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Researchers and decision-makers use health gain measures to assess the value of health interventions. However, our current understanding of how these measures are understandable and accessible to the community is limited. This study examined a diverse group of stakeholders' attitudes and preferences for 9 commonly used health gain measures. We recruited 20 stakeholders, including patients, caregivers, pharmacists, allied health professionals, and citizens. We conducted 2 in-person deliberative meetings in which participants learned, discussed, deliberated on, and ranked 9 health gain measures. The final ranking conducted after unified deliberation showed the quality-adjusted life year (QALY) as the top-ranked measure, followed by the clinical benefit rating method used by the U.S. Preventive Services Task Force, and multicriteria decision analysis (MCDA). We identified 3 themes during deliberations: the importance of using patient values in population-based health gain measures, examining complementary measures together, and choosing measures that are intuitive and easy to understand. Future policymaking should consider incorporating the QALY, clinical benefit rating, and MCDA into prioritization decisions., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials. See Appendix S5., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Of these, approximately 25% will have liver metastasis. We performed 394 microwave ablations (MWAs) and analyzed outcomes for survival and ablation failure., Study Design: We conducted a retrospective review of patients who underwent a surgical MWA at a single-center high-volume institution from October 2006 to September 2022 using a prospectively maintained database. The primary outcome was overall survival., Results: A total of 394 operations were performed on 328 patients with 842 tumors undergoing MWA. Median tumor size was 1.5 cm (range 0.4 to 7.0 cm), with the median number of tumors ablated per operation being 1 (range 1 to 11). A laparoscopic approach was used 77.9% of the time. Concomitant procedures were performed 63% of the time, most commonly hepatectomy (22.3%), cholecystectomy (17.5%), and colectomy (6.6%). Clavien-Dindo grade III or IV complication occurred in 12 patients (3.6%), and all of these patients had undergone concomitant procedures. Mortality within 30 days occurred in 4 patients (1.2%). The rate of incomplete ablation was 1.5% per tumor. Local recurrence occurred at a rate of 6.3% per tumor. Black patients were found to have a higher incidence of incomplete ablation and local recurrence. One-year survival probability was 91% (95% CI 87.9 to 94.3), with a mean overall survival of 57.6 months (95% CI 49.9 to 65.4 months)., Conclusions: Surgical MWA offers a low-morbidity approach to treatment of colorectal liver metastasis, with low rate of failure. This large series reviews the outcomes of MWA as definitive treatment for colorectal liver metastasis., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Microwave ablation is becoming increasingly common for the treatment of liver tumors. Despite numerous studies aimed at identifying risk factors for local recurrence after microwave ablation, a consensus on modifiable risk factors for failure remains elusive, partly because of the limited statistical power of these studies. This study investigated the incidence of technical failure after microwave ablation, encompassing both incomplete ablation and local recurrence, and aimed to identify modifiable factors that reduce technical failure., Methods: This retrospective review included patients who underwent surgical microwave ablation at a high-volume institution between October 2006 and March 2023. Univariate analysis, multivariate analysis, and propensity score matching were performed to identify risk factors for technical failure., Results: A total of 1,613 surgical microwave ablations were performed on 3,035 tumors, with 226 instances (14% per procedure, 7.4% per tumor) of technical failure. Incomplete ablation occurred at a rate of 1.7% per tumor, whereas local recurrence was identified in 6.5% of ablations in per-tumor analysis. Body mass index >25 was significant for failure (odds ratio, 1.50; 95% confidence interval, 1.07-2.11; P < .05), suggesting that more difficult targeting may lead to increased technical failure rates. African American race (odds ratio, 1.62; 95% confidence interval, 1.16-2.27; P < .05), pre-microwave ablation transarterial chemoembolization (odds ratio, 1.54; 95% confidence interval, 1.08-2.21; P < .05), and previous ablation (odds ratio, 1.58; 95% confidence interval, 1.09-2.29; P < .05) were found to be statistically significant., Conclusion: On the basis of the largest microwave ablation database available to date, this study identified novel modifiable and nonmodifiable risk factors of microwave ablation failure. These results can lead to decreasing technical failure rates after microwave ablation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain., Methods: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort., Findings: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant., Conclusion: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated speech and nonspeech auditory processing of temporal and spectral cues in people who do and do not stutter. We also asked whether self-reported stuttering severity was predicted by performance on the auditory processing measures., Method: People who stutter ( n = 23) and people who do not stutter ( n = 28) completed a series of four auditory processing tasks online. These tasks consisted of speech and nonspeech stimuli differing in spectral or temporal cues. We then used independent-samples t -tests to assess differences in phonetic categorization slopes between groups and linear mixed-effects models to test differences in nonspeech auditory processing between stuttering and nonstuttering groups, and stuttering severity as a function of performance on all auditory processing tasks., Results: We found statistically significant differences between people who do and do not stutter in phonetic categorization of a continuum differing in a temporal cue and in discrimination of nonspeech stimuli differing in a spectral cue. A significant proportion of variance in self-reported stuttering severity was predicted by performance on the auditory processing measures., Conclusions: Taken together, these results suggest that people who stutter process both speech and nonspeech auditory information differently than people who do not stutter and may point to subtle differences in auditory processing that could contribute to stuttering. We also note that these patterns could be the consequence of listening to one's own speech, rather than the cause of production differences.

