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Abstract Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5 mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating upregulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine’s molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

Abstract The healthy lifestyle index (HLI), defined as the unweighted sum of individual lifestyle components, was used to investigate the combined role of lifestyle factors on health-related outcomes. We introduced weighted outcome-specific versions of the HLI, where individual lifestyle components were weighted according to their associations with disease outcomes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the association between the standard and the outcome-specific HLIs and the risk of T2D, CVD, cancer, and all-cause premature mortality. Estimates of the hazard ratios (HRs), the Harrell’s C-index and the population attributable fractions (PAFs) were compared. For T2D, the HR for 1-SD increase of the standard and T2D-specific HLI were 0.66 (95% CI: 0.64, 0.67) and 0.43 (0.42, 0.44), respectively, and the C-index were 0.63 (0.62, 0.64) and 0.72 (0.72, 0.73). Similar, yet less pronounced differences in HR and C-index were observed for standard and outcome-specific estimates for cancer, CVD and all-cause mortality. PAF estimates for mortality before age 80 were 57% (55%, 58%) and 33% (32%, 34%) for standard and mortality-specific HLI, respectively. The use of outcome-specific HLI could improve the assessment of the role of lifestyle factors on disease outcomes, thus enhancing the definition of public health recommendations.

Abstract Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Alteplase, a biosynthetic form of human tissue‐type plasminogen activator, is Food and Drug Administration‐approved for the treatment of acute ischemic stroke and currently the standard of care for thrombolytic therapy. Tenecteplase, a modified form of alteplase using recombinant technology, has several pharmacological advantages over alteplase, including longer half‐life, higher fibrin specificity, and greater resistance to plasminogen activator inhibitor‐1. Additionally, tenecteplase is given as a single bolus administration compared to the bolus plus 1‐hour continuous infusion of alteplase. Given these pharmacologic and logistical differences along with studies demonstrating noninferiority compared with alteplase, tenecteplase has become an alternative thrombolytic for the management of acute ischemic stroke. There is a growing body of evidence that suggests tenecteplase is a safe and effective alternative to alteplase. This systematic review evaluates the available literature for the use of tenecteplase in acute ischemic stroke and provides relevant discussion regarding role in therapy, therapeutic strategies, and areas requiring further research.

Abstract Background Monte Carlo simulation of radiation transport for medical linear accelerators (linacs) requires accurate knowledge of the geometrical description of the linac head. Since the geometry of Varian TrueBeam machines has not been disclosed, the manufacturer distributes phase-space files of the linac patient-independent part to allow researchers to compute absorbed dose distributions using the Monte Carlo method. This approach limits the possibility of achieving an arbitrarily small statistical uncertainty. This work investigates the use of the geometry of the Varian Clinac 2100, which is included in the Monte Carlo system PRIMO, as a surrogate. Methods Energy, radial and angular distributions extracted from the TrueBeam phase space files published by the manufacturer and from phase spaces tallied with PRIMO for the Clinac 2100 were compared for the 6, 8, 10 and 15 MV flattened-filtered beams. Dose distributions in water computed for the two sets of PSFs were compared with the Varian Representative Beam Data (RBD) for square fields with sides ranging from 3 to 30 cm. Output factors were calculated for square fields with sides ranging from 2 to 40 cm. Results Excellent agreement with the RBD was obtained for the simulations that employed the phase spaces distributed by Varian as well as for those that used the surrogate geometry, reaching in both cases Gamma ( $$2\%$$ 2 % , 2 mm) pass rates larger than $$99\%$$ 99 % , except for the 15 MV surrogate. This result supports previous investigations that suggest a change in the material composition of the TrueBeam 15 MV flattening filter. In order to get the said agreement, PRIMO simulations were run using enlarged transport parameters to compensate the discrepancies between the actual and surrogate geometries. Conclusions This work sustains the claim that the simulation of the 6, 8 and 10 MV flattening-filtered beams of the TrueBeam linac can be performed using the Clinac 2100 model of PRIMO without significant loss of accuracy.

Diuresis with loop diuretics is the mainstay treatment for volume optimization in patients with congestive heart failure, in which perfusion and volume expansion play a crucial role. There are robust guidelines with extensive evidence for the management of heart failure; however, clear guidance is needed for patients who do not respond to standard diuretic treatment. Diuretic resistance (DR) can be defined as an insufficient quantity of natriuresis with proper diuretic therapy. A combination of diuretic regimens is used to overcome DR and, more recently, SGLT2 inhibitors have been shown to improve diuresis. Despite DR being relatively common, it is challenging to treat and there remains a notable lack of substantial data guiding its management. Moreover, DR has been linked with poor prognosis. This review aims to expose the multiple approaches for treatment of patients with DR and the importance of intravascular volume expansion in the response to therapy.

The association between hyperuricemia and cardiovascular diseases has been studied for many years. Research has shown a link between high uric acid levels and increased risk of including coronary artery disease hypertension and other cardiovascular conditions. Urate-lowering therapy, particularly with xanthine oxidase inhibitors like allopurinol, has shown promising results in reducing blood pressure in individuals with hyperuricemia and hypertension. Clinical trials and studies have demonstrated significant reductions in both systolic and diastolic blood pressure with urate-lowering treatment. Urate-lowering treatment has shown a favorable effect on reducing systolic blood pressure and major adverse cardiovascular events in patients with previous cardiovascular disease. In terms of cardiovascular safety, clinical trials have indicated that xanthine oxidase inhibitors such as febuxostat are non-inferior to allopurinol and do not increase the risk of death or serious adverse events. Overall, these findings highlight the importance of managing hyperuricemia and utilizing urate-lowering therapy to mitigate the adverse cardiovascular effects associated with elevated uric acid levels.

Abstract Background Renal cell carcinoma (RCC) is twice as common among men compared with women, and hormonal factors have been suggested to partially explain this difference. There is currently little evidence on the roles of reproductive and hormonal risk factors in RCC aetiology. Materials & Methods We investigated associations of age at menarche and age at menopause, pregnancy‐related factors, hysterectomy and ovariectomy and exogenous hormone use with RCC risk among 298,042 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Results During 15 years of follow‐up, 438 RCC cases were identified. Parous women had higher rates of RCC compared with nulliparous women (HR = 1.71, 95% CI 1.18, 2.46), and women who were older at age of first pregnancy had lower rates of RCC (30 years + vs.

Background: In Cuba, there is neither a registry of ST Elevation Myocardial Infarction (STEMI), nor are analysis of performance measures widely reported.Objective: A review of Cuban studies of patients with STEMI was carried out to describe quality of medical care.Methods: Cochrane Library, EMBASE, PubMed, Scopus and SciELO, as well as archives of national journals, were all searched for articles on STEMI in Cuba, from 2000 to March 2020. They were included if they reported number or percentage of application of reperfusion therapy; administration of aspirin, enalapril-captopril (ACEI) or beta-blockers; status of patients at discharge; and patient or system delay times. Finally, 17 reports with 7823 patients were included.Results: Thrombolytic therapy was administered to 3991 patients (51%), and 695 patients (8.9%) died. Only four studies, with 880 patients, presented data about prescription of ACEI, aspirin, and beta-blockers, which were administered to 381 (45.3%), 824 (93.6%), 464 (52.7%) patients, respectively. Coronary intervention was reported in 5 studies with 3422 patients, being performed in 661 (19.3%). Conclusions: Quality of care of patients with STEMI seems to be poorer than reported in similar scenarios. Thrombolytic administration is still low, although mortality decreases in this period. Other pharmacological treatments were insufficiently fulfilled.

Abstract Aim Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real‐life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Methods and results Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1 year was 26.8% and median survival was 24.7 [95% CI: 20.4–26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1 year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P 12 g/dL (+1.5), amiodarone use (−1.5) HF visit 1 year before levosimendan (−1.5) and heart rate >70 b.p.m. (−2). Patients with a score less than −1 had a very low probability of response (21.5% free of death or HF event at 1 year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1 year). LEVO‐D score performed well in the ROC analysis. Conclusion In this large real‐life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO‐D Score could be of help when deciding about futile therapy in this population.

Introduction Transradial access (TRA) has become increasingly utilized among neurointerventionalists. There is evidence of reduced complications and higher patient satisfaction compared to transfemoral access (TFA), but more data directly comparing the safety and efficacy of the two approaches is needed. To assess the proportion of technical success and complications with TRA versus TFA in patients who underwent neuroendovascular diagnostic and therapeutic procedures. Methods PRISMA guidelines were used to conduct a systematic review of the literature with PubMed/Medline, Scopus, Embase, and Cochrane databases up to February 2023. Randomized clinical trials (RCT) and observational studies that compared TRA and TFA were included. Studies reporting results of patients who underwent diagnostic angiograms, endovascular management of acute stroke, aneurysm repair, and carotid or vertebral stenting were included. Our primary outcome was technical success, defined as successful arterial access and completion of the intended procedure without crossover. Secondary safety outcomes were rate of complications including access site and non‐access site related, and other efficacy measures such as procedure duration, fluoroscopy time, and radiation exposure. Random effects model was used to perform a meta‐analysis. The Mantel‐Haenszel method was used to calculate risk ratio (RR) and 95% confidence intervals (CI) for each outcome. Heterogeneity was evaluated using I2 and considered high if over 70%. Results Twenty‐nine studies comprising 14,523 patients met inclusion criteria. TRA was attempted in 5,865 (40.38%) patients and TFA in 8,658 (59.62%). Baseline characteristics were similar between groups. The rate of technical success was 95.46% (95% CI: 93.59 – 96.81; p < 0.01) in the TRA group compared with 98.43% (95% CI: 97.60 – 98.97; p = 0.02) in the TFA group. Patients who underwent a diagnostic or therapeutic angiogram via TRA had a slightly lower chance of achieving technical success (RR = 0.98; 95% CI: 0.96 – 0.99; p < 0.01) compared to TFA, with substantial heterogeneity (I2 = 68%). Major access site complications were non‐significantly lower in the TRA group (RR = 0.64; 95% CI: 0.29 – 1.41; p = 0.81) with null heterogenicity (I2 = 0%) between groups. Minor access site complications were significantly lower in the TRA group (RR = 0.43; 95% CI 0.28 – 0.67; p < 0.01), with moderate heterogeneity (I2 = 57%). Non‐access site related complications (including mortality) were lower in the TRA group (RR = 0.69; 95% CI 0.51 – 0.94; p = 0.14) with low heterogeneity (I2 = 26%) between groups; for this outcome, the TRA approach shows a protective but not statistically significant result. Conclusion Our study suggests TRA is feasible and safe for diagnostic and therapeutic neuroendovascular procedures with low certainty of evidence. Minor complications were lower in the TRA group. RCTs directly comparing TRA vs TFA for these procedures are needed to confirm these results.

Introduction Clopidogrel is a P2Y12 inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its potential complications, including sudden cardiac death and ischaemic strokes in patients with significant vascular disease.Areas covered As a prodrug, the metabolism and efficacy of clopidogrel are contingent on the presence of wild-type CYP450 (CYP2C19) alleles. Genetic polymorphisms and variants are well known to impair its ability to prevent major adverse cardiovascular events in these patients, with inadequate response rates as high as 30% in previous publications. Patterns of allelic frequencies are expected to exhibit similarities between individuals of the same ancestry, ethnic group or geographic region. Accordingly, we seek to further elucidate worldwide prevalence rates for genetic polymorphisms in the CYP2C19-dependent metabolism of clopidogrel and review the potential of personalised CYP2C19 genotyping in clinical practice to mitigate this high treatment resistance and its associated burden on patients.Experts’ commentary Our findings support the consideration of genotyping before initiation of therapy to guide adequate dosage or substitutions of other P2Y12 inhibitors to promote personalised, precision medicine and to prevent adverse events when these therapies may inevitably fail in patients with variants of the CYP450 (CYP2C19) system.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC‐CVD (European Prospective Investigation Into Cancer and Nutrition‐Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC‐CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow‐up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2‐sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

BackgroundIn radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment.Materials and methodsOrgan doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider et al.ResultsOut-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 μSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 μSv (testes) and 48 μSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs.ConclusionThe complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.

The SARS-CoV-2 pandemic is the most globally impacting health issue our world has faced over the last century. As of January 7, 2022, around 300 million cases have been reported worldwide, with over 5 million deaths. The SARS-CoV-2 infection causes a hyperactive host immune response leading to an excessive inflammatory reaction with the release of many cytokines — cytokine storm — commonly noticed in acute respiratory distress syndrome, sepsis and fulminant multiorgan failure. Since the beginning of the pandemic, the scientific medical community has worked on therapeutic procedures that interfere with the exaggerated immune response. Thromboembolic complications are widespread in patients who are critically ill with COVID-19. Anticoagulant therapy was initially considered a cornerstone in hospitalized patients and even in the early post-discharge period; however, later trials have aborted the clinical benefits except for suspicion of or confirmed thrombosis. Immunomodulatory therapies are still crucial in moderate to severe COVID-19. Immunomodulator therapies include various medications from steroids to hydroxychloroquine, tocilizumab and Anakinra. Anti-inflammatory agents, vitamin supplements and antimicrobial therapy had initial encouraging evidence, but there are limited data to review. Convalescent plasma, immunoglobulins, eculizumab, neutralizing IgG1 monoclonal antibodies and remdesivir have positively impacted inpatient mortality and hospital length of stay. Eventually, wide population vaccination was proven to be the best tool to overcome the SARS-CoV-2 pandemic and help humanity return to regular life. Many vaccines and various strategies have been used since December 2020. This review discusses how the SARS-CoV-2 pandemic has progressed and surged, and summarizes the safety and efficacy of the most used therapies and vaccines in the light of recent evidence.

Pregnant women are especially vulnerable to respiratory diseases. We aimed to study seroconversion rates during pregnancy in a cohort of consecutive pregnancies tested in the first and third trimesters and to compare the maternal and obstetric complications in the women who seroconverted in the first trimester and those who did so in the third. This was an observational cohort study carried out at the Hospital Universitario de Torrejón, in Madrid, Spain, during the first peak of the COVID-19 pandemic. All consecutive singleton pregnancies with a viable fetus attending their 11–13-week scan between 1 January and 15 May 2020 were included and seropositive women for SARS-CoV2 were monthly follow up until delivery. Antibodies against SARS-CoV-2 (IgA and IgG) were analyzed on stored serum samples obtained from first- and third-trimester routine antenatal bloods in 470 pregnant women. Antibodies against SARS-CoV-2 were detected in 31 (6.6%) women in the first trimester and in 66 (14.0%) in the third trimester, including 48 (10.2%) that were negative in the first trimester (seroconversion during pregnancy). Although the rate of infection was significantly higher in the third versus the first trimester (p = 0.003), no significant differences in maternal or obstetric complications were observed in women testing positive in the first versus the third trimester.

ObjectivesTo investigate differences in lung cancer (LC) management and survival using data from European population cancer registries.MethodsWe analysed 4,602 lung cancer cases diagnosed in 2010–2013, followed-up to 2019 in five countries. Multivariable logistic regression was used to calculate the Odds Ratio (OR) of surgery for stages I–II LC or chemo- or radiotherapy for stages III–IV LC. Relative survival (RS) was estimated by the actuarial method; Relative Excess Risk of death (RER), with 95% CI, was calculated by generalized linear models.ResultsDiagnostic work-up was extensive for 65.9% patients (range 57%, Estonia, Portugal - 85% (Belgium). Sixty-six percent of stages I–II patients underwent surgery; compared to non-operated, their adjusted OR decreased with age and was associated with main bronchus cancer (OR vs. lobes 0.25, CI, 0.08–0.82), stage II (OR vs. stage I: 0.42, CI, 0.29–0.60), comorbidity (OR vs. absent: 0.55, CI, 0.33–0.93), country (ORs: Estonia 1.82, CI, 1.28–2.60; Belgium 0.62, CI, 0.42–0.91; Portugal 0.69, CI, 0.52–0.93).Almost half of stages III–IV patients received chemo- or radiotherapy only; the adjusted OR vs. non receiving decreased with age and was associated with unspecified cancer topography or morphology. The adjusted five-year RER increased with age and stage and was lower for women (0.78, CI, 0.72–0.86), above the reference for main bronchus cancer (1.37, CI, 1.21–1.54) and unspecified morphology (1.17, CI, 1.05–1.30). Surgery carried the lowest mortality (RS 56.9; RER 0.13, CI, 0.11–0.15) with RER above the mean in Estonia (1.20, CI, 1.10–1.30), below it in Portugal (0.88, CI, 0.82–0.93) and Switzerland (0.91, CI, 0.84–0.99). Comorbidity (1.21, CI, 1.09–1.35) and not smoking (0.68, CI, 0.57–0.81) were associated with RER.ConclusionsThe survival benefit of early diagnosis, allowing curative surgery, was evident at the population level. Screening for subjects at risk and adhesion to standard care should be incremented across the EU by funding better equipment and training health personnel.

We recently proposed a high-granularity calorimeter insert for the Electron-Ion Collider (EIC) that uses plastic scintillator tiles read out by SiPMs. Among its features are an ASIC-away-from-SiPM strategy for reducing cooling requirements and minimizing space use, along with employing 3D-printed frames to reduce optical crosstalk and dead areas. To evaluate these features, we built a 40-channel prototype and tested it using a 4 GeV positron beam at Jefferson Laboratory. The measured energy spectra and 3D shower shapes are well described by simulations, confirming the effectiveness of the design, construction techniques, and calibration strategy. This constitutes the first use of SiPM-on-tile technology in an EIC detector design.

Phantom limb pain is a chronic pain syndrome that is difficult to cope with. Despite neurostimulation treatment is indicated for refractory neuropathic pain, there is scant evidence from randomized controlled trials to recommend it as the treatment choice. Thus, a systematic review was performed to analyze the efficacy of central nervous system stimulation therapies as a strategy for pain management in patients with phantom limb pain. A literature search for studies conducted between 1970 and September 2020 was carried out using the MEDLINE and Embase databases. Principles of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline were followed. There were a total of 10 full-text articles retrieved and included in this review. Deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and motor cortex stimulation were the treatment strategies used in the selected clinical trials. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation were effective therapies to reduce pain perception, as well as to relieve anxiety and depression symptoms in phantom limb pain patients. Conversely, invasive approaches were considered the last treatment option as evidence in deep brain stimulation and motor cortex stimulation suggests that the value of phantom limb pain treatment remains controversial. However, the findings on use of these treatment strategies in other forms of neuropathic pain suggest that these invasive approaches could be a potential option for phantom limb pain patients.

Multipactor has become a keylimiting factor of the final performance of satellite communication systems, due to the increase in power levels and/or operating frequency bands. As a result, the critical components of these systems must meet demanding multipactor specifications which should be considered during the design process. This paper describes the different techniques available to predict the multipactor threshold power for radio frequency (RF) and microwave passive hardware under continuous wave (CW) excitation, from cumbersome particle simulations to fast approximate methods based on circuit models. All these techniques have been described and compared together for the first time, including also a detailed description of the configuration issues of commercial particle simulators required to obtain accurate multipactor threshold predictions. The techniques are applied to both wideband and narrowband application examples. The predictions have been compared with measured thresholds of manufactured samples obtained with a novel multipactor test bed, thus allowing to highlight the advantages and limitations of each technique and particle simulator. From this paper, it will be possible to choose the most suitable procedure (and an appropriate simulator, if needed) to obtain multipactor threshold prediction of passive hardware.

Abstract Aim To provide data on the fears of pregnant women during the confinement period and to learn about the factors, which may have exacerbated fear in Spanish pregnant women during the pandemic. Design A cross‐sectional observational and descriptive study. Methods An anonymous survey was carried out using virtual media in a pregnant population (aged ≥18 years) during the confinement period from 1 April to 1 May 2020. Results The total sample comprised of 62 individuals, with a mean age of 33.6 ± 3.6 years and a mean gestation time of 23.6 ± 9.8 weeks. All of the women used preventive measures against SARS‐CoV‐2. The most common preventive measures were social isolation (82.3%, n = 51) and frequent handwashing (69.4%, n = 43). The most common feeling was fear (29%, n = 18). The main fears were related to transplacental infection (27%, n = 16), loneliness during childbirth, and being separated from the newborn (27%, n = 16). In addition, 59.7% (n = 37) considered changing their child‐rearing practices after the pandemic.

Abstract Background The objective of the study was to understand how pregnant women learned about Zika infection and to identify what sources of information were likely to influence them during their pregnancy. Methods We conducted 13 semi-structed interviews in English and Spanish with women receiving prenatal care who were tested for Zika virus infection. We analyzed the qualitative data using descriptive approach. Results Pregnant women in the Bronx learned about Zika from family, television, the internet and their doctor. Informational sources played different roles. Television, specifically Spanish language networks, was often the initial source of information. Women searched the internet for additional information about Zika. Later, they engaged in further discussions with their healthcare providers. Conclusions Television played an important role in providing awareness about Zika to pregnant women in the Bronx, but that information was incomplete. The internet and healthcare providers were sources of more complete information and are likely the most influential. Efforts to educate pregnant women about emerging infectious diseases will benefit from using a variety of approaches including television messages that promote public awareness followed up by reliable information via the internet and healthcare providers.

Objetivo: En este artículo de investigación se propone un algoritmo genético continuo (CGA) para realizar el diseño óptimo de un resorte helicoidal de bobina cerrada. Metodología: La metodología de solución emplea como función objetivo la minimización del volumen total de un resorte helicoidal, considerando como variables principales el diámetro del alambre, el diámetro promedio y el número de bobinas activas. Como conjunto de restricciones se implementan los requerimientos físicos y técnicos para el diseño seguro y adecuado del elemento mencionado. Como método de solución se emplea un CGA, y como métodos de comparación son usados diferentes algoritmos de optimización que han sido implementados en la literatura especializada para dar solución al problema abordado. Resultados: Los resultados obtenidos muestran que el CGA obtiene el mínimo valor de volumen, siendo menor en un 1,5% en comparación con la mejor técnica reportada, con un tiempo de procesamiento menor a 1 s, lo cual demuestra que la metodología propuesta obtiene los mejores resultados en términos de calidad de la solución y tiempo de procesamiento. Conclusiones: Los resultados de simulación muestran que el CGA obtiene la mejor solución en comparación con las demás técnicas, a un bajo costo computacional y entregando una solución que cumple con los requerimientos físicos y técnicos del diseño.

Abstract Aim Chronic diseases often occur simultaneously and tend to be associated with adverse health outcomes, but limited research has been undertaken to understand their role in lung cancer mortality. Therefore, this study aims to describe the prevalence and patterns of having one (comorbidity) or ≥ 2 chronic diseases (multimorbidity) among lung cancer patients in Spain, and to examine the association between comorbidity or multimorbidity and short-term mortality risk at six months after cancer diagnosis. Methods In this population-based cohort study, data were drawn from two Spanish population-based cancer registries, Girona and Granada, and electronic health records. We identified 1259 adult lung cancer patients, diagnosed from 1st January 2011 to 31st December 2012. We identified the most common patterns of individual comorbidities and their pairwise correlations. We used a flexible parametric modelling approach to assess the overall short-term mortality risk 6 months after cancer diagnosis by levels of comorbidity after adjusting for age, sex, smoking status, province of residence, surgery, cancer stage, histology, and body mass index. Results We found high prevalence of comorbidity in lung cancer patients, especially among the elderly, men, those diagnosed with advanced-stage tumours, smokers, and obese patients. The most frequent comorbidities were chronic obstructive pulmonary disease (36.6%), diabetes (20.7%) and heart failure (16.8%). The strongest pairwise correlation was the combination of heart failure with renal disease (r = 0.20, p

Los conceptos, los estilos y las estrategias de enseñanza se encuentran íntimamente ligados, quedando supeditados a la experiencia del propio docente. De esta forma, no sólo quedará configurado el aprendizaje del alumnado a partir de las metas que este asuma, sino que estos estilos docentes también tendrán una impronta en diferentes elementos de dicho proceso, como la motivación e implicación en el aprendizaje. El objetivo de este estudio, por tanto, fue conocer los diferentes estilos y su evolución dentro del profesorado de ciencias experimentales y tecnología, así como su impacto en las estrategias de aula. Para ello, se diseñó un estudio cualitativo descriptivo de corte fenomenológico, a partir de un estudio de caso. Se realizaron un total de 6 entrevistas a profesores/as de diferentes niveles educativos dentro del área de ciencias experimentales y tecnología, acompañadas de observaciones no participantes en el aula y análisis documental. Los resultados mostraron datos interesantes sobre el uso de diferentes estilos de enseñanza, más cercanos a un estilo mixto a estrategias de aprendizaje cooperativas. Como conclusión, merece especial atención la evolución de los participantes hacia estilos y estrategias más activas, aunque queda pendiente la tarea de profundizar en el proceso de evaluación y reflexión docente.

