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Nous sommes heureux que notre article sur la santé publique clinique1 ait reçu l’appui du Dr Shah2, qui mentionne également des éléments historiques importants au sujet de la santé publique clinique. Le Dr Shah a été le premier directeur d’un nouveau programme de résidence lancé en 1976 à l’Université de Toronto, soit le programme de résidence en médecine communautaire, qui porte maintenant le nom de programme de résidence en santé publique et en médecine préventive. Même s’il prétend ne pas avoir « su rassembler les cliniciens et les professionnels de la santé publique pour définir les éléments communs et les synergies nécessaires »2, nous sommes d’avis qu’il n’a pas échoué, car ses efforts ont inspiré ses étudiants (dont plusieurs ont corédigé l’article en question1). Tirant parti de son héritage important, les générations suivantes de cliniciens et de professionnels en santé publique ont fait des avancées sur le plan d’une collaboration efficace entre médecine clinique et santé publique.

We are pleased that our paper on clinical public health1 received support from Dr. Shah,2 who also provides important historical aspects of clinical public health. Dr. Shah was the inaugural director of a newly created residency program (Community Medicine, now known as Public Health and Preventive Medicine) at the University of Toronto in 1976. Although he claims to have failed to “bring clinicians and public health professionals together to define the common elements and synergy needed,”2 we believe he did not fail, because his efforts ignited sparks among his students (including several co-authors of this paper1). Building on his important legacy, subsequent generations of clinicians and public health professionals have made strides towards effective collaboration of clinical medicine and public health.

We report on the search for the 7Be ii isotope in the outbursts of the classical nova V6595 Sgr by means of high-resolution Ultraviolet and Visual Echelle Spectrograph (UVES) observations taken at the European Southern Observatory's Very Large Telescope in 2021 April, about two weeks after its discovery and under difficult circumstances due to the pandemic. Narrow absorption components with velocities at -2620 and-2820 km s-1, superposed on broader and shallow absorption, are observed in the outburst spectra for the 7Be ii λλ313.0583, 313.1228 nm doublet resonance lines, as well as in several other elements such as Ca ii, Fe i, Mg i, Na i, H i and Li i. Using the Ca ii K line as a reference element, we infer N(7Be)/N(H) ≈ 7.4 × 10-6, or ≈ 9.8 × 10-6 when the 7Be decay is taken into account. The 7Be abundance is about half of the value most frequently measured in novae. The possible presence of overionization in the layers where 7Be ii is detected is also discussed. Observations taken at the Telescopio Nazionale Galileo in La Palma 91 days after discovery showed prominent emission lines of oxygen and neon, which allow us to classify the nova as ONe type. Therefore, although 7Be is expected to be higher in CO novae, it is found at comparable levels in both nova types., LI was supported by two grants from VILLUM FONDEN (project number 16599 and 25501). M. H. acknowledges support from grant PID2019-108709GB-100 from MICINN (Spain).

We aimed to evaluate the value of ATN biomarker classification system (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) for predicting conversion from mild cognitive impairment (MCI) to dementia. In a sample of people with MCI (n = 415) we assessed predictive performance of ATN classification using empirical knowledge-based cut-offs for each component of ATN and compared it to two data-driven approaches, logistic regression and RUSBoost machine learning classifiers, which used continuous clinical or biomarker scores. In data-driven approaches, we identified ATN features that distinguish normals from individuals with dementia and used them to classify persons with MCI into dementia-like and normal groups. Both data-driven classification methods performed better than the empirical cut-offs for ATN biomarkers in predicting conversion to dementia. Classifiers that used clinical features performed as well as classifiers that used ATN biomarkers for prediction of progression to dementia. We discuss that data-driven modeling approaches can improve our ability to predict disease progression and might have implications in future clinical trials.

What, precisely, are we seeking to achieve in offering 'life-saving' treatment to patients with cancer? Research funding agencies and pharmaceutical industry media releases, and government cancer screening programs all promise that their cancer programs save lives. But everybody dies. The nature of life and death from cancer is explored philosophically in this essay, with particular reference to the quality of life, and its meaning, during the period of prolongation of survival by 'life-saving' cancer care.

PURPOSE This study assessed the economic impact of increased use of comprehensive genomic profiling (CGP) versus conventional testing strategies among patients with advanced non–small-cell lung cancer (aNSCLC) from a US commercial health plan perspective. METHODS A decision analytic model was developed to estimate the incremental benefits and costs across testing methodologies (CGP v non-CGP), as well as across sample types (tissue-based and liquid-based), for patients with newly diagnosed aNSCLC. Model outcomes included total direct costs, testing costs, and per member per month budget impact. Secondary model outcomes included the number of patients needed to test with CGP to add 1 life-year, and the number of patients needed to test with CGP to treat one individual with a biomarker-matched therapy. RESULTS In a hypothetical 2,000,000-member health plan, 790 members were estimated to have incident aNSCLC; 609 underwent molecular diagnostic testing with 122 (20%) tested with CGP (109 tissue-based and 13 liquid) in the base-case. An increase in CGP from 20% to 30% (an additional 61 patients tested with CGP) was associated with 3.11 additional life-years gained and a $0.01 in US dollars per member per month budget impact. Approximately 19.6 patients would need to be tested with CGP versus non-CGP to add one life-year and 5.9 patients would need to be tested with CGP to treat at least one patient with a biomarker-matched therapy. CONCLUSION An increase in CGP from 20% to 30% among patients with aNSCLC undergoing molecular diagnostic testing was associated with modest budget impact, most of which was attributable to prolonged survival associated with increased use of more effective treatments.

In planning randomized clinical trials (RCTs) for diseases such as Alzheimer's disease (AD), researchers frequently rely on the use of existing data obtained from only two time points to estimate sample size via the subtraction of baseline from follow-up measurements in each subject. However, the inadequacy of this method has not been reported. The aim of this study is to discuss the limitation of sample size estimation based on the subtraction of available data from only two time points for RCTs. Mathematical equations are derived to demonstrate the condition under which the obtained data pairs with variable time intervals could be used to adequately estimate sample size. The MRI-based hippocampal volume measurements from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Monte Carlo simulations (MCS) were used to illustrate the existing bias and variability of estimates. MCS results support the theoretically derived condition under which the subtraction approach may work. MCS also show the systematically under- or over-estimated sample sizes by up to 32.27 % bias. Not used properly, such subtraction approach outputs the same sample size regardless of trial durations partly due to the way measurement errors are handled. Estimating sample size by subtracting two measurements should be treated with caution. Such estimates can be biased, the magnitude of which depends on the planned RCT duration. To estimate sample sizes, we recommend using more than two measurements and more comprehensive approaches such as linear mixed effect models.

Improper disposal and burning of agricultural residues are commonly practiced in some developing countries in which harmful gaseous products released into the atmosphere and some are depleted and reacted with the soil causing environmental pollution. Renewable technology can therefore be introduced for the utilization of the residues and ensure proper storage medium of the residues. An investigation was carried out on the pollution potential of oil palm residues on surface and underground water resources at the processing centre. Oil palm residues and water samples from the stream and well located near the oil processing site were used for the experiment. Water samples were collected during the raining and dry season to determine the level of pollution caused by the residues. Physical, chemical and bacteriological parameters of the water samples were determined. The chemical compounds of the palm residues were investigated. Results showed that aromatics compounds are mainly dominant of the palm fruit fiber which was characterized for bio-fuel production. It is revealed that effect of pollution on water bodies is significant at p

Qualitative Network Models (QNMs), Fuzzy Cognitive Maps (FCMs), and Bayesian Belief Networks (BBNs) have been proposed as methods to formalize conceptual models of social–ecological systems and project system responses to management interventions or environmental change. To explore how these different methods might influence conclusions about system dynamics, we assembled conceptual models representing three different coastal systems, adapted them to the network approaches, and evaluated outcomes under scenarios representing increased fishing effort and environmental warming. The sign of projected change was the same across the three network models for 31–60% of system variables on average. Pairwise agreement between network models was higher, ranging from 33 to 92%; average levels of similarity were comparable between network pairs. Agreement measures based on both the sign and strength of change were substantially worse for all model comparisons. These general patterns were similar across systems and scenarios. Different outcomes between models led to different inferences regarding trade-offs under the scenarios. We recommend deployment of all three methods, when feasible, to better characterize structural uncertainty and leverage insights gained under one framework to inform the others. Improvements in precision will require model refinement through data integration and model validation.

