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The association between residential greenness and allostatic load (AL), a marker of composite physiological burden and predictor of chronic disease, remains understudied. This study comprised 212,600 UK Biobank participants recruited over 2007 and 2010 at the baseline. Residential greenness was modeled as the normalized difference vegetation index (NDVI) from high spatial resolution (0.50 m) color infrared imagery and measured within a 0.5 km radial catchment. AL was measured as a composite index from 13 biomarkers comprising three physiological systems (metabolic, cardiovascular, and inflammatory systems) and two organ systems (liver and kidney). Multilevel mixed-effects generalized linear models with a random intercept for UK Biobank assessment centers were employed to examine the association between residential greenness and AL. Each interquartile range (IQR = 0.24) increment in NDVI greenness was associated with lower AL (beta (β) = -0.28, 95% confidence interval (CI) = -0.55, -0.01). Consistently, relative to the lowest NDVI greenness quintile, participants in the highest quintile had lower AL (β = -0.64, 95% CI = -1.02, -0.26). The proportion of the association between greenness and AL mediated by the physical activity was 3.2%. In conclusion, residential greenness was protectively associated with AL, a composite marker of wear and tear and general health.

The arcuate nucleus (Arc) of the medulla is found in almost all human brains and in a small percentage of chimpanzee brains. It is absent in the brains of other mammalian species including mice, rats, cats, and macaque monkeys. The Arc is classically considered a precerebellar relay nucleus, receiving input from the cerebral cortex and projecting to the cerebellum via the inferior cerebellar peduncle. However, several studies have found aplasia of the Arc in babies who died of SIDS (Sudden Infant Death Syndrome), and it was suggested that the Arc is the locus of chemosensory neurons critical for brainstem control of respiration. Aplasia of the Arc, however, has also been reported in adults, suggesting that it is not critical for survival. We have examined the Arc in closely spaced Nissl-stained sections in thirteen adult human cases to acquire a better understanding of the degree of variability of its size and location in adults. We have also examined immunostained sections to look for neurochemical compartments in this nucleus. Caudally, neurons of the Arc are ventrolateral to the pyramidal tracts (py); rostrally, they are ventro-medial to the py and extend up along the midline. In some cases, the Arc is discontinuous, with a gap between sections with the ventrolaterally located and the ventromedially located neurons. In all cases, there is some degree of left-right asymmetry in Arc position, size, and shape at all rostro-caudal levels. Somata of neurons in the Arc express calretinin (CR), neuronal nitric oxide synthase (nNOS), and nonphosphorylated neurofilament protein (NPNFP). Calbindin (CB) is expressed in puncta whereas there is no expression of parvalbumin (PV) in somata or puncta. There is also immunostaining for GAD and GABA receptors suggesting inhibitory input to Arc neurons. These properties were consistent among cases. Our data show differences in location of caudal and rostral Arc neurons and considerable variability among cases in the size and shape of the Arc. The variability in size suggests that "hypoplasia" of the Arc is difficult to define. The discontinuity of the Arc in many cases suggests that establishing aplasia of the Arc requires examination of many closely spaced sections through the brainstem., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Comparing with the enduring efforts to reduce carbon emissions in design, construction, and operation stages of a construction project, less attention has been paid to emission abatement potential in the end-of-life stage, particularly by recycling waste generated by construction and demolition (C&D) activities. This research aims to cover this knowledge void by quantifying the embodied carbon saving potential of recycling C&D waste. It does so by adopting a Life Cycle Assessment (LCA) and choosing the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) in South China for a case study. The carbon emission is treated as embodied in construction materials, by recycling which the equivalent amount of carbon generated from the virgin materials can be saved. It is estimated that the GBA produced 128.49 Mt. of C&D waste in 2018, which implies an embodied carbon saving potential of 92.26 Mt. carbon emissions. The research goes further to understand the future C&D waste generation and their corresponding embodied carbon saving potential. A first-of-its-kind dynamic approach is developed to simulate the future 42-year saving potential under four construction development scenarios. Depending on different construction growth rates, the embodied carbon saving potential in 2060 can be up to 894.80 Mt. and down to 166.34 Mt. This research can help achieve China's 2060 carbon neutral goal by focusing on a non-negligible sector in an economically important region. Methods proposed in this paper are also applicable to other regions worldwide, especially where C&D waste data is insufficient., 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 © 2021 Elsevier B.V. All rights reserved.)

The principles of comparability assessments have been accepted globally as offering sensitive and reliable tools with which to evaluate potential changes to biologics that may arise either through processing changes or through the creation of a copy (biosimilar) by a different sponsor. The comparability approach has evolved through systematic advances in four areas: clear and convergent guidelines for evaluation of potential changes to biologics; risk-based systems of weighting analytical data; progressive improvements in analytical methods; and advanced understanding of post-translational modifications. Routine regulatory expectations for clinical equivalence data are being reevaluated, as they seldom contribute to the assessment of similarity. Similarly, we show that requirements to compare biosimilars and locally sourced versions of their reference products are of questionable scientific value and represent a double standard by comparison with the invariable acceptance of the clinical profiles of novel biologics without reference to their sources. The consistent application of evidentiary standards for comparability to all biologics offers an opportunity for regulators to curtail their own assessments of new biosimilars and instead to recognize comparability assessments made in another jurisdiction (reliance), thereby gaining important efficiencies in the regulatory review of biosimilars and improving the competitiveness of the biosimilars market. Such consistency can also enhance the confidence of all stakeholders, especially patients and their providers, in all biologics., (© 2021. The Author(s).)

The claustrum (CLA) is a subcortical structure that is reciprocally and topographically connected with the cerebral cortex. The complexity of the cerebral cortex varies dramatically across mammals, raising the question of whether there might also be differences in CLA organization, circuitry, and function. Species variations in the shape of the CLA are well documented. Studies in multiple species have identified subsets of neurochemically distinct interneurons; some data suggest species variations in the nature, distribution, and numbers of different neurochemically identified neuronal types. We have studied the CLA in a smooth-brained primate, the squirrel monkey, using Nissl-stained sections and immunohistochemistry. We found that the shape of the CLA is different from that in other primates. We found several different neurochemically defined populations of neurons equally distributed throughout the CLA. Immunoreactivity to GAD 65/67 and GABA A receptors suggest that GABAergic interneurons provide widespread inhibitory input to CLA neurons. Immunoreactivity to glutamate transporters suggests widespread and overlapping excitatory input from cortical and possibly subcortical sources. Comparison of CLA organization in different species suggests that there may be major species differences both in the organization and in the functions of the CLA. Anat Rec, 303:1439-1454, 2020. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

The current development paradigm for biosimilars required by regulators in highly regulated jurisdictions is derived from the development of novel drugs and is unnecessarily burdensome and inefficient. It requires the accumulation of data from analytical, nonclinical (including in vivo studies in some jurisdictions), and clinical studies (including powered efficacy studies in most cases); this paradigm is known as 'totality of evidence' (ToE) and does not admit a conclusion of biosimilarity from analytical data alone. The record of biosimilar approvals in these jurisdictions shows that no biosimilar candidate that has been found highly similar to its reference in analytical and pharmacokinetic studies has failed to be approved. We propose a new paradigm ('confirmation of sufficient likeness', CSL) that emphasizes the demonstration of analytical resemblance between the biosimilar candidate and its reference, and permits the conclusion of biosimilarity upon this basis. CSL does not entail bridging studies between reference products, in vivo nonclinical studies, or powered efficacy studies and is, therefore, substantially more efficient than ToE while maintaining equivalent scientific rigor. Such efficiency will contribute to the attractiveness as well as the sustainability of biosimilars as a therapeutic modality.

In high-density cities around the world, alleys are common but neglected spaces that are perceived as unsafe. While cities have invested resources in environmental interventions to improve safety in urban allies, it is not clear how these interventions impact perceived safety. We review two important criminology theories that discuss the environmental and social factors that lead to crime: the Broken Windows Theory and the Routine Activity Theory. We argue that these theories can also be used to explain safety perceptions of urban environments, and then develop urban alley interventions based on these theories. We test people's perceived safety of these interventions through a photograph survey. Results show that all interventions yielded higher perceived safety than existing alley scenes. Interventions based on the Broken Windows Theory (cleaning or vegetation interventions) yielded only modest improvements in perceived safety, while interventions based on the Routine Activity Theory (urban function interventions) yielded higher ratings. Our findings question the dominant use of the Broken Windows Theory in environmental interventions to promote perceived safety and argue for a more effective approach: urban function interventions inspired by the Routine Activity Theory.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: None. This work is supported by the Wellcome Trust (grants 205208/Z/16/Z and 209376/Z/17/Z).

Furthermore, these errors were mistakenly introduced by the Production team managing this article and, as such were not the fault of the authors.

The skin functions as the primary interface between the human body and the external environment. To understand how the microbiome varies within urban mass transit and influences the skin microbiota, we profiled the human palm microbiome after contact with handrails within the Hong Kong Mass Transit Railway (MTR) system. Intraday sampling time was identified as the primary determinant of the variation and recurrence of the community composition, whereas human-associated species and clinically important antibiotic resistance genes (ARGs) were captured as p.m. signatures. Line-specific signatures were notably correlated with line-specific environmental exposures and city characteristics. The sole cross-border line appeared as an outlier in most analyses and showed high relative abundance and a significant intraday increment of clinically important ARGs (24.1%), suggesting potential cross-border ARG transmission, especially for tetracycline and vancomycin resistance. Our study provides an important reference for future public health strategies to mitigate intracity and cross-border pathogen and ARG transmission., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Household income (as a marker of socioeconomic position) and neighbourhood fast-food outlet exposure may be related to diet and body weight, which are key risk factors for non-communicable diseases. However, the research evidence is equivocal. Moreover, understanding the double burden of these factors is a matter of public health importance. The purpose of this study was to test associations of neighbourhood fast-food outlet exposure and household income, in relation to frequency of consumption of processed meat and multiple measures of adiposity, and to examine possible interactions., Methods: We employed an observational, cross-sectional study design. In a cohort of 51,361 adults aged 38-72 years in Greater London, UK, we jointly classified participants based on household income (£/year, four groups) and GIS-derived neighbourhood fast-food outlet proportion (counts of fast-food outlets as a percentage of all food outlets, quartiles). Multivariable regression models estimated main effects and interactions (additive and multiplicative) of household income and fast-food outlet proportion on odds of self-reported frequent processed meat consumption (> 1/week), measured BMI (kg/m 2 ), body fat (%), and odds of obesity (BMI ≥ 30)., Results: Income and fast-food proportion were independently, systematically associated with BMI, body fat, obesity and frequent processed meat consumption. Odds of obesity were greater for lowest income participants compared to highest (OR = 1.54, 95% CI: 1.41, 1.69) and for those most-exposed to fast-food outlets compared to least-exposed (OR = 1.51, 95% CI: 1.40, 1.64). In jointly classified models, lowest income and highest fast-food outlet proportion in combination were associated with greater odds of obesity (OR = 2.43, 95% CI: 2.09, 2.84), with relative excess risk due to interaction (RERI = 0.03). Results were similar for frequent processed meat consumption models. There was no evidence of interaction on a multiplicative scale between fast-food outlet proportion and household income on each of BMI (P = 0.230), obesity (P = 0.054) and frequent processed meat consumption (P = 0.725)., Conclusions: Our study demonstrated independent associations of neighbourhood fast-food outlet exposure and household income, in relation to diet and multiple objective measures of adiposity, in a large sample of UK adults. Moreover, we provide evidence of the double burden of low income and an unhealthy neighbourhood food environment, furthering our understanding of how these factors contribute jointly to social inequalities in health.

Major drug regulators have indicated in guidance their flexibility to accept some development data for biosimilars generated with reference product versions licensed outside their own jurisdictions, but most authorities require new bridging studies between these versions and the versions of them licensed locally. The costs of these studies are not trivial in absolute terms and, due to the multiplier effect of required repetition by each biosimilar sponsor, their collective costs are substantial. Yet versions of biologics licensed in different jurisdictions usually share the same development data, and any manufacturing changes between versions have been justified by a rigorous comparability process. The fact that a biosimilar is usually expected to be licensed in multiple jurisdictions, in each case as similar to the local reference product, confirms that minor analytical differences between versions of reference biologics are typically inconsequential for clinical outcomes and licensing. A greatly simplified basis for selecting a reference comparator, that does not require conducting new bridging studies, is proposed and justified based on the shared data of the reference product versions as well as the proof offered where biosimilars have already been approved. The relevance of this proposal to the interchangeability designation available in the US is discussed.

Currency is possibly one of the main media transmitting pathogens and drug resistance due to its wide circulation in daily life. In this study, we made a comprehensive characterization of the bacterial community present on banknotes collected from different geographical regions of Hong Kong (HK) by performing in vitro characterization of the bacterial presence and resistome profile, as well as metagenomic analysis including microbial diversity, the prevalence of potential pathogens, the dissemination potential of antibiotic-resistance genes (ARGs), among others. When comparing the bacterial community of HK banknotes with other HK environmental samples, including water and marine sediment, we revealed that HK banknotes cover nearly 50% of total genera found in all the environmental samples, implying that banknotes harbor diverse bacteria originated from a variety of environments. Furthermore, the banknotes have higher abundance of potential pathogenic species (~5 times more) and ARGs (~5 times more) with higher dissemination potential (~48 times more) compared with other environmental samples. These findings unveiled the capabilities of this common medium of exchange to accommodate various bacteria, and transmit pathogens and antibiotic resistance. Furthermore, the observed independence of microbiome profile from the city's topological indices led us to formulate a hypothesis that due to their high circulation banknotes may harbor a homogenized microbiome.