BackgroundThe Mediterranean diet (MD) has been proposed as a healthy diet with a potential to lower the incidence of several types of cancer, but there is no data regarding thyroid cancer (TC). We investigated the association between MD adherence, and its components, and the differentiated TC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.MethodsOver 450,000 men and women from nine European countries were followed up for a mean of 14.1 years, during which 712 differentiated TC cases were identified. Adherence to MD was estimated using the relative MD (rMED) score, an 18-point scale including alcohol, and the adapted rMED (arMED) score, a 16-point scale excluding alcohol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors.ResultsAdherence to the arMED score was not associated with the risk of differentiated TC (HRhigh vs. low adherence = 0.94, 95% CI: 0.70–1.25; p-trend 0.27), while a suggestive, but non-statistically significant inverse relationship was observed with rMED (HRhigh vs. low adherence = 0.88, 95% CI: 0.68–1.14; p-trend 0.17). Low meat (HRlow vs. high meat intake = 0.81, 95% CI: 0.67–0.99; p-trend = 0.04) and moderate alcohol (HRmoderate vs. non−moderate intake = 0.88, 95% CI: 0.75–1.03) intake were related with lower differentiated TC risk.ConclusionsOur study shows that a high adherence to MD is not strongly related to differentiated TC risk, although further research is required to confirm the impact of MD and, especially, meat intake in TC risk.

Biofouling of gasoline can occur during fuel storage caused by bacteria and fungi that form a biofilm at a fuel/water interface and that produce organic acids and sulfides. Fuel additives are applied to gasoline to prevent biofouling but are relatively expensive, are not always effective against biofilms, and do not contribute to the combustibility of gasoline. Bio-isobutanol is an approved, certified advanced biofuel and is added up to 16% (v/v) in gasoline blends “iBut16”; n-butanol blends are currently under review. Microorganisms are inhibited by n-butanol or isobutanol when the aqueous concentration reaches >2-3% (w/v). We determined that n-butanol partitions into the aqueous phase of a model gasoline/water system reaching concentrations of 42 g/L and up to 48 g/L from gasoline blends at 10% and 24% (v/v), respectively. Likewise, isobutanol blended in gasoline at 10% and 24% (v/v) partitioned into an aqueous phase at 45 g/L and 53 g/L, respectively. Several bacterial and fungal strains that originate from fuel storage tanks, or are known to be solvent tolerant, were evaluated for their potential growth in a range of n- and isobutanol concentrations. Growth rates for all strains tested were reduced by 40–100% relative to untreated controls in n- and isobutanol concentrations of 1.5 and 2.0% (v/v). No observable growth occurred for any of the microorganisms in solvent concentrations at 3.0% (v/v). T amphiphilic and chaotropic properties of n- or isobutanol help them inhibit microbial growth and could serve as effective biocides during fuel storage as well as being valuable fuel additives.

This article explores international students' experiences in their graduate STEM programs at predominantly white US institutions through in-depth qualitative interviews and thematic analysis. International students reported encountering social and cultural barriers with American peers and sometimes even with other international students. These barriers include language, popular cultural, and social norms. Some students, who were less culturally represented in their cohorts, felt isolated but later found other people outside of their departments, often people from their same cultural background. The experiences of our participants varied by the representation of their culture in their departments, where students from less represented countries experienced more isolation. Connections to current acculturation theory will be discussed, as well as further implications and possible solutions for increasing intercultural exchanges.

Abstract Woody biomass is an important feedstock for biofuel production. Manipulation of wood properties that enable efficient conversion of biomass to biofuel reduces cost of biofuel production. Wood cell wall composition is regulated at several levels that involve expression of transcription factors such as wood‐/secondary cell wall‐associated NAC domains (WND or SND). In Arabidopsis thaliana, SND1 regulates cell wall composition through activation of its down‐stream targets such as MYBs. The functional aspects of SND1 homologs in the woody Populus have been studied through transgenic manipulation. In this study, we investigated the role of PdWND1B, Populus SND1 sequence ortholog, in wood formation using transgenic manipulation through over‐expression or silencing under the control of a vascular‐specific 4‐coumarate‐CoA ligase (4CL) promoter. As compared with control plants, PdWND1B‐RNAi plants were shorter in height, with significantly reduced stem diameter and dry biomass, whereas there were no significant differences in growth and productivity of PdWND1B over‐expression plants. Conversely, PdWND1B over‐expression lines showed a significant reduction in cellulose and increase in lignin content, whereas there was no significant impact on lignin content of downregulated lines. Stem carbohydrate composition analysis revealed a decrease in glucose, mannose, arabinose, and galactose, but an increase in xylose in the over‐expression lines. Transcriptome analysis revealed upregulation of several downstream transcription factors and secondary cell wall related structural genes in the PdWND1B over‐expression lines, partly explaining the observed phenotypic changes in cell wall chemistry. Relative to the control, glucose release efficiency and ethanol production from stem biomass was significantly reduced in over‐expression lines. Our results show that PdWND1B is an important factor determining biomass productivity, cell wall chemistry and its conversion to biofuels in Populus.

ABSTRACT Pathogenic fungal infections in plants may, in some cases, lead to downstream systematic impacts on the plant metabolome and microbiome that may either alleviate or exacerbate the effects of the fungal pathogen. While Sphaerulina musiva is a well-characterized fungal pathogen which infects Populus tree species, an important wood fiber and biofuel feedstock, little is known about its systematic effects on the metabolome and microbiome of Populus. Here, we investigated the metabolome of Populus trichocarpa and Populus deltoides leaves and roots and the microbiome of the leaf and root endospheres, phylloplane, and rhizosphere to understand the systematic impacts of S. musiva abundance and infection on Populus species in a common garden field setting. We found that S. musiva is indeed present in both P. deltoides and P. trichocarpa, but S. musiva abundance was not statistically related to stem canker onset. We also found that the leaf and root metabolomes significantly differ between the two Populus species and that certain leaf metabolites, particularly the phenolic glycosides salirepin and salireposide, are diminished in canker-infected P. trichocarpa trees compared to their uninfected counterparts. Furthermore, we found significant associations between the metabolome, S. musiva abundance, and microbiome composition and α-diversity, particularly in P. trichocarpa leaves. Our results show that S. musiva colonizes both resistant and susceptible hosts and that the effects of S. musiva on susceptible trees are not confined to the site of canker infection. IMPORTANCE Poplar (Populus spp.) trees are ecologically and economically important trees throughout North America. However, many western North American poplar plantations are at risk due to the introduction of the nonnative fungal pathogen Sphaerulina musiva, which causes leaf spot and cankers, limiting their production. To better understand the interactions among the pathogen S. musiva, the poplar metabolome, and the poplar microbiome, we collected leaf, root, and rhizosphere samples from poplar trees consisting of 10 genotypes and two species with differential resistance to S. musiva in a common garden experiment. Here, we outline the nuanced relationships between the poplar metabolome, microbiome, and S. musiva, showing that S. musiva may affect poplar trees in tissues distal to the site of infection (i.e., stem). Our research contributes to improving the fundamental understanding of S. musiva and Populus sp. ecology and the utility of a holobiont approach in understanding plant disease.

BackgroundThe out-of-the-field absorbed dose affects the probability of primary second radiation-induced cancers. This is particularly relevant in the case of pediatric treatments. There are currently no methods employed in the clinical routine for the computation of dose distributions from stray radiation in radiotherapy. To overcome this limitation in the framework of conventional teletherapy with photon beams, two computational tools have been developed—one based on an analytical approach and another depending on a fast Monte Carlo algorithm. The purpose of this work is to evaluate the accuracy of these approaches by comparison with experimental data obtained from anthropomorphic phantom irradiations.Materials and MethodsAn anthropomorphic phantom representing a 5-year-old child (ATOM, CIRS) was irradiated considering a brain tumor using a Varian TrueBeam linac. Two treatments for the same planned target volume (PTV) were considered, namely, intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). In all cases, the irradiation was conducted with a 6-MV energy beam using the flattening filter for a prescribed dose of 3.6 Gy to the PTV. The phantom had natLiF : Mg, Cu, P (MCP-N) thermoluminescent dosimeters (TLDs) in its 180 holes. The uncertainty of the experimental data was around 20%, which was mostly attributed to the MCP-N energy dependence. To calculate the out-of-field dose, an analytical algorithm was implemented to be run from a Varian Eclipse TPS. This algorithm considers that all anatomical structures are filled with water, with the exception of the lungs which are made of air. The fast Monte Carlo code dose planning method was also used for computing the out-of-field dose. It was executed from the dose verification system PRIMO using a phase-space file containing 3x109 histories, reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1 ) on all voxels scoring more than 50% of the maximum dose. The standard statistical uncertainty of out-of-field voxels in the Monte Carlo simulation did not exceed 5%. For the Monte Carlo simulation the actual chemical composition of the materials used in ATOM, as provided by the manufacturer, was employed.ResultsIn the out-of-the-field region, the absorbed dose was on average four orders of magnitude lower than the dose at the PTV. For the two modalities employed, the discrepancy between the central values of the TLDs located in the out-of-the-field region and the corresponding positions in the analytic model were in general less than 40%. The discrepancy in the lung doses was more pronounced for IMRT. The same comparison between the experimental and the Monte Carlo data yielded differences which are, in general, smaller than 20%. It was observed that the VMAT irradiation produces the smallest out-of-the-field dose when compared to IMRT.ConclusionsThe proposed computational methods for the routine calculation of the out-of-the-field dose produce results that are similar, in most cases, with the experimental data. It has been experimentally found that the VMAT irradiation produces the smallest out-of-the-field dose when compared to IMRT for a given PTV.

Proton therapy enables to deliver highly conformed dose distributions owing to the characteristic Bragg peak and the finite range of protons. However, during proton therapy, secondary neutrons are created, which can travel long distances and deposit dose in out-of-field volumes. This out-of-field absorbed dose needs to be considered for radiation-induced secondary cancers, which are particularly relevant in the case of pediatric treatments. Unfortunately, no method exists in clinics for the computation of the out-of-field dose distributions in proton therapy. To help overcome this limitation, a computational tool has been developed based on the Monte Carlo code TOPAS. The purpose of this work is to evaluate the accuracy of this tool in comparison to experimental data obtained from an anthropomorphic phantom irradiation. An anthropomorphic phantom of a 5-year-old child (ATOM, CIRS) was irradiated for a brain tumor treatment in an IBA Proteus Plus facility using a pencil beam dedicated nozzle. The treatment consisted of three pencil beam scanning fields employing a lucite range shifter. Proton energies ranged from 100 to 165 MeV. A median dose of 50.4 Gy(RBE) with 1.8 Gy(RBE) per fraction was prescribed to the initial planning target volume (PTV), which was located in the cerebellum. Thermoluminescent detectors (TLDs), namely, Li-7-enriched LiF : Mg, Ti (MTS-7) type, were used to detect gamma radiation, which is produced by nuclear reactions, and secondary as well as recoil protons created out-of-field by secondary neutrons. Li-6-enriched LiF : Mg,Cu,P (MCP-6) was combined with Li-7-enriched MCP-7 to measure thermal neutrons. TLDs were calibrated in Co-60 and reported on absorbed dose in water per target dose (μGy/Gy) as well as thermal neutron dose equivalent per target dose (μSv/Gy). Additionally, bubble detectors for personal neutron dosimetry (BD-PND) were used for measuring neutrons (>50 keV), which were calibrated in a Cf-252 neutron beam to report on neutron dose equivalent dose data. The Monte Carlo code TOPAS (version 3.6) was run using a phase-space file containing 1010 histories reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1) on all voxels scoring more than 50% of the maximum dose. The primary beam was modeled following a Fermi–Eyges description of the spot envelope fitted to measurements. For the Monte Carlo simulation, the chemical composition of the tissues represented in ATOM was employed. The dose was tallied as dose-to-water, and data were normalized to the target dose (physical dose) to report on absorbed doses per target dose (mSv/Gy) or neutron dose equivalent per target dose (μSv/Gy), while also an estimate of the total organ dose was provided for a target dose of 50.4 Gy(RBE). Out-of-field doses showed absorbed doses that were 5 to 6 orders of magnitude lower than the target dose. The discrepancy between TLD data and the corresponding scored values in the Monte Carlo calculations involving proton and gamma contributions was on average 18%. The comparison between the neutron equivalent doses between the Monte Carlo simulation and the measured neutron doses was on average 8%. Organ dose calculations revealed the highest dose for the thyroid, which was 120 mSv, while other organ doses ranged from 18 mSv in the lungs to 0.6 mSv in the testes. The proposed computational method for routine calculation of the out-of-the-field dose in proton therapy produces results that are compatible with the experimental data and allow to calculate out-of-field organ doses during proton therapy.

Abstract Aim To understand and describe the experiences and perceptions of migrant Spanish nurses working in the UK. Design Online survey with open‐ended questions. Methods A total of 371 participants were recruited from online groups related to Spanish nurses working in the UK. Results Four themes emerged from their content analysis: “Motivations for emigration: running away from job insecurity and unemployment,” “Professional recognition,” “Seeking better life stability” and “Future neediness: between a rock and a hard place.” In these results, professional recognition was highlighted as a reason to stay in the host country, although the uncertainty represented by Brexit is reversing the migration trend that began years ago. Policymakers should be aware of these experiences to promote strategies and programmes, which encourage inclusion in the host country and will help these nurses in their transition process.

The world has faced the most challenging pandemic of the modern era, that of severe acute respiratory syndrome coronavirus 2 infection, causing coronavirus disease and affecting over 35 million people globally. The wide range of clinical manifestations associated with this viral disease is thought to be related to the overexpression of inflammatory markers. Due to a dysregulated host response, the most severe form involves multi-organ failure and thromboembolic complications. Immunomodulatory therapies may help prevent its progression and anticoagulation has been shown to reduce the risk of thrombotic complications. As this is a new entity for the medical world, there are no known therapeutic options nor has the prevention of complications been established. Anti-inflammatory agents, antimicrobial therapy, and vitamin supplements are short of clear benefits, but there is limited data to review. Other agents, such as convalescent plasma, eculizumab, immunoglobulins, neutralizing IgG1 monoclonal antibodies, remdesivir, steroids, and tocilizumab, have shown a possible impact on inpatient length of stay and mortality rate. This review aims to assess the efficacy and safety of these available therapies in light of current evidence. We compare these treatment options based on their impact on symptom management, inpatient length of stay, and overall morbidity and mortality.