Although the pathogenesis of migraine is not fully understood, accumulating evidence indicates migraine may be driven by impaired brain energy metabolism in the context of pathologically high levels of adenosine. Considerable evidence indicates that aminophylline, an adenosine receptor antagonist, can provide strong therapeutic relief in pain, particularly post-dural headache. Moreover, direct observations from a previously published observational case series have demonstrated a strong therapeutic impact of low-dose aminophylline in patients with severe, unremitting migraine attacks. Although higher doses of aminophylline are associated with an unfavourable adverse effect profile, low doses of aminophylline are associated with minimal adverse effects. Despite this promise, double-blinded randomized trials will be needed to determine the true therapeutic efficacy of low-dose aminophylline in migraine.

Metabolic dysfunction is an important factor in the pathogenesis of motor neuron disease, but its prevalence and association with survival in this disorder is unknown. We hypothesized that patients with motor neuron disease would show a higher prevalence of metabolic syndrome compared to the general New Zealand population, and that metabolic syndrome would be associated with worsened survival. We undertook a retrospective analysis in 109 motor neuron disease patients diagnosed and treated at Waikato Hospital from 2013 to 2020. Demographic, clinical, and laboratory data were collected. Survival was defined as the date of initial symptom onset to the date of death. Of 104 eligible patients, 34 patients (33%) had metabolic syndrome (33% of Europeans, 46% of Māori). Mean survival in motor neuron disease patients with metabolic syndrome was significantly reduced compared to patients without metabolic syndrome (38 vs. 61 months, P = 0.044), with a 5-year survival rate of 21% for the former and 38% for the latter (P = 0.012). Compared with the general New Zealand population, metabolic syndrome is highly prevalent amongst motor neuron disease patients in the Waikato region and it is associated with worsened survival. Metabolic dysfunction may be a key factor underlying the pathogenesis of motor neuron disease., (© 2023. The Author(s).)

The role of ambient oxygen gas (O2) on molecular and nanoparticle formation and agglomeration was studied in laser ablation plumes. As a lab-scale surrogate to a high explosion detonation event, nanosecond laser ablation of an aluminum alloy (AA6061) target was performed in atmospheric pressure conditions. Optical emission spectroscopy and two mass spectrometry techniques were used to monitor the early to late stages of plasma generation to track the evolution of atoms, molecules, clusters, nanoparticles, and agglomerates. The experiments were performed under atmospheric pressure air, atmospheric pressure nitrogen, and 20% and 5% O2 (balance N2), the latter specifically with in situ mass spectrometry. Electron microscopy was performed ex situ to identify crystal structure and elemental distributions in individual nanoparticles. We find that the presence of ≈20% O2 leads to strong AlO emission, whereas in a flowing N2 environment (with trace O2), AlN and strong, unreacted Al emissions are present. In situ mass spectrometry reveals that as O2 availability increases, Al oxide cluster size increases. Nanoparticle agglomerates formed in air are found to be larger than those formed under N2 gas. High-resolution transmission electron microscopy demonstrates that Al2O3 and AlN nanoparticle agglomerates are formed in both environments; indicating that the presence of trace O2 can lead to Al2O3 nanoparticle formation. The present results highlight that the availability of O2 in the ambient gas significantly impacts spectral signatures, cluster size, and nanoparticle agglomeration behavior. These results are relevant to understanding debris formation in an explosion event, and interpreting data from forensic investigations., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2 -Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans., Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks., Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects., Conclusions: In mice lacking endogenous Plin2 , expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251 . Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD., Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

We present experimental results using a swept-wavelength external cavity quantum cascade laser (swept-ECQCL) diagnostic to measure broadband absorption spectra over a range of 920-1180 c m -1 (8.47-10.87 µm) with 2 ms temporal resolution in premixed hydrogen/oxygen flames propagating inside an enclosed chamber. Broadband spectral fits are used to determine time-resolved temperatures and column densities of H 2 O produced during combustion. Modeling of the flowfield within the test chamber under both equilibrium conditions and using a 1D freely propagating flame model is compared with the experiment in terms of temporal dynamics, temperatures, and H 2 O column density. Outputs from the numerical models were used to simulate radiative transport through an inhomogeneous combustion region and evaluate the performance of the spectral fitting model. Simulations show that probing hot-band H 2 O transitions in the high-temperature combustion regions minimizes errors due to spatial inhomogeneity. Good agreement is found between the experimental and modeling results considering experimental uncertainties and model assumptions.

Background and Aims: LCAT esterifies cholesterol in both HDL (α-activity) and apoB-containing lipoproteins (β-activity). The main activator of LCAT β-activity is apoE, which in humans exists in 3 main different isoforms (E2, E3 and E4). Here, to gather insights into the potential role of LCAT in apoB-containing lipoprotein metabolism, we investigated the ability of apoE isoforms to promote LCAT-mediated cholesterol esterification., Methods: We evaluated the plasma cholesterol esterification rate (CER) in 311 individuals who express functional LCAT and either apoE2, apoE3, or apoE4 and in 28 individuals who also carried LCAT mutations causing selective loss of LCAT α-activity (Fish-Eye Disease (FED)-causing mutations). The association of carrier status with CER was determined using an adjusted linear regression model. The kinetic of LCAT activity towards reconstituted HDLs (rHDLs) containing each apoE isoform was determined using the Michaelis-Menten model., Results: Plasma CER was ∼20% higher in apoE2 carriers compared to apoE3 carriers, and ∼30% higher in apoE2 carriers compared to apoE4 carriers. After adjusting for age, sex, total cholesterol, HDL-C, apoA-I, apoB, chronic kidney disease diagnosis, zygosity, and LCAT concentration, CER remained significantly different among carriers of the three apoE isoforms. The same trend was observed in carriers of FED-causing mutations. rHDLs containing apoE2 were associated with a lower affinity but higher maximal esterification rate, compared to particles containing apoE3 or apoE4., Conclusion: The present results suggest that the apoE2 isoform is associated with a higher LCAT-mediated cholesterol esterification. This observation may contribute to the characterization of the peculiar functional properties of apoE2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The belief that antibiotics must be administered intravenously (IV) to treat bacteraemia and endocarditis has its origins 70 years ago and has engrained itself in the psyche of the medical community and the public at large. This has led to hesitancy in adopting evidence-based strategies utilizing oral transitional therapy for the treatment of these infections. We aim to reframe the narrative around this debate, focusing on patient safety over vestigial psychology., Objectives: This narrative review summarizes the current state of the literature regarding the use of oral transitional therapy for the treatment of bacteraemia and infective endocarditis, focusing on studies comparing it to the traditional, IV-only approach., Sources: Relevant studies and abstracts from PubMed reviewed in April 2023., Content: Treating bacteraemia with oral transitional therapy has been studied in 9 randomized controlled trials (RCTs), totalling 625 patients, as well as numerous large, retrospective cohorts, including 3 published in the last 5 years alone, totalling 4763 patients. We identified 3 large, retrospective cohort studies; one quasi-experimental, pre-post study, and 3 RCTs of patients with endocarditis, totalling 748 patients in the retrospective cohorts and 815 patients in prospective, controlled studies. In all these studies, no worse outcomes were observed in the oral transitional therapy arm as compared with IV-only therapy. The main difference has consistently been longer durations of inpatient hospitalization and increased risk of catheter-related adverse events like venous thrombosis and line-associated blood stream infections in the IV-only groups., Implications: There are ample data showing that choosing oral therapy reduces hospital stay and has fewer adverse events for patients than IV-only therapy, all with similar or better outcomes. In selected patients, choosing IV-only therapy may serve more as an anxiolytic "placebo" for the patient and provider rather than a necessity for treating the actual infection., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Individuals differ in their ability to perceive and learn unfamiliar speech sounds, but we lack a comprehensive theoretical account that predicts individual differences in this skill. Predominant theories largely attribute difficulties of non-native speech perception to the relationships between non-native speech sounds/contrasts and native-language categories. The goal of the current study was to test whether the predictions made by these theories can be extended to predict individual differences in naive perception of non-native speech sounds or learning of these sounds. Specifically, we hypothesized that the internal structure of native-language speech categories is the cause of difficulty in perception of unfamiliar sounds such that learners who show more graded (i.e., less categorical) perception of sounds in their native language would have an advantage for perceiving non-native speech sounds because they would be less likely to assimilate unfamiliar speech tokens to their native-language categories. We tested this prediction in two experiments in which listeners categorized speech continua in their native language and performed tasks of discrimination or identification of difficult non-native speech sound contrasts. Overall, results did not support the hypothesis that individual differences in categorical perception of native-language speech sounds is responsible for variability in sensitivity to non-native speech sounds. However, participants who responded more consistently on a speech categorization task showed more accurate perception of non-native speech sounds. This suggests that individual differences in non-native speech perception are more related to the stability of phonetic processing abilities than to individual differences in phonetic category structure. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

High-resolution tunable laser absorption spectroscopy is used to measure time-resolved absorption spectra for six neutral uranium transitions in a laser-produced plasma. Analysis of the spectra shows that kinetic temperatures are similar for all six transitions, but excitation temperatures are higher than kinetic temperatures from 10-100 μs, indicating departures from local thermodynamic equilibrium.

Like all fields of medicine, Infectious Diseases is rife with dogma that underpins much clinical practice. In this study, we discuss 2 specific examples of historical practice that have been overturned recently by numerous prospective studies: traditional durations of antimicrobial therapy and the necessity of intravenous (IV)-only therapy for specific infectious syndromes. These dogmas are based on uncontrolled case series from >50 years ago, amplified by the opinions of eminent experts. In contrast, more than 120 modern, randomized controlled trials have established that shorter durations of therapy are equally effective for many infections. Furthermore, 21 concordant randomized controlled trials have demonstrated that oral antibiotic therapy is at least as effective as IV-only therapy for osteomyelitis, bacteremia, and endocarditis. Nevertheless, practitioners in many clinical settings remain refractory to adopting these changes. It is time for Infectious Diseases to move beyond its history of eminent opinion-based medicine and truly into the era of evidenced-based medicine., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The evolution from gas-phase oxidation to nanoparticle and agglomerate formation was studied in nanosecond laser-produced plasmas of a multi-principal element alloy target in air. Gas-phase oxidation of plasma species was monitored in situ via optical emission spectroscopy, while a custom-built single particle mass spectrometer was used to measure size and compositions of agglomerated nanoparticles formed in laser ablation plumes. Ex situ analysis employing transmission electron microscopy was used to study nanoparticle morphology, crystal structure, and element distribution at the nanoscale. Emission spectra indicate that gas-phase oxidation of elements in the alloy target are formed at varying times during plume evolution, and mass spectrometry results indicate fractal agglomerates contain all principal alloying elements and their oxides. Finally, electron microscopy characterization illustrates that these agglomerates consist of multiple material types: sub-10 nm diameter amorphous, multi-element nanoparticles, ≈10-30 nm diameter Ti-rich crystalline oxide nanoparticles, and ejected base material. Results highlight that the multi-component target composition impacts molecular formation in the gas phase and the morphology, composition, and structure of nanoparticles and agglomerates formed.

Modern healthcare systems are founded on a disease-centric paradigm, which has conferred many notable successes against infectious disorders in the past. However, today's leading causes of death are dominated by non-infectious "lifestyle" disorders, broadly represented by the metabolic syndrome, atherosclerosis, cancer, and neurodegeneration. Our disease-centric paradigm regards these disorders as distinct disease processes, caused and driven by disease targets that must be suppressed or eliminated to clear the disease. By contrast, a health-centric paradigm recognizes the lifestyle disorders as a series of hormonal and metabolic responses to a singular, lifestyle-induced disease of mitochondria dysfunction, a disease target that must be restored to improve health, which may be defined as optimized mitochondria function. Seen from a health-centric perspective, most drugs target a response rather than the disease, whereas metabolic strategies, such as fasting and carbohydrate-restricted diets, aim to restore mitochondria function, mitigating the impetus that underlies and drives the lifestyle disorders. Substantial human evidence indicates either strategy can effectively mitigate the metabolic syndrome. Preliminary evidence also indicates potential benefits in atherosclerosis, cancer, and neurodegeneration. Given the existing evidence, integrating metabolic strategies into modern healthcare systems should be identified as a global health priority., Competing Interests: Conflicts of interest The author declares no conflict of interest., (Copyright: © 2022 Phillips et al.)

Aim: Anticipating local surges in COVID-19 cases has predominantly been based on observation of increasing cases. We sought to determine if temporal trends in SARS-CoV-2 Cycle threshold (Ct) values from clinical testing were predictive of future cases., Methods: Data were collected from a large, safety-net hospital in Los Angeles, California. Ct values for all SARS-CoV-2 detections by the GeneXpert system (Cepheid) between October 2020 to March 2021 were analyzed., Results: A total of 2,114 SARS-CoV-2-positive samples were included. Cases increased dramatically in December 2020, peaking the first week of January, before returning to pre-surge numbers by mid-February. Ct values fell during this same period, with values in December and January (25.6 ± 7.8 and 27±7.9, respectively) significantly lower than those of the other months (30±9.3 to 37.7 ± 6.3). Average weekly Ct values for all patients negatively correlated with the number of tests run two weeks in the future (r= -0.74, p<0.0001), whereas Ct values for asymptomatic patients negatively correlated most strongly with total number of tests performed one month later (r= -0.88, p<0.0001). Predictive modeling using these Ct values correctly predicted whether cases would increase or decrease 65% of the time for a subsequent surge (May-July 2021)., Conclusions: During the largest COVID-19 surge in Los Angeles to date, we observed significantly lower Ct values (representing higher levels of viral RNA) suggesting that increased transmission of COVID-19 was temporarily associated with higher viral loads. Decreasing Ct values appear to be a leading indicator for predicting future COVID-19 cases, which can facilitate improved hospital-level surge planning., (Copyright © 2022. Published by Elsevier B.V.)

Broadband and high-resolution absorption spectra of molecular cerium oxide (CeO) are obtained in a laser-produced plasma using dual-comb spectroscopy. Simultaneous measurements of Ce and CeO are used to probe time-resolved dynamics of the system. A spectral resolution of 1.24 GHz (2.4 pm) over a bandwidth of 378.7-383.7 THz (781.1-791.5 nm) allows simultaneous detection of hundreds of closely spaced rotational transitions in complex CeO bands.

Despite improvements in treatment, cancer remains a leading cause of death worldwide. While chemotherapy is effective, it also damages healthy tissue, leading to severe, dose-limiting side effects that can impair efficacy and even contribute to chemoresistance. Nano-based drug-delivery systems can potentially target the delivery of chemotherapy to improve efficacy and reduce adverse effects. A number of nanocarriers have been investigated for the delivery of chemotherapy, and many of the most promising agents have advanced to clinical trials. This review examines the safety and efficacy of nanoformulated chemotherapeutic agents in clinical trials, with particular emphasis on anthracyclines, taxanes and platinum compounds. It also briefly discusses the role nano-targeting might play in the prevention and treatment of chemoresistance.

Background: We sought to determine if controlled, prospective clinical data validate the long-standing belief that intravenous (IV) antibiotic therapy is required for the full duration of treatment for 3 invasive bacterial infections: osteomyelitis, bacteremia, and infective endocarditis., Methods: We performed a systematic review of published, prospective, controlled trials that compared IV-only to oral stepdown regimens in the treatment of these diseases. Using the PubMed database, we identified 7 relevant randomized controlled trials (RCTs) of osteomyelitis, 9 of bacteremia, 1 including both osteomyelitis and bacteremia, and 3 of endocarditis, as well as one quasi-experimental endocarditis study. Study results were synthesized via forest plots and funnel charts (for risk of study bias), using RevMan 5.4.1 and Meta-Essentials freeware, respectively., Results: The 21 studies demonstrated either no difference in clinical efficacy, or superiority of oral versus IV-only antimicrobial therapy, including for mortality; in no study was IV-only treatment superior in efficacy. The frequency of catheter-related adverse events and duration of inpatient hospitalization were both greater in IV-only groups., Discussion: Numerous prospective, controlled investigations demonstrate that oral antibiotics are at least as effective, safer, and lead to shorter hospitalizations than IV-only therapy; no contrary data were identified. Treatment guidelines should be modified to indicate that oral therapy is appropriate for reasonably selected patients with osteomyelitis, bacteremia, and endocarditis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Objectives: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide., Methods: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression., Results: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36)., Discussion: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs., (© 2021 American Academy of Neurology.)

When hospitals first encountered coronavirus disease 2019 (COVID-19), there was a dearth of therapeutic options and nearly 1 in 3 patients died from the disease. By the summer of 2020, as deaths from the disease declined nationally, multiple single-center studies began to report declining mortality of patients with COVID-19. To evaluate the effect of COVID-19 on hospital-based mortality, we searched the Vizient Clinical Data Base for outcomes data from approximately 600 participating hospitals, including 130 academic medical centers, from January 2017 through December 2020. More than 32 million hospital admissions were included in the analysis. After an initial spike, mortality from COVID-19 declined in all regions of the country to under 10% by June 2020 and remained constant for the remainder of the year. Despite this, inpatient, all-cause mortality has increased since the beginning of the pandemic, even those without respiratory failure. Inpatient mortality has particularly increased in elderly patients and in those requiring intubation for respiratory failure. Since June 2020, COVID-19 kills one in every 10 patients admitted to the hospital with this diagnosis. The addition of this new disease has raised overall hospital mortality especially those who require intubation for respiratory failure., (© 2021 Wiley Periodicals LLC.)

Estrogenic signaling is an important focus in studies of gonadal and brain sexual differentiation in fishes and vertebrates generally. This study examined variation in estrogenic signaling (1) across three sexual phenotypes (female, female-mimic initial phase [IP] male, and terminal phase [TP] male), (2) during socially-controlled female-to-male sex change, and (3) during tidally-driven spawning cycles in the protogynous bluehead wrasse (Thalassoma bifasciatum). We analyzed relative abundances of messenger RNAs (mRNAs) for the brain form of aromatase (cyp19a1b) and the three nuclear estrogen receptors (ER) (ERα, ERβa, and ERβb) by qPCR. Consistent with previous reports, forebrain/midbrain cyp19a1b was highest in females, significantly lower in TP males, and lowest in IP males. By contrast, ERα and ERβb mRNA abundances were highest in TP males and increased during sex change. ERβa mRNA did not vary significantly. Across the tidally-driven spawning cycle, cyp19a1b abundances were higher in females than TP males. Interestingly, cyp19a1b levels were higher in TP males close (~1 h) to the daily spawning period when sexual and aggressive behaviors rise than males far from spawning (~10-12 h). Together with earlier findings, our results suggest alterations in neural estrogen signaling are key regulators of socially-controlled sex change and sexual phenotype differences. Additionally, these patterns suggest TP male-typical sociosexual behaviors may depend on intermediate rather than low estrogenic signaling. We discuss these results and the possibility that an inverted-U shaped relationship between neural estrogen and male-typical behaviors is more common than presently appreciated., (© 2021 Wiley Periodicals LLC.)

Background: We sought to determine the comparative efficacy of fosfomycin vs ertapenem for outpatient treatment of complicated urinary tract infections (cUTIs)., Methods: We conducted a multicenter, retrospective cohort study involving patients with cUTI treated with outpatient oral fosfomycin vs intravenous ertapenem at 3 public hospitals in Los Angeles County between January 2018 and September 2020. The primary outcome was resolution of clinical symptoms 30 days after diagnosis., Results: We identified 322 patients with cUTI treated with fosfomycin (n = 110) or ertapenem (n = 212) meeting study criteria. The study arms had similar demographics, although patients treated with ertapenem more frequently had pyelonephritis or bacteremia while fosfomycin-treated patients had more retained catheters, nephrolithiasis, or urinary obstruction. Most infections were due to extended-spectrum β-lactamase-producing E. coli and Klebsiella pneumoniae , 80%-90% of which were resistant to other oral options. Adjusted odds ratios for clinical success at 30 days, clinical success at last follow-up, and relapse were 1.21 (95% CI, 0.68-2.16), 0.84 (95% CI, 0.46-1.52), and 0.94 (95% CI, 0.52-1.70) for fosfomycin vs ertapenem, respectively. Patients treated with fosfomycin had significant reductions in length of hospital stay and length of antimicrobial therapy and fewer adverse events (1 vs 10). Fosfomycin outcomes were similar irrespective of duration of lead-in intravenous (IV) therapy or fosfomycin dosing interval (daily, every other day, every third day)., Conclusions: These results would support the conduct of a randomized controlled trial to verify efficacy. In the meantime, they suggest that fosfomycin may be a reasonable stepdown from IV antibiotics for cUTI., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background & Aims: A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC., Methods: We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet., Results: Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02)., Conclusions: In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We introduce a new, to the best of our knowledge, modality of dual-comb spectroscopy (DCS) that enables a simplified and powerful new approach for time-resolved measurements with increased acquisition rates. This "burst mode" form of DCS relies on the multiplexing of each probe pulse into a short train of pulses. With this approach we demonstrate a time-resolved series of absorption-based spectroscopic measurements of a laser-induced plasma using only a single laser ablation shot and identify 22 Nd lines not previously reported in the literature. The transmission spectra spanned 3.1 THz and were acquired at an effective acquisition rate of 25 kHz with 40 µs time resolution. This simple modification to ∼100 M H z level dual-comb systems provides a flexible approach for studying transient and low-duty-cycle events such as laser-induced plasmas, combustion, and explosive reactions.

Background & Aims: Chronic colonic inflammation leads to dysplasia and cancer in patients with inflammatory bowel disease. We have described the critical role of innate immune signaling via Toll-like receptor 4 (TLR4) in the pathogenesis of dysplasia and cancer. In the current study, we interrogate the intersection of TLR4 signaling, epithelial redox activity, and the microbiota in colitis-associated neoplasia., Methods: Inflammatory bowel disease and colorectal cancer data sets were analyzed for expression of TLR4, dual oxidase 2 (DUOX2), and NADPH oxidase 1 (NOX1). Epithelial production of hydrogen peroxide (H 2 O 2 ) was analyzed in murine colonic epithelial cells and colonoid cultures. Colorectal cancer models were carried out in villin-TLR4 mice, carrying a constitutively active form of TLR4, their littermates, and villin-TLR4 mice backcrossed to DUOXA-knockout mice. The role of the TLR4-shaped microbiota in tumor development was tested in wild-type germ-free mice., Results: Activation of epithelial TLR4 was associated with up-regulation of DUOX2 and NOX1 in inflammatory bowel disease and colorectal cancer. DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H 2 O 2 . Epithelial H 2 O 2 was significantly increased in villin-TLR4 mice; TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Mucosa-associated microbiota transferred from villin-TLR4 mice to wild-type germ-free mice caused increased H 2 O 2 production and tumorigenesis., Conclusions: Increased TLR4 signaling in colitis drives expression of DUOX2 and epithelial production of H 2 O 2 . The local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial reactive oxygen species and increased development of colitis-associated tumors. The inter-relationship between epithelial reactive oxygen species and tumor-promoting microbiota requires a 2-pronged strategy to reduce the risk of dysplasia in colitis patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Time-resolved tunable laser absorption spectroscopy is used to characterize the physical properties of ultrafast laser-produced plasmas. The plasmas were produced from an Inconel target, with ≤0.4wt% Al, using ∼35fs, ∼800nm, ∼5mJ laser pulses at varying Ar background pressures from 1 to 100 Torr. The absorption spectrum of atomic Al is measured with high spectral and temporal resolution when the probe laser is stepped across the selected Al transition at 394.4 nm. Spectral fitting is used to infer linewidths, kinetic temperature, Al column density, and pressure broadening coefficient. The late time physical properties of plasmas are compared for various pressure levels. Our studies highlight that a significant lower state population exists even at early times of ultrafast laser-produced plasma evolution, and lower state population persistence decreases with increasing ambient pressure. We also show that the fundamental optical properties, such as pressure broadening, can be measured using ultrafast laser-produced plasmas combined with laser absorption spectroscopy.

AbstractPopulations that tolerate extreme environmental conditions with frequent fluctuations can give valuable insights into physiological limits and adaptation. In some estuarine and marine ecosystems, organisms must adapt to extreme and fluctuating salinities, but not much is known about how varying salinities impact local adaptation across a wide geographic range. We used eight geographically and genetically divergent populations of the intertidal copepod Tigriopus californicus to test whether northern populations have greater tolerance to low salinity stresses, as they experience greater precipitation and less evaporation. We used a common-garden experiment approach and exposed all populations to acute low (1 and 3 ppt) and high (110 and 130 ppt) salinities for 24 h and to a fluctuation between baseline salinity and moderate low (7 ppt) and high (80 ppt) salinities for over 49 h. We also performed RNA sequencing at several time points during the fluctuation between baseline and salinity of 7 ppt to understand the molecular basis of divergence between two populations with differing physiological responses. We present these novel findings: (1) acute low salinity conditions caused more deaths than high salinity; (2) molecular processes that elevate proline levels increased in salinity of 7 ppt, which contrasts with other physiological studies in T. californicus that mainly associated accumulation of proline with hyperosmotic stress; and (3) tolerance to a salinity fluctuation did not follow a latitudinal trend but was instead governed by a complex interplay of factors, including population and duration of salinity stress. This highlights the importance of including a wider variety of environmental conditions in empirical studies to understand local adaptation.

The chemistry evolution in a laser ablation plume depends strongly on its initial physical conditions. In this article, we investigate the impact of plasma generation conditions on the interrelated phenomena of expansion dynamics, plasma chemistry, and physical conditions. Plasmas are produced from a uranium metal target in air using nanosecond, femtosecond, and femtosecond filament-assisted laser ablation. Time-resolved two-dimensional spectral imaging was performed to evaluate the spatio-temporal evolution of atoms, diatoms, polyatomic molecules, and nanoparticles in situ. Emission spectral features reveal that molecular formation occurs at early times in both femtosecond and filament ablation plumes, although with different temporal decays. In contrast, molecular formation is found to occur at much later times in nanosecond plasma evolution. Spectral modeling is used to infer temporal behavior of plasma excitation temperature. We find U atoms and UO molecules co-exist in ultrafast laser-produced plasmas even at early times after plasma onset owing to favorable temperatures for molecular formation. Regardless of irradiation conditions, plume emission features showed the presence of higher oxides (i.e., U x O y ), although with different temporal histories. Our study provides insight into the impact of plasma generation conditions on chemistry evolution in plasmas produced from traditional focused femtosecond, nanosecond, and filament-assisted laser ablation.

Acinetobacter baumannii has among the highest rates of antibiotic resistance encountered in hospitals. New therapies are critically needed. We found that rifabutin has previously unrecognized hyperactivity against most strains of A. baumannii. Here we review the pharmacology and adverse effects of rifabutin to inform potential oral dosing strategies in patients with A. baumannii infections. Rifabutin demonstrates dose-dependent increases in blood levels up to 900 mg per day, but plateaus thereafter. Furthermore, rifabutin induces its own metabolism after prolonged dosing, lowering its blood levels. Pending future development of an intravenous formulation, a rifabutin oral dose of 900-1200 mg per day for 1 week is a rational choice for adjunctive therapy of A. baumannii infections. This dosage maximizes AUC 24 to drive efficacy while simultaneously minimizing toxicity. Randomized controlled trials will be needed to definitively establish the safety and efficacy of rifabutin to treat A. baumannii infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Laser ablation in conjunction with optical emission spectroscopy is a potential non-contact, stand-off detection method for all elements in the periodic table and certain isotopes such as radionuclides. Currently, significant development efforts are on-going to use ultrafast laser filaments for remote detection of materials. The application of filaments is of particular interest in extending the range of stand-off capability associated with elemental and isotopic detection via laser-induced breakdown spectroscopy. In this study, we characterize the expansion dynamics and chemical evolution of filament-produced uranium (U) plasmas. Laser filaments are generated in the laboratory by loosely focusing 35 femtosecond (fs), 6 milli Joule (mJ) pulses in air. Time-resolved, two-dimensional plume and spectral imaging was performed to study hydrodynamics and evolution of U atomic and UO molecular emission in filament-produced U plasmas. Our results highlight that filament ablation of U plasmas gives a cylindrical plume morphology with an appearance of plume splitting into slow and fast moving components at later times of its evolution. Emission from the slow-moving component shows no distinct spectral features (i.e. broadband-like) and is contributed in part by nanoparticles generated during ultrafast laser ablation. Additionally, we find U atoms and U oxide molecules (i.e. UO, UxOy) co-exist in the filament produced plasma, which can be attributed to the generation of low-temperature plasma conditions during filament ablation.

Perry syndrome is a rare neurological condition characterised clinically by depression, sleep disturbance, central hypoventilation and parkinsonism. Perry syndrome is a TAR DNA-binding protein 43 (TDP-43) proteinopathy associated with mutated dynactin-1 protein, inherited in an autosomal dominant manner. Several pathogenic mutations in exon 2 in the dynactin 1 gene have been identified; p. F521, p. G67d, p. G71R, p. G71E, p. G71A, p. T72p, p. Q74p and p. Y78C. We present the second known case Perry syndrome with confirmed DCTN1 mutation (p. Y78C) in New Zealand, who initially was thought to have a depressive illness. Perry syndrome should be considered in the differential diagnosis of young parkinsonism, especially if there is family history of sleep disorders, weight loss and/or marked depression., Competing Interests: Gemma Poke received funding from the Health Research Council of New Zealand for research into epileptic encephalopathies.

Broadband high-speed absorption spectroscopy using swept-wavelength external cavity quantum cascade lasers (ECQCLs) is applied to measure multiple pyrolysis and combustion gases in biomass burning experiments. Two broadly-tunable swept-ECQCL systems were used, with the first tuned over a range of 2089-2262 cm -1 (4.42-4.79 µm) to measure spectra of CO 2 , H 2 O, and CO. The second was tuned over a range of 920-1150 cm -1 (8.70-10.9 µm) to measure spectra of ammonia (NH 3 ), ethene (C 2 H 4 ), and methanol (MeOH). Absorption spectra were measured continuously at a 100 Hz rate throughout the burn process, including inhomogeneous flame regions, and analyzed to determine time-resolved gas concentrations and temperature. The results provide in-situ, dynamic information regarding gas-phase species as they are generated, close to the biomass fuel source.

