhea and weakness. Her serum VIP level was elevated and imaging discovered a mass in the region of the pancreatic tail. Laparoscopic partial pancreatic resection was performed and a 3.7-cm diameter, solitary stage T2 N0 M0, well-differentiated carcinoma was removed. CONCLUSIONS A high index of suspicion is important when diagnosing chronic diarrhea. Minimally invasive surgery is an option in the surgical treatment of pancreatic VIPoma.

Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 10 9 /l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.

Survey responses in public health surveys are heterogeneous. The quality of a respondent's answers depends on many factors, including cognitive abilities, interview context, and whether the interview is in person or self-administered. A largely unexplored issue is how the language used for public health survey interviews is associated with the survey response. We introduce a machine learning approach, Fuzzy Forests, which we use for model selection. We use the 2013 California Health Interview Survey (CHIS) as our training sample and the 2014 CHIS as the test sample. We found that non-English language survey responses differ substantially from English responses in reported health outcomes. We also found heterogeneity among the Asian languages suggesting that caution should be used when interpreting results that compare across these languages. The 2013 Fuzzy Forests model also correctly predicted 86% of good health outcomes using 2014 data as the test set. We show that the Fuzzy Forests methodology is potentially useful for screening for and understanding other types of survey response heterogeneity. This is especially true in high-dimensional and complex surveys.

Assuring election integrity is essential for the legitimacy of elected representative democratic government. Until recently, other than in-person election observation, there have been few quantitative methods for determining the integrity of a democratic election. Here we present a machine learning methodology for identifying polling places at risk of election fraud and estimating the extent of potential electoral manipulation, using synthetic training data. We apply this methodology to mesa-level data from Argentina's 2015 national elections., Competing Interests: The authors have declared that no competing interests exist.

BACKGROUND Epithelioid hemangioendothelioma (EHE) is a rare vascular malignancy that occurs in multiple organs and tissues with a predilection for the extremities, bone, liver, and lung. It is often characterized by a clinically indolent course, delayed diagnosis, and unestablished standardized treatment options. CASE REPORT A 46-year-old female presented with a 2-month history of right shoulder and arm pain. Imaging revealed involvement of the humerus, lung, liver; and brain and biopsies of both the lung and humerus were performed. A diagnosis of epithelioid hemangioendothelioma was confirmed and the patient received radiation therapy to the right humerus and brain stereotactic radiosurgery. She was scheduled to begin palliative chemotherapy with doxorubicin but developed complications and never received chemotherapeutic agents. She died 5.5 months from her first admission with widespread metastasis. CONCLUSIONS Epithelioid hemangioendothelioma (EHE) is typically a low-to-intermediate grade vascular malignancy, but, as seen in this case, can be aggressive. In the future, diagnosis, prognosis, and treatment may improve using genetic or immune therapy considering a structural chromosomal translocation has been identified.

Dalbavancin is a lipoglycopeptide with potent activity against Gram-positive microorganisms, a long half-life, a favorable safety profile, and a high concentration in bone, which makes it an interesting alternative for treatment of osteoarticular infections. We performed a multicentric retrospective study of all patients with an osteoarticular infection (septic arthritis, spondylodiscitis, osteomyelitis, or orthopedic implant-related infection) treated with at least one dose of dalbavancin between 2016 and 2017 in 30 institutions in Spain. In order to evaluate the response, patients with or without an orthopedic implant were separated. A total of 64 patients were included. Staphylococcus epidermidis and Staphylococcus aureus were the most frequent microorganisms. The reasons for switching to dalbavancin were simplification (53.1%), adverse events (25%), or failure (21.9%). There were 7 adverse events, and no patient had to discontinue dalbavancin. In 45 cases, infection was related to an orthopedic implant. The implant material was retained in 23 cases, including that in 15 (65.2%) patients that were classified as cured and 8 (34.8%) that presented improvement. In 21 cases, the implants were removed, including those in 16 (76.2%) cases that were considered successes, 4 (19%) cases were considered improved, and 1 (4.8%) case that was considered a failure. Among the 19 cases without implants, 14 (73.7%) were considered cured, 3 (15.8%) were considered improved, and 2 (10.5%) were considered failures. The results show that dalbavancin is a well-tolerated antibiotic, even when >2 doses are administered, and is associated with a high cure rate. These are preliminary data with a short follow-up; therefore, it is necessary to gain more experience and, in the future, to establish the most appropriate dose and frequency., (Copyright © 2019 American Society for Microbiology.)

Anterior gradient 2 (AGR2) is a member of the protein disulfide isomerase (PDI) family, which plays a role in the regulation of protein homeostasis and the unfolded protein response pathway (UPR). AGR2 has also been characterized as a proto-oncogene and a potential cancer biomarker. Cellular localization of AGR2 is emerging as a key component for understanding the role of AGR2 as a proto-oncogene. Here, we provide evidence that extracellular AGR2 (eAGR2) promotes tumor metastasis in various in vivo models. To further characterize the role of the intracellular-resident versus extracellular protein, we performed a comprehensive protein-protein interaction screen. Based on these results, we identify AGR2 as an interacting partner of the mTORC2 pathway. Importantly, our data indicates that eAGR2 promotes increased phosphorylation of RICTOR (T1135), while intracellular AGR2 (iAGR2) antagonizes its levels and phosphorylation. Localization of AGR2 also has opposing effects on the Hippo pathway, spheroid formation, and response to chemotherapy in vitro. Collectively, our results identify disparate phenotypes predicated on AGR2 localization. Our findings also provide credence for screening of eAGR2 to guide therapeutic decisions.