Background: Dioxins and polychlorobiphenyls (PCBs) are persistent organic pollutants that have demonstrated endocrine disrupting properties. Several of these chemicals are carcinogenic and positive associations have been suggested with breast cancer risk. In general population, diet represents the main source of exposure. Methods: Associations between dietary intake of 17 dioxins and 35 PCBs and breast cancer were evaluated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries using multivariable Cox regressions. The present study included 318,607 women (mean ± SD age: 50.7 ± 9.7) with 13,241 incident invasive breast cancers and a median follow-up of 14.9 years (IQR = 13.5–16.4). Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with food contamination data provided by the European Food Safety Authority. Results: Exposure to dioxins, dioxins + Dioxin-Like-PCBs, Dioxin-Like-PCBs (DL-PCBs), and Non-Dioxin-Like-PCBs (NDL-PCBs) estimated from reported dietary intakes were not associated with breast cancer incidence, with the following hazard ratios (HRs) and 95% confidence intervals for an increment of 1 SD: HRdioxins = 1.00 (0.98 to 1.02), HRdioxins+DL-PCB = 1.01 (0.98 to 1.03), HRDL-PCB = 1.01 (0.98 to 1.03), and HRNDL-PCB = 1.01 (0.99 to 1.03). Results remained unchanged when analyzing intakes as quintile groups, as well as when analyses were run separately per country, or separating breast cancer cases based on estrogen receptor status or after further adjustments on main contributing food groups to PCBs and dioxins intake and nutritional factors. Conclusions: This large European prospective study does not support the hypothesis of an association between dietary intake of dioxins and PCBs and breast cancer risk.

Industrialised economies are experiencing a decline in mortality alongside low fertility rates – a situation that puts social security systems under severe pressure. Population ageing is associated not only with longer periods of pension claims but also smaller cohorts eventually entering the labour market. This threatens the sustainability of pay-as-you-go social security systems for implementing or further improving appropriate reform measures; adequate forecasts of the future population structure are needed. We propose a probabilistic approach to forecast the number of pensions in Germany up to 2040. Our model considers trends in population development, labour force participation, and early retirement, as well as the effects of pension reforms. Principal component analysis is used to manage the high degree of complexity involved in forecasting trends in old-age and disability pension claims, which arises because of cross-correlations between old-age and disability pension rates, different age groups, and gender. Time series methods enable the inclusion of autocorrelations of the pension rate time series in the model. Monte Carlo simulation is used to quantify future risk. The latter is an important feature of our model, as the future development of the population and, eventually, the pension claims and the financial burden resulting from those claims, are highly stochastic. The model predicts that, in the median trajectory, the number of old-age pensions will increase by almost 5 million between 2017 and 2036, alongside increases in the number of disability pensions by 2036. These numbers take account of the increase in legal retirement ages as part of the 2007 pension reform. After the mid-2030s, however, a moderate decrease can be expected. The results show a clear need for further reforms, especially in the medium term.

Abstract Background Microbial electrolysis is a promising technology for converting aqueous wastes into hydrogen. However, substrate adaptability is an important feature, seldom documented in microbial electrolysis cells (MECs). In addition, the correlation between substrate composition and community structure has not been well established. This study used an MEC capable of producing over 10 L/L-day of hydrogen from a switchgrass-derived bio-oil aqueous phase and investigated four additional substrates, tested in sequence on a mature biofilm. The additional substrates included a red oak-derived bio-oil aqueous phase, a corn stover fermentation product, a mixture of phenol and acetate, and acetate alone. Results The MECs fed with the corn stover fermentation product resulted in the highest performance among the complex feedstocks, producing an average current density of 7.3 ± 0.51 A/m2, although the acetate fed MECs outperformed complex substrates, producing 12.3 ± 0.01 A/m2. 16S rRNA gene sequencing showed that community structure and community diversity were not predictive of performance, and replicate community structures diverged despite identical inoculum and enrichment procedure. The trends in each replicate, however, were indicative of the influence of the substrates. Geobacter was the most dominant genus across most of the samples tested, but its abundance did not correlate strongly to current density. High-performance liquid chromatography (HPLC) showed that acetic acid accumulated during open circuit conditions when MECs were fed with complex feedstocks and was quickly degraded once closed circuit conditions were applied. The largest net acetic acid removal rate occurred when MECs were fed with red oak bio-oil aqueous phase, consuming 2.93 ± 0.00 g/L-day. Principal component analysis found that MEC performance metrics such as current density, hydrogen productivity, and chemical oxygen demand removal were closely correlated. Net acetic acid removal was also found to correlate with performance. However, no bacterial genus appeared to correlated to these performance metrics strongly, and the analysis suggested that less than 70% of the variance was accounted for by the two components. Conclusions This study demonstrates the robustness of microbial communities to adapt to a range of feedstocks and conditions without relying on specific species, delivering high hydrogen productivities despite differences in community structure. The results indicate that functional adaptation may play a larger role in performance than community composition. Further investigation of the roles each microbe plays in these communities will help MECs to become integral in the 21st-century bioeconomy to produce zero-emission fuels.

Evidence that somatic mutation rates in introns exceed those in exons challenges the molecular evolution tenet that mutation rate and sequence function are independent. Here, authors analyze germline de novo mutations and reveal no evidence for mutation rate differences between exons and introns.

Abstract Objectives Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives: To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection. To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial. To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection. To evaluate seroconversion timing post-symptom onset. Exploratory objectives: To compare severity of COVID-19 between men and women. To evaluate the influence of sleep and diet on prevention from SARS-CoV-2 infection. To evaluate the effect of melatonin on the incidence and characteristics of lymphopenia and increase of inflammatory cytokines related to COVID-19. Trial design This is a two-arm parallel randomised double-blind controlled trial to evaluate the efficacy of melatonin versus placebo in the prophylaxis of coronavirus disease 2019 among healthcare workers. Participants Inclusion Criteria: Male or female participants ≥ 18 and ≤ 80 years of age. Healthcare workers from the public and private Spanish hospital network at risk of SARS-CoV 2 infection. Not having a previous COVID19 diagnosis. Understanding the purpose of the trial and not having taken any pre-exposure prophylaxis (PrEP) including HIV PrEP from March 1st 2020 until study enrolment. Having a negative SARS-CoV 2 reverse-transcription PCR (RT-PCR) result or a negative serologic rapid test (IgM/IgG) result before randomization. Premenopausal women must have a negative urinary pregnancy test in the 7 days before starting the trial treatment. Premenopausal women and males with premenopausal couples must commit to using a high efficiency anticonceptive method. Exclusion Criteria: HIV infection. Active hepatitis B infection. Renal failure (CrCl < 60 mL/min/1.73 m2) or need for hemodialysis. Osteoporosis. Myasthenia gravis. Pre-existent maculopathy. Retinitis pigmentosa. Bradycardia (less than 50 bpm). Weight less than 40 Kg. Participant with any immunosuppressive condition or hematological disease. Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone. Hereditary intolerance to galactose, Lapp lactase deficiency or glucose or galactose malabsorption. Treatment with fluvoxamine. Treatment with benzodiazepines or benzodiazepine analogues such as zolpidem, zopiclone or zaleplon. Pregnancy. Breastfeeding. History of potentially immune derived diseases such as: lupus, Crohn's disease, ulcerative colitis, vasculitis or rheumatoid arthritis. Insulin-dependent diabetes mellitus. Known history of hypersensitivity to the study drug or any of its components. Patients that should not be included in the study at the judgment of the research team. Participants will be recruited from the following eight hospitals in Madrid, Spain: Hospital Universitario La Paz, Hospital Ramón y Cajal, Hospital Infanta Sofía, Hospital 12 de Octubre, Hospital Clínico San Carlos, Hospital Central de la defensa Gómez Ulla,Hospital de La Princesa and Hospital Infanta Leonor. Intervention and comparator Experimental: Melatonin (Circadin®, Exeltis Healthcare, Spain): 2 mg of melatonin orally before bedtime for 12 weeks. Comparator: Identical looking placebo (Laboratorios Liconsa, Spain) orally before bedtime for 12 weeks. Main outcomes Number of SARS-CoV-2 (COVID-19) symptomatic infections confirmed by polymerase chain reaction (PCR) test or serologic test or according to each centre diagnosis protocol. Primary outcome will be measured until the end of treatment for each participant (until the date of the last dose taken by each patient). Randomisation Patients who meet all inclusion and no exclusion criteria will be randomised, stratified by centres, sex and age (