Yelloweye rockfish Sebastes ruberrimus in the Puget Sound/Georgia Basin (PSGB) region are genetically differentiated from those of the outer Pacific coast of North America, while canary rockfish S. pinniger show no population structure between these regions. These characteristics helped determine each species’ status as a distinct population segment (DPS) under the US Endangered Species Act. Here, we explore larval dispersal patterns and test whether these patterns could explain the differences in population structure. We used a 3-D oceanographic model to simulate dispersal of each species’ larvae from sites inside and outside PSGB for up to 120 d. Dispersal patterns were similar across species and site-specific. Most larvae were found in the same DPS region or management basin from which they were released, but dispersal across boundaries was greatest from release sites nearest the DPS boundary for both species. Dispersal of larvae into the DPS from release sites outside the DPS increased and retention of larvae within the DPS increased with increasing pelagic larval duration, but this was also influenced by a simulated ontogenetic shift in larval depth distribution. The proportion of cross boundary dispersal observed for both species was likely high enough by Day 90 to allow gene flow across boundaries, which is consistent with the lack of population structure observed in canary rockfish but conflicts with the differentiated population structure observed in yelloweye rockfish. Understanding the potential larval dispersal pathways within and across management boundaries is an important step in the successful spatial management and recovery of important and protected species.

The pathophysiology of empty nose syndrome (ENS) remains unclear despite significant research. The pathophysiologic mechanism of ENS was systematically reviewed.MEDLINE and Embase.Data were systematically reviewed for studies that provided original data on pathophysiology.A total of 2476 studies were screened, and 19 met the inclusion criteria: 13 case-control and 6 cross-sectional. Nine pathophysiologic themes were identified.• Demographics: ENS symptoms had no relationship with climatic factors.• Symptomatology: ENS patients demonstrated high symptom severity.• Mental health: Anxiety and depression including hyperventilation were reported in50% of ENS patients and correlated with ENS symptom severity.• Anatomic features: Structural changes in response to turbinate surgery were similar between ENS and non-ENS patients.• Airflow analysis: Airflow parameters were similar between ENS and non-ENS patients after turbinate surgery. On computational fluid dynamic analysis, differences were found on multiple outcomes.• Diagnostic testing: The menthol detection test was impaired in ENS, and cotton placement in the airway improved ENS symptoms.• Cognitive function: Functional magnetic resonance imaging showed activation in emotional processing area during breathing.• Olfactory function: Subjective impairment was reported in ENS, but quantitative measures were similar to non-ENS patients.• Mucosal physiology/innate immunity: Turbinate histopathology in ENS showed a tissue-remodeling pattern. Nasal nitric oxide level was lower in ENS patients.There is evidence of high comorbid mental health disorders in ENS patients. An abnormal trigeminal-thermoreceptor response may be present in some patients. The influence of altered airflow and the evidence of surgery as the cause for ENS are unclear.

The landscape of nuclear oncology is rapidly changing. The advent of molecular radionuclide theranostics, multidisciplinary tumor board decision making, artificial intelligence and radiomics interpretation of diagnostic imaging, evolution of pharmacogenomics prediction of tumor response, and regulatory requirements for prospective individual dosimetry are just some of the elements which are broadening the essence of physician responsibility. The burgeoning knowledge base essential for mastering the emergent technologies, and their profound effect on moral philosophic aspects of provision of cancer care, are challenging. The new relationship of the theranostic nuclear physician with respect to shared care of the individual patient, particularly with regard to transparency, accountability, and responsibility for targeted radionuclide diagnosis and therapy of cancer, will be explored in this update.

The cyclotide T20K inhibits the proliferation of human immune cells and is currently in clinical trials for multiple sclerosis. Here, we provide novel functional data and mechanistic insights into structure-activity relationships of T20K. Analogs with partial or complete reduction of the cystine knot had loss of function in proliferation experiments. Similarly, an acyclic analog of T20K was inactive in lymphocyte bioassays. The lack of activity of non-native peptide analogs appears to be associated with the ability of cyclotides to interact with and penetrate cell membranes, since cellular uptake studies demonstrated fast fractional transfer only of the native peptide into the cytosol of human immune cells. Therefore, structural differences between cyclic and linear native folded peptides were investigated by NMR to elucidate structure-activity relationships. Acyclic T20K had a less rigid backbone and considerable structural changes in loops 1 and 6 compared to the native cyclic T20K, supporting the idea that the cyclic cystine knot motif is a unique bioactive scaffold. This study provides evidence that this structural motif in cyclotides governs bioactivity, interactions with and transport across biological membranes, and the structural integrity of these peptides. These observations could be useful to understand the structure-activity of other cystine knot proteins due to the structural conservation of the cystine knot motif across evolution and to provide guidance for the design of novel cyclic cysteine-stabilized molecules.

INTRODUCTION The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION ADNI has had a profound impact in improving clinical trials for AD.

BACKGROUND AND PURPOSE Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. EXPERIMENTAL APPROACH We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. KEY RESULTS Similar levels of α and β receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αβ receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. CONCLUSION AND IMPLICATIONS Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.

Small macrocyclic peptides are promising candidates for new anti-infective drugs. To date, such peptides have been poorly studied in the context of anti-virulence targets. Using phage display and a self-designed peptide library, we identified a cyclic heptapeptide that can bind the carbon storage regulator A (CsrA) from Yersinia pseudotuberculosis and displace bound RNA. This disulfide-bridged peptide, showed an IC50 value in the low micromolar range. Upon further characterization, cyclisation was found to be essential for its activity. To increase metabolic stability, a series of disulfide mimetics were designed and a redox-stable 1,4-disubstituted 1,2,3-triazole analogue displayed activity in the double-digit micromolar range. Further experiments revealed that this triazole peptidomimetic is also active against CsrA from Escherichia coli and RsmA from Pseudomonas aeruginosa. This study provides an ideal starting point for medicinal chemistry optimization of this macrocyclic peptide and might pave the way towards broad-acting virulence modulators.

IntroductionAntimicrobial stewardship (AMS) strategies, such as intravenous-to-oral switch (IVOS), promote optimal antimicrobial use, contributing to safer and more effective patient care and tackling antimicrobial resistance (AMR).AimThis study aimed to achieve nationwide multidisciplinary expert consensus on antimicrobial IVOS criteria for timely switch in hospitalised adult patients and to design an IVOS decision aid to operationalise agreed IVOS criteria in the hospital setting.MethodA 4-step Delphi process was chosen to achieve expert consensus on IVOS criteria and decision aid; it included Step One) Pilot/1stround questionnaire, Step Two) Virtual meeting, Step Three) 2ndround questionnaire and Step 4) Workshop. This study follows the Appraisal of Guidelines for Research and Evaluation II instrument checklist.ResultsStep One questionnaire of 42 IVOS criteria had 24 respondents, 15 of whom participated in Step Two, where 37 criteria were accepted for the next step. Step Three had 242 respondents (England n=195, Northern Ireland n=18, Scotland n=18, Wales n=11); 27 criteria were accepted. Step Four had 48 survey respondents and 33 workshop participants; where consensus was achieved for 24 criteria and comments received on a proposed IVOS decision aid. Research recommendations include the use of evidence-based standardised IVOS criteria.Discussion and ConclusionThis study achieved nationwide expert consensus on antimicrobial IVOS criteria for timely switch in the hospitalised adult population. For criteria operationalisation, an IVOS decision aid was developed. Further research is required to provide clinical validation of the consensus IVOS criteria and to expand this work into the paediatric and international settings.

Accurate assessment of burn severity is a critical need for an improved understanding of fire behavior and ecology and effective post-fire management. Although NASA Landsat satellites have a long history of use for remotely sensed mapping of burn severity, the recently launched (2015 and 2017) European Space Agency Sentinel-2 satellite constellation offers increased temporal and spatial resolution with global coverage, combined with free data access. Evaluations of burn severity derived from Landsat and Sentinel generally show comparable results, but these studies only assessed a small number of fires with limited field data. We used 912 ground calibration plots from 26 fires that burned between 2016 and 2019 in western North America to compare Sentinel- and Landsat-derived burn severity estimates with the field-based composite burn index. We mapped burn severity using two methods; the well-established paired scene approach, in which a single pre- and post-fire scene are selected for each fire, and also a mean image compositing approach that automatically integrates multiple scenes using the cloud-based remote sensing platform Google Earth Engine. We found that Sentinel generally performed as well or better than Landsat for four spectral indices of burn severity, particularly when using atmospherically corrected Sentinel imagery. Additionally, we tested the effects of mapping burn severity at Sentinel’s finer spatial resolution (10 m) on estimates of the spatial complexity of stand-replacing fire, resulting in a 5% average reduction per-fire in area mapped as high-severity patch interiors (24,273 ha total) compared to mapping at the resolution of Landsat (30 m). These findings suggest Sentinel may improve ecological discrimination of fine-scale fire effects, but also warrant caution when comparing estimates of burn severity spatial patterns derived at different resolutions. Overall, these results indicate that burn severity mapping will benefit substantially from the integration of Sentinel imagery through increased imagery availability, and that Sentinel’s higher spatial resolution improves opportunities for examining finer-scale fire effects across ecosystems.

Follicle-stimulating hormone (FSH), an α/β heterodimeric glycoprotein hormone, consists of functionally significant variants resulting from the presence or absence of either one of two FSHβ subunit N-glycans. The two most abundant variants are fully-glycosylated FSH24 (based on 24 kDa FSHβ band in Western blots) and hypo-glycosylated FSH21 (21 kDa band, lacks βAsn24 glycans). Due to its ability to bind more rapidly to the FSH receptor and occupy more FSH binding sites than FSH24, hypo-glycosylated FSH21 exhibits greater biological activity. Endoglycosidase F1-deglycosylated FSH bound to the complete extracellular domain of the FSH receptor crystallized as a trimeric complex. It was noted that a single biantennary glycan attached to FSHα Asn52 might preemptively fill the central pocket in this complex and prevent the other two FSH ligands from binding the remaining ligand-binding sites. As the most active FSH21 preparations possessed more rapidly migrating α-subunit bands in Western blots, we hypothesized that Asn52 glycans in these preparations were small enough to enable greater FSH21 receptor occupancy in the putative FSHR trimer model. Highly purified hFSH oligosaccharides derived from each FSH subunit, were characterized by electrospray ionization-ion mobility-collision-induced dissociation (ESI-IM-CID) mass spectrometry. FSHβ glycans typically possessed core-linked fucose and were roughly one third bi-antennary, one third tri-antennary and one third tetra-antennary. FSHα oligosaccharides largely lacked core fucose and were bi- or tri-antennary. Those αAsn52 glycans exhibiting tetra-antennary glycan m/z values were found to be tri-antennary, with lactosamine repeats accounting for the additional mass. Selective αAsn52 deglycosylation of representative pituitary hFSH glycoform Superdex 75 gel filtration fractions followed by ESI-IM-CID mass spectrometry revealed tri-antennary glycans predominated even in the lowest molecular weight FSH glycoforms. Accordingly, the differences in binding capacity of the same receptor preparation to different FSH glycoforms are likely the organization of the FSH receptor in cell membranes, rather than the αAsn52 oligosaccharide.

Background Climate change is eroding forest resilience to disturbance directly through warming climate and indirectly through increasing disturbance activity. Forests characterized by stand-replacing fire regimes and dominated by serotinous species are at risk when the inter-fire period is insufficient for canopy seed bank development and climate conditions for recruitment in the post-fire growing season are unsuitable. Although both factors are critical to serotinous forest persistence, their relative importance for post-fire regeneration in serotinous forests remains poorly understood. To assess the relative effects of each factor, we established plots in severely burned knobcone pine (Pinus attenuata Lemmon) forests in Oregon and California, USA, representing a range of past fire intervals (6 to 31+ years). Specifically, we evaluated effects of fire interval and pre-fire canopy seed bank (proxies for seed supply) and post-fire climate on three metrics of post-fire tree regeneration (seedling density, probability of self-replacement, percent population recovery). Results Seed supply consistently had the strongest effect on post-fire regeneration. Between 6- and 31-year fire intervals, post-fire seedling density increased from 1000 to 100,000 seedlings ha−1, while probability of self-replacement increased from ~ 0 to ~ 100% and percent population recovery increased from 20 to 2000% of the pre-fire population, respectively. Similarly, increasing the canopy seed bank by two orders of magnitude increased seedling density and percent population recovery by two orders and one order of magnitude, respectively, and increased the probability of self-replacement by > 50%. Greater post-fire climatic moisture deficit exacerbated the effect of seed supply; an additional 4–6 years between fires was required under high moisture stress conditions to reach similar regeneration levels as under low moisture stress conditions. Conclusion The overriding effect of seed supply—strongly driven by pre-fire stand age—on post-fire regeneration suggests that altered fire frequency (an indirect effect of climate change) will have a profound impact on serotinous forests. Although direct effects of hot and dry climate are lower in magnitude, they can alter forest recovery where seed supply nears a threshold. These findings reveal how fire interval and climate combine to determine changes in forest cover in the future, informing management and vulnerability mapping.