Rapid and sensitive standoff measurement techniques are needed for detection of trace chemicals in outdoor plume releases, for example from industrial emissions, unintended chemical leaks or spills, burning of biomass materials, or chemical warfare attacks. Here, we present results from 235 m standoff detection of transient plumes for 5 gas-phase chemicals: Freon 152a (1,1-difluoroethane), Freon 134a (1,1,1,2-tetrafluoroethane), methanol (CH 3 OH), nitrous oxide (N 2 O), and ammonia (NH 3 ). A swept-wavelength external cavity quantum cascade laser (ECQCL) measures infrared absorption spectra over the range 955-1195 cm -1 (8.37- 10.47 µm), from which chemical concentrations are determined via spectral fits. The fast 400 Hz scan rate of the swept-ECQCL enables measurement above the turbulence time-scales, reducing noise and allowing plume fluctuations to be measured. For high-speed plume detection, noise-equivalent column densities of 1-2 ppm*m are demonstrated with 2.5 ms time resolution, improving to 100-400 ppb*m with 100 ms averaging.

Background & Aims: The interaction between intestinal microbiota and the immune system plays a vital role in inflammatory bowel disease (IBD). Although numerous deep-sequencing studies have suggested dysbiosis in IBD, identifying specific bacteria from the stool or mucosa that are responsible for disease susceptibility or severity has remained a challenge. Lamina propria phagocytes ideally are localized to interact with bacteria that are in close proximity to, or have invaded, the tissue. Thus, we examined the microbial populations associated with the lamina propria phagocytes in 20 Crohn's disease and 12 ulcerative colitis patients. Specifically, we aimed to address whether the phagocyte-associated microbiota differed from the mucosa-associated microbiota and whether this varied based on IBD type or the state of inflammation., Methods: 16S ribosomal RNA gene sequencing and innate immune gene expression profiling was done on CD11b+ lamina propria phagocytes isolated from the biopsies obtained from IBD patients., Results: Phagocyte-associated microbiota was enriched in bacterial species belonging to phylum Proteobacteria, whereas species belonging to phylum Bacteroidetes were enriched in the mucosal microbiota of IBD patients. Disease type was the most influential factor in driving differences in the microbiota of both the mucosa and the lamina propria phagocytes, irrespective of inflammation state o`r anatomic location. Crohn's disease and ulcerative colitis specimens showed similar patterns of increased inflammatory gene expression in phagocytes isolated from inflamed areas compared with those isolated from uninflamed regions., Conclusions: This pilot study shows the feasibility of using lamina propria phagocytes to characterize the microbiota in IBD patients. The approach used in this study can narrow the spectrum of potentially dysbiotic bacterial populations and clinically relevant gene expression signatures in IBD patients., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients., Methods and Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence., Ethics and Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We investigate the oxidation of uranium (U) species, the physical conditions leading to uranium monoxide (UO) formation and the interplay between plume hydrodynamics and plasma chemistry in a laser-produced U plasma. Plasmas are produced by ablation of metallic U using nanosecond laser pulses. An ambient gas environment with varying oxygen partial pressures in 100 Torr inert Ar gas is used for controlling the plasma oxidation chemistry. Optical emission spectroscopic analysis of U atomic and monoxide species shows a reduction in the emission intensity and persistence with increasing oxygen partial pressure. Spectral modelling is used for identifying the physical conditions in the plasma that favor UO formation. The optimal temperature for UO formation is found to be in the temperature range of ∼1500-5000 K. The spectrally integrated and spectrally filtered (monochromatic) imaging of U atomic and molecular species reveals the evolutionary paths of various species in the plasma. Our results also highlight that oxidation in U plasmas predominantly occurs at the cooler periphery and is delayed with respect to plasma formation, and the dissipation of molecular species strongly depends on oxygen partial pressure.

Tropical South America plays a central role in global climate. Bowen ratio teleconnects to circulation and precipitation processes far afield, and the global CO 2 growth rate is strongly influenced by carbon cycle processes in South America. However, quantification of basin-wide seasonality of flux partitioning between latent and sensible heat, the response to anomalies around climatic norms, and understanding of the processes and mechanisms that control the carbon cycle remains elusive. Here, we investigate simulated surface-atmosphere interaction at a single site in Brazil, using models with different representations of precipitation and cloud processes, as well as differences in scale of coupling between the surface and atmosphere. We find that the model with parameterized clouds/precipitation has a tendency toward unrealistic perpetual light precipitation, while models with explicit treatment of clouds produce more intense and less frequent rain. Models that couple the surface to the atmosphere on the scale of kilometers, as opposed to tens or hundreds of kilometers, produce even more realistic distributions of rainfall. Rainfall intensity has direct consequences for the "fate of water," or the pathway that a hydrometeor follows once it interacts with the surface. We find that the model with explicit treatment of cloud processes, coupled to the surface at small scales, is the most realistic when compared to observations. These results have implications for simulations of global climate, as the use of models with explicit (as opposed to parameterized) cloud representations becomes more widespread., (©2019. The Authors.)

We utilize time-resolved dual-comb spectroscopy to measure the temporal evolution of the population number densities and absorption excitation temperature of Fe in a laser-induced plasma. The spectra of three excited-state transitions of Fe around 533 nm are simultaneously measured at different time delays following laser ablation of a stainless steel sample. This Letter probes late-time behaviors of laser-induced ablation plumes during plasma cooling. The high spectral resolution and broad spectral coverage of the dual-comb technique, combined with the time-resolved measurement capability shown here, will aid in the characterization of laser induced plasmas, including species identification and molecule and particle formation that can occur at later times in the plasma evolution.