Abstract Background Caldicellulosiruptor bescii, a promising biocatalyst being developed for use in consolidated bioprocessing of lignocellulosic materials to ethanol, grows poorly and has reduced conversion at elevated medium osmolarities. Increasing tolerance to elevated fermentation osmolarities is desired to enable performance necessary of a consolidated bioprocessing (CBP) biocatalyst. Results Two strains of C. bescii showing growth phenotypes in elevated osmolarity conditions were identified. The first strain, ORCB001, carried a deletion of the FapR fatty acid biosynthesis and malonyl-CoA metabolism repressor and had a severe growth defect when grown in high-osmolarity conditions—introduced as the addition of either ethanol, NaCl, glycerol, or glucose to growth media. The second strain, ORCB002, displayed a growth rate over three times higher than its genetic parent when grown in high-osmolarity medium. Unexpectedly, a genetic complement ORCB002 exhibited improved growth, failing to revert the observed phenotype, and suggesting that mutations other than the deleted transcription factor (the fruR/cra gene) are responsible for the growth phenotype observed in ORCB002. Genome resequencing identified several other genomic alterations (three deleted regions, three substitution mutations, one silent mutation, and one frameshift mutation), which may be responsible for the observed increase in osmolarity tolerance in the fruR/cra-deficient strain, including a substitution mutation in dnaK, a gene previously implicated in osmoresistance in bacteria. Differential expression analysis and transcription factor binding site inference indicates that FapR negatively regulates malonyl-CoA and fatty acid biosynthesis, as it does in many other bacteria. FruR/Cra regulates neighboring fructose metabolism genes, as well as other genes in global manner. Conclusions Two systems able to effect tolerance to elevated osmolarities in C. bescii are identified. The first is fatty acid biosynthesis. The other is likely the result of one or more unintended, secondary mutations present in another transcription factor deletion strain. Though the locus/loci and mechanism(s) responsible remain unknown, candidate mutations are identified, including a mutation in the dnaK chaperone coding sequence. These results illustrate both the promise of targeted regulatory manipulation for osmotolerance (in the case of fapR) and the challenges (in the case of fruR/cra).

Penetration testing is a popular and instantaneous technique for subsurface mapping, contaminant tracking, and the determination of soil characteristics. While the small footprint and reproducibility of cone penetrometer testing makes it an ideal method for in-situ subsurface investigations at contaminated sites, the effects to local shallow groundwater wells and measurable influence on monitoring networks common at contaminated sites is unknown. Physical and geochemical parameters associated with cone penetrometer testing were measured from a transect of shallow groundwater monitoring wells adjacent to penetrometer testing. For wells screened above the depth of cone refusal, the physical advancement and retraction of the cone had a significant effect (p < 0.01) on water level for several pushes within 10 meters of a monitoring well, and a measured increase in specific conductivity. No effect on geochemistry or water level was observed in continuous monitoring data from wells screened below the depth of cone refusal, but variability in specific conductivity from these wells during penetration testing was only a fraction of the natural variation measured during precipitation events. Continuous measurements of specific conductivity and water level demonstrated that the effects of penetration testing have limited spatial and temporal distributions with a null effect post-testing.

BackgroundFood biodiversity, encompassing the variety of plants, animals, and other organisms consumed as food and drink, has intrinsic potential to underpin diverse, nutritious diets and improve Earth system resilience. Dietary species richness (DSR), which is recommended as a crosscutting measure of food biodiversity, has been positively associated with the micronutrient adequacy of diets in women and young children in low- and middle-income countries (LMICs). However, the relationships between DSR and major health outcomes have yet to be assessed in any population.Methods and findingsWe examined the associations between DSR and subsequent total and cause-specific mortality among 451,390 adults enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) study (1992 to 2014, median follow-up: 17 years), free of cancer, diabetes, heart attack, or stroke at baseline. Usual dietary intakes were assessed at recruitment with country-specific dietary questionnaires (DQs). DSR of an individual's yearly diet was calculated based on the absolute number of unique biological species in each (composite) food and drink. Associations were assessed by fitting multivariable-adjusted Cox proportional hazards regression models. In the EPIC cohort, 2 crops (common wheat and potato) and 2 animal species (cow and pig) accounted for approximately 45% of self-reported total dietary energy intake [median (P10-P90): 68 (40 to 83) species consumed per year]. Overall, higher DSR was inversely associated with all-cause mortality rate. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing total mortality in the second, third, fourth, and fifth (highest) quintiles (Qs) of DSR to the first (lowest) Q indicate significant inverse associations, after stratification by sex, age, and study center and adjustment for smoking status, educational level, marital status, physical activity, alcohol intake, and total energy intake, Mediterranean diet score, red and processed meat intake, and fiber intake [HR (95% CI): 0.91 (0.88 to 0.94), 0.80 (0.76 to 0.83), 0.69 (0.66 to 0.72), and 0.63 (0.59 to 0.66), respectively; PWald < 0.001 for trend]. Absolute death rates among participants in the highest and lowest fifth of DSR were 65.4 and 69.3 cases/10,000 person-years, respectively. Significant inverse associations were also observed between DSR and deaths due to cancer, heart disease, digestive disease, and respiratory disease. An important study limitation is that our findings were based on an observational cohort using self-reported dietary data obtained through single baseline food frequency questionnaires (FFQs); thus, exposure misclassification and residual confounding cannot be ruled out.ConclusionsIn this large Pan-European cohort, higher DSR was inversely associated with total and cause-specific mortality, independent of sociodemographic, lifestyle, and other known dietary risk factors. Our findings support the potential of food (species) biodiversity as a guiding principle of sustainable dietary recommendations and food-based dietary guidelines.

Abstract Aims The aim of this study is to evaluate changes in cardiopulmonary exercise test (CPET) after percutaneous mitral valve repair (PMVR) with MitraClip in patients with heart failure with reduced ejection fraction who are potentially candidates for heart transplantation or destination left ventricular assist device. Methods and results Prospective registry of all consecutive patients with heart failure with reduced ejection fraction and functional mitral regurgitation (MR) underwent elective PMVR between October 2015 and March 2018 in our institution. Patients with preserved or mid‐range left ventricular ejection fraction (>40%), advanced age (>75 years old), or severe co‐morbidities (end‐stage organ damage) were not included. Treadmill exercise testing with respiratory gas exchange analysis was carried out in 11 patients (male, 72.7%; median age, 67 years old) within the month prior to the procedure and at 6 month follow‐up. PMVR was successfully performed in all patients. At 6 month follow‐up, PMVR was associated with an improvement in New York Heart Association functional class (P = 0.021) and a reduction in MR severity (P = 0.013) and N‐terminal pro‐brain natriuretic peptide levels (2805 [1878–5022] vs. 1485 [654–3032] pg/mL; P = 0.012). All patients completed pre‐procedural and post‐procedural CPET, and all the studies showed a respiratory exchange ratio ≥1 and were consistent with sufficient exercise effort. Compared with pre‐procedural CPET, patients showed a significant increase in exercise time (295 [110–335] vs. 405 [261–540] s; P = 0.047), VO2 (9.8 [9.1–13.4] vs. 13.5 [12.1–16.8] mL/kg/min; P = 0.033), ventilatory anaerobic threshold (510 [430–950] vs. 850 [670–1070] mL/kg/min; P = 0.033), peak O2 pulse (7.2 [4.3–8.6] vs. 8.3 [6.2–11.8] mL/beat; P = 0.033), and workload (5 [3–6] vs. 6 [5–8] metabolic equivalents; P = 0.049). Conclusions Percutaneous mitral valve repair with MitraClip was associated with an enhancement in cardiopulmonary performance in patients with systolic heart failure and secondary MR.

Abstract Genes responsible for the anaerobic catabolism of benzoate in the thermophilic archaeon Ferroglobus placidus were expressed in the thermophilic lignocellulose-degrading bacterium Caldicellulosiruptor bescii, as a first step to engineering this bacterium to degrade this lignin metabolite. The benzoyl-CoA ligase gene was expressed individually, and in combination with benzoyl-CoA reductase and a putative benzoate transporter. This effort also assessed heterologous expression from a synthetically designed operon whereby each coding sequence was proceeded by a unique C. bescii ribosome binding site sequence. The F. placidicus benzoyl-CoA ligase gene was expressed in C. bescii to produce a full-length protein with catalytic activity. A synthetic 6-gene operon encoding three enzymes involved in benzoate degradation was also successfully expressed in C. bescii as determined by RNA analysis, though the protein products of only four of the genes were detected. The discord between the mRNA and protein measurements, especially considering the two genes lacking apparent protein abundance, suggests variable effectiveness of the ribosome binding site sequences utilized in this synthetic operon. The engineered strains did not degrade benzoate. Although the heterologously expressed gene encoding benzoyl-CoA ligase yielded a protein that was catalytically active in vitro, expression in C. bescii of six benzoate catabolism-related genes combined in a synthetic operon yielded mixed results. More effective expression and in vivo activity might be brought about by validating and using different ribosome binding sites and different promoters. Expressing additional pathway components may alleviate any pathway inhibition and enhance benzoyl-CoA reductase activity.

Abstract Background The PRIMO system is a computer software that allows the Monte Carlo simulation of linear accelerators and the estimation of the subsequent absorbed dose distributions in phantoms and computed tomographies. The aim of this work is to validate the methods incorporated in PRIMO to evaluate the deviations introduced in the dose distributions by errors in the positioning of the leaves of the multileaf collimator recorded in the dynalog files during patient treatment. Methods The reconstruction of treatment plans from Varian’s dynalog files was implemented in the PRIMO system. Dose distributions were estimated for volumetric-modulated arc therapy clinical cases of prostate and head&neck using the PRIMO fast Monte Carlo engine DPM. Accuracy of the implemented reconstruction methods was evaluated by comparing dose distributions obtained from the simulations of the plans imported from the treatment planning system with those obtained from the simulations of the plans reconstructed from the expected leaves positions recorded in the dynalog files. The impact on the dose of errors in the positions of the leaves was evaluated by comparing dose distributions estimated for plans reconstructed from expected leaves positions with dose distributions estimated from actual leaves positions. Gamma pass rate (GPR), a hereby introduced quantity named percentage of agreement (PA) and the percentage of voxels with a given systematic difference (α/Δ) were the quantities used for the comparisons. Errors were introduced in leaves positions in order to study the sensitivity of these quantities. Results A good agreement of the dose distributions obtained from the plan imported from the TPS and from the plan reconstructed from expected leaves positions was obtained. Not a significantly better agreement was obtained for an imported plan with an increased number of control points such as to approximately match the number of records in the dynalogs. When introduced errors were predominantly in one direction, the methods employed in this work were sensitive to dynalogs with root-mean-square errors (RMS) ≥0.2 mm. Nevertheless, when errors were in both directions, only RMS >1.2 mm produced detectable deviations in the dose. The PA and the α/Δ showed more sensitive to errors in the leaves positions than the GPR. Conclusions Methods to verify the accuracy of the radiotherapy treatment from the information recorded in the Varian’s dynalog files were implemented and verified in this work for the PRIMO system. Tolerance limits could be established based on the values of PA and α/Δ. GPR 3,3 is not recommended as a solely evaluator of deviations introduced in the dose by errors captured in the dynalog files.

Abstract Background The availability of photon and electron spectra in digital form from current accelerators and Monte Carlo (MC) systems is scarce, and one of the packages widely used refers to linacs with a reduced clinical use nowadays. Such spectra are mainly intended for the MC calculation of detector-related quantities in conventional broad beams, where the use of detailed phase-space files (PSFs) is less critical than for MC-based treatment planning applications, but unlike PSFs, spectra can easily be transferred to other computer systems and users. Methods A set of spectra for a range of Varian linacs has been calculated using the PENELOPE/PRIMO MC system. They have been extracted from PSFs tallied for field sizes of 10 cm × 10 cm and 15 cm × 15 cm for photon and electron beams, respectively. The influence of the spectral bin width and of the beam central axis region used to extract the spectra have been analyzed. Results Spectra have been compared to those by other authors showing good agreement with those obtained using the, now superseded, EGS4/BEAM MC code, but significant differences with the most widely used photon data set. Other spectra, particularly for electron beams, have not been published previously for the machines simulated in this work. The influence of the bin width on the spectrum mean energy for 6 and 10 MV beams has been found to be negligible. The size of the region used to extract the spectra yields differences of up to 40% for the mean energies in 10 MV beams, but the maximum difference for TPR 20,10 values derived from depth-dose distributions does not exceed 2% relative to those obtained using the PSFs. This corresponds to k Q differences below 0.2% for a typical Farmer-type chamber, considered to be negligible for reference dosimetry. Different configurations for using electron spectra have been compared for 6 MeV beams, concluding that the geometry used for tallying the PSFs used to extract the spectra must be accounted for in subsequent calculations using the spectra as a source. Conclusions An up-to-date set of consistent spectra for Varian accelerators suitable for the calculation of detector-related quantities in conventional broad beams has been developed and made available in digital form.

Abstract Background PRIMO is a dose verification system based on the general-purpose Monte Carlo radiation transport code penelope, which implements an accurate physics model of the interaction cross sections and the radiation transport process but with low computational efficiency as compared with fast Monte Carlo codes. One of these fast Monte Carlo codes is the Dose Planning Method (DPM). The purpose of this work is to describe the adaptation of DPM as an alternative PRIMO computation engine, to validate its performance against penelope and to validate it for some specific cases. Methods DPM was parallelized and modified to perform radiation transport in quadric geometries, which are used to describe linacs, thus allowing the simulation of dynamic treatments. To benchmark the new code versus penelope, both in terms of accuracy of results and simulation time, several tests were performed, namely, irradiation of a multi-layer phantom, irradiation of a water phantom using a collimating pattern defined by the multileaf collimator (MLC), and four clinical cases. The gamma index, with passing criteria of 1 mm/1%, was used to compare the absorbed dose distributions. Clinical cases were compared using a 3-D gamma analysis. Results The percentage of voxels passing the gamma criteria always exceeded 99% for the phantom cases, with the exception of the transport through air, for which dose differences between DPM and penelope were as large as 24%. The corresponding percentage for the clinical cases was larger than 99%. The speedup factor between DPM and penelope ranged from 2.5 ×, for the simulation of the radiation transport through a MLC and the subsequent dose estimation in a water phantom, up to 11.8 × for a lung treatment. A further increase of the computational speed, up to 25 ×, can be obtained in the clinical cases when a voxel size of (2.5 mm)3 is used. Conclusions DPM has been incorporated as an efficient and accurate Monte Carlo engine for dose estimation in PRIMO. It allows the concatenated simulation of the patient-dependent part of the linac and the patient geometry in static and dynamic treatments. The discrepancy observed between DPM and penelope, which is due to an artifact of the cross section interpolation algorithm for low energy electrons in air, does not affect the results in other materials.

Renal cell carcinoma (RCC) a common malignancy with potential to metastasize to visceral organs. However, it uncommonly spreads to the lower genitourinary tract. We present a man with a history of RCC status post radical nephrectomy in April 2012. He presented 8 years later with obstructive lower urinary tract symptoms and an elevated prostate specific antigen (PSA). Further imaging showed a large enhancing mass with internal blood vessels posterior to the left prostate and seminal vesicle. A prostate biopsy was performed and consistent with metastatic RCC. He was ultimately treated with immunotherapy and focal stereotactic radioablation.

Importance. Sibutramine was withdrawn from the US market due to association with adverse cardiovascular outcomes especially with patients having preexisting cardiac disease. However, continued presence of sibutramine in herbal medications is a concern to public safety. Results. We report a case of a patient with no evidence of previous coronary heart disease, who presented with non-ST elevation acute coronary syndrome (NSTE-ACS). Urgent coronary catheterization showed nonobstructive coronaries. However, patient died unexpectedly within 24 hours of admission. The patient denied toxic habits but was taking over-the-counter weight loss herbal supplements. Complete autopsy was performed which showed sibutramine in the toxicology. Patient died due to complications of acute inadvertent intoxication of sibutramine. Conclusion and Relevance. This is the first case report in literature showing association of sibutramine to sudden cardiac death in patients with no prior cardiac history. The continued presence of sibutramine in some over-the-counter weight loss formulations is a very concerning public health issue.