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Michael Weekes

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Nick K. Jones1,2*, Lucy Rivett1,2*, Chris Workman3, Mark Ferris3, Ashley Shaw1, Cambridge COVID-19 Collaboration1,4, Paul J. Lehner1,4, Rob Howes5, Giles Wright3, Nicholas J. Matheson1,4,6¶, Michael P. Weekes1,7¶1 Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK2 Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, UK3 Occupational Health and Wellbeing, Cambridge Biomedical Campus, Cambridge, UK4 Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK5 Cambridge COVID-19 Testing Centre and AstraZeneca, Anne Mclaren Building, Cambridge, UK6 NHS Blood and Transplant, Cambridge, UK7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK*Joint first authorship¶Joint last authorshipCorrespondence: UK has initiated mass COVID-19 immunisation, with healthcare workers (HCWs) given early priority because of the potential for workplace exposure and risk of onward transmission to patients. The UK’s Joint Committee on Vaccination and Immunisation has recommended maximising the number of people vaccinated with first doses at the expense of early booster vaccinations, based on single dose efficacy against symptomatic COVID-19 disease.1-3At the time of writing, three COVID-19 vaccines have been granted emergency use authorisation in the UK, including the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). A vital outstanding question is whether this vaccine prevents or promotes asymptomatic SARS-CoV-2 infection, rather than symptomatic COVID-19 disease, because sub-clinical infection following vaccination could continue to drive transmission. This is especially important because many UK HCWs have received this vaccine, and nosocomial COVID-19 infection has been a persistent problem.Through the implementation of a 24 h-turnaround PCR-based comprehensive HCW screening programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT), we previously demonstrated the frequent presence of pauci- and asymptomatic infection amongst HCWs during the UK’s first wave of the COVID-19 pandemic.4 Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and cycle threshold (Ct) values in the asymptomatic arm of our programme, which now offers weekly screening to all staff.Vaccination of HCWs at CUHNFT began on 8th December 2020, with mass vaccination from 8th January 2021. Here, we analyse data from the two weeks spanning 18thto 31st January 2021, during which: (a) the prevalence of COVID-19 amongst HCWs remained approximately constant; and (b) we screened comparable numbers of vaccinated and unvaccinated HCWs. Over this period, 4,408 (week 1) and 4,411 (week 2) PCR tests were performed from individuals reporting well to work. We stratified HCWs <12 days or > 12 days post-vaccination because this was the point at which protection against symptomatic infection began to appear in phase III clinical trial.226/3,252 (0·80%) tests from unvaccinated HCWs were positive (Ct<36), compared to 13/3,535 (0·37%) from HCWs <12 days post-vaccination and 4/1,989 (0·20%) tests from HCWs ≥12 days post-vaccination (p=0·023 and p=0·004, respectively; Fisher’s exact test, Figure). This suggests a four-fold decrease in the risk of asymptomatic SARS-CoV-2 infection amongst HCWs ≥12 days post-vaccination, compared to unvaccinated HCWs, with an intermediate effect amongst HCWs <12 days post-vaccination.A marked reduction in infections was also seen when analyses were repeated with: (a) inclusion of HCWs testing positive through both the symptomatic and asymptomatic arms of the programme (56/3,282 (1·71%) unvaccinated vs 8/1,997 (0·40%) ≥12 days post-vaccination, 4·3-fold reduction, p=0·00001); (b) inclusion of PCR tests which were positive at the limit of detection (Ct>36, 42/3,268 (1·29%) vs 15/2,000 (0·75%), 1·7-fold reduction, p=0·075); and (c) extension of the period of analysis to include six weeks from December 28th to February 7th 2021 (113/14,083 (0·80%) vs 5/4,872 (0·10%), 7·8-fold reduction, p=1x10-9). In addition, the median Ct value of positive tests showed a non-significant trend towards increase between unvaccinated HCWs and HCWs > 12 days post-vaccination (23·3 to 30·3, Figure), suggesting that samples from vaccinated individuals had lower viral loads.We therefore provide real-world evidence for a high level of protection against asymptomatic SARS-CoV-2 infection after a single dose of BNT162b2 vaccine, at a time of predominant transmission of the UK COVID-19 variant of concern 202012/01 (lineage B.1.1.7), and amongst a population with a relatively low frequency of prior infection (7.2% antibody positive).5This work was funded by a Wellcome Senior Clinical Research Fellowship to MPW (108070/Z/15/Z), a Wellcome Principal Research Fellowship to PJL (210688/Z/18/Z), and an MRC Clinician Scientist Fellowship (MR/P008801/1) and NHSBT workpackage (WPA15-02) to NJM. Funding was also received from Addenbrooke’s Charitable Trust and the Cambridge Biomedical Research Centre. We also acknowledge contributions from all staff at CUHNFT Occupational Health and Wellbeing and the Cambridge COVID-19 Testing Centre.

Guangming Wang

and 4 more

Tam Hunt

and 1 more

Tam Hunt [1], Jonathan SchoolerUniversity of California Santa Barbara Synchronization, harmonization, vibrations, or simply resonance in its most general sense seems to have an integral relationship with consciousness itself. One of the possible “neural correlates of consciousness” in mammalian brains is a combination of gamma, beta and theta synchrony. More broadly, we see similar kinds of resonance patterns in living and non-living structures of many types. What clues can resonance provide about the nature of consciousness more generally? This paper provides an overview of resonating structures in the fields of neuroscience, biology and physics and attempts to coalesce these data into a solution to what we see as the “easy part” of the Hard Problem, which is generally known as the “combination problem” or the “binding problem.” The combination problem asks: how do micro-conscious entities combine into a higher-level macro-consciousness? The proposed solution in the context of mammalian consciousness suggests that a shared resonance is what allows different parts of the brain to achieve a phase transition in the speed and bandwidth of information flows between the constituent parts. This phase transition allows for richer varieties of consciousness to arise, with the character and content of that consciousness in each moment determined by the particular set of constituent neurons. We also offer more general insights into the ontology of consciousness and suggest that consciousness manifests as a relatively smooth continuum of increasing richness in all physical processes, distinguishing our view from emergentist materialism. We refer to this approach as a (general) resonance theory of consciousness and offer some responses to Chalmers’ questions about the different kinds of “combination problem.”  At the heart of the universe is a steady, insistent beat: the sound of cycles in sync…. [T]hese feats of synchrony occur spontaneously, almost as if nature has an eerie yearning for order. Steven Strogatz, Sync: How Order Emerges From Chaos in the Universe, Nature and Daily Life (2003) If you want to find the secrets of the universe, think in terms of energy, frequency and vibration.Nikola Tesla (1942) I.               Introduction Is there an “easy part” and a “hard part” to the Hard Problem of consciousness? In this paper, we suggest that there is. The harder part is arriving at a philosophical position with respect to the relationship of matter and mind. This paper is about the “easy part” of the Hard Problem but we address the “hard part” briefly in this introduction.  We have both arrived, after much deliberation, at the position of panpsychism or panexperientialism (all matter has at least some associated mind/experience and vice versa). This is the view that all things and processes have both mental and physical aspects. Matter and mind are two sides of the same coin.  Panpsychism is one of many possible approaches that addresses the “hard part” of the Hard Problem. We adopt this position for all the reasons various authors have listed (Chalmers 1996, Griffin 1997, Hunt 2011, Goff 2017). This first step is particularly powerful if we adopt the Whiteheadian version of panpsychism (Whitehead 1929).  Reaching a position on this fundamental question of how mind relates to matter must be based on a “weight of plausibility” approach, rather than on definitive evidence, because establishing definitive evidence with respect to the presence of mind/experience is difficult. We must generally rely on examining various “behavioral correlates of consciousness” in judging whether entities other than ourselves are conscious – even with respect to other humans—since the only consciousness we can know with certainty is our own. Positing that matter and mind are two sides of the same coin explains the problem of consciousness insofar as it avoids the problems of emergence because under this approach consciousness doesn’t emerge. Consciousness is, rather, always present, at some level, even in the simplest of processes, but it “complexifies” as matter complexifies, and vice versa. Consciousness starts very simple and becomes more complex and rich under the right conditions, which in our proposed framework rely on resonance mechanisms. Matter and mind are two sides of the coin. Neither is primary; they are coequal.  We acknowledge the challenges of adopting this perspective, but encourage readers to consider the many compelling reasons to consider it that are reviewed elsewhere (Chalmers 1996, Griffin 1998, Hunt 2011, Goff 2017, Schooler, Schooler, & Hunt, 2011; Schooler, 2015).  Taking a position on the overarching ontology is the first step in addressing the Hard Problem. But this leads to the related questions: at what level of organization does consciousness reside in any particular process? Is a rock conscious? A chair? An ant? A bacterium? Or are only the smaller constituents, such as atoms or molecules, of these entities conscious? And if there is some degree of consciousness even in atoms and molecules, as panpsychism suggests (albeit of a very rudimentary nature, an important point to remember), how do these micro-conscious entities combine into the higher-level and obvious consciousness we witness in entities like humans and other mammals?  This set of questions is known as the “combination problem,” another now-classic problem in the philosophy of mind, and is what we describe here as the “easy part” of the Hard Problem. Our characterization of this part of the problem as “easy”[2] is, of course, more than a little tongue in cheek. The authors have discussed frequently with each other what part of the Hard Problem should be labeled the easier part and which the harder part. Regardless of the labels we choose, however, this paper focuses on our suggested solution to the combination problem.  Various solutions to the combination problem have been proposed but none have gained widespread acceptance. This paper further elaborates a proposed solution to the combination problem that we first described in Hunt 2011 and Schooler, Hunt, and Schooler 2011. The proposed solution rests on the idea of resonance, a shared vibratory frequency, which can also be called synchrony or field coherence. We will generally use resonance and “sync,” short for synchrony, interchangeably in this paper. We describe the approach as a general resonance theory of consciousness or just “general resonance theory” (GRT). GRT is a field theory of consciousness wherein the various specific fields associated with matter and energy are the seat of conscious awareness.  A summary of our approach appears in Appendix 1.  All things in our universe are constantly in motion, in process. Even objects that appear to be stationary are in fact vibrating, oscillating, resonating, at specific frequencies. So all things are actually processes. Resonance is a specific type of motion, characterized by synchronized oscillation between two states.  An interesting phenomenon occurs when different vibrating processes come into proximity: they will often start vibrating together at the same frequency. They “sync up,” sometimes in ways that can seem mysterious, and allow for richer and faster information and energy flows (Figure 1 offers a schematic). Examining this phenomenon leads to potentially deep insights about the nature of consciousness in both the human/mammalian context but also at a deeper ontological level.

Susanne Schilling*^

and 9 more

Jessica mead

and 6 more

The construct of wellbeing has been criticised as a neoliberal construction of western individualism that ignores wider systemic issues including increasing burden of chronic disease, widening inequality, concerns over environmental degradation and anthropogenic climate change. While these criticisms overlook recent developments, there remains a need for biopsychosocial models that extend theoretical grounding beyond individual wellbeing, incorporating overlapping contextual issues relating to community and environment. Our first GENIAL model \cite{Kemp_2017} provided a more expansive view of pathways to longevity in the context of individual health and wellbeing, emphasising bidirectional links to positive social ties and the impact of sociocultural factors. In this paper, we build on these ideas and propose GENIAL 2.0, focusing on intersecting individual-community-environmental contributions to health and wellbeing, and laying an evidence-based, theoretical framework on which future research and innovative therapeutic innovations could be based. We suggest that our transdisciplinary model of wellbeing - focusing on individual, community and environmental contributions to personal wellbeing - will help to move the research field forward. In reconceptualising wellbeing, GENIAL 2.0 bridges the gap between psychological science and population health health systems, and presents opportunities for enhancing the health and wellbeing of people living with chronic conditions. Implications for future generations including the very survival of our species are discussed.  

Mark Ferris

and 14 more

IntroductionConsistent with World Health Organization (WHO) advice [1], UK Infection Protection Control guidance recommends that healthcare workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) should use fluid resistant surgical masks type IIR (FRSMs) as respiratory protective equipment (RPE), unless aerosol generating procedures (AGPs) are being undertaken or are likely, when a filtering face piece 3 (FFP3) respirator should be used [2]. In a recent update, an FFP3 respirator is recommended if “an unacceptable risk of transmission remains following rigorous application of the hierarchy of control” [3]. Conversely, guidance from the Centers for Disease Control and Prevention (CDC) recommends that HCWs caring for patients with COVID-19 should use an N95 or higher level respirator [4]. WHO guidance suggests that a respirator, such as FFP3, may be used for HCWs in the absence of AGPs if availability or cost is not an issue [1].A recent systematic review undertaken for PHE concluded that: “patients with SARS-CoV-2 infection who are breathing, talking or coughing generate both respiratory droplets and aerosols, but FRSM (and where required, eye protection) are considered to provide adequate staff protection” [5]. Nevertheless, FFP3 respirators are more effective in preventing aerosol transmission than FRSMs, and observational data suggests that they may improve protection for HCWs [6]. It has therefore been suggested that respirators should be considered as a means of affording the best available protection [7], and some organisations have decided to provide FFP3 (or equivalent) respirators to HCWs caring for COVID-19 patients, despite a lack of mandate from local or national guidelines [8].Data from the HCW testing programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT) during the first wave of the UK severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic indicated a higher incidence of infection amongst HCWs caring for patients with COVID-19, compared with those who did not [9]. Subsequent studies have confirmed this observation [10, 11]. This disparity persisted at CUHNFT in December 2020, despite control measures consistent with PHE guidance and audits indicating good compliance. The CUHNFT infection control committee therefore implemented a change of RPE for staff on “red” (COVID-19) wards from FRSMs to FFP3 respirators. In this study, we analyse the incidence of SARS-CoV-2 infection in HCWs before and after this transition.

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Mauricio Herrera

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INTRODUCTIONTrisomy 9 is a rare genetic alteration that represents 2.7% of all trisomies. (1,2,7) It was reported for the first time in 1973 by Feingold and Atkins, through the study of lymphocytes in the blood of a male newborn, with multiple congenital anomalies (4,5). Complete gain of chromosome 9 has a fatal prognosis and usually results in first trimester miscarriage. (2) However, in exceptional cases, pregnancies that reach term die in the early neonatal period (4).From the cytogenetic point of view, cases of trisomy 9 present completely, which is not mosaicism, or in a state of mosaicism. The spectrum of this syndrome, in addition to trisomy 9, includes partial trisomies of the short arm 9p, of the long arm 9q, mosaicisms, mosaicisms confined to the placenta and pseudo mosaicisms. (4,5). In the case of trisomy 9, most correspond to de novo mutations. Mosaicisms are related to balanced rearrangement mutations (5). However, phenotypic heterogeneity, as well as the incidence and severity of associated malformations, are directly related to the variable size of the duplicated segment and the frequent concomitant monosomy (2,3,4,6).Most of the cases of trisomy 9 reported in the literature occurred in women under 35 years of age, which makes evident the usefulness of screening for congenital anomalies, even in low-risk populations (1,2). Fetal screening in the first and second trimesters allows early detection of fetal structural abnormalities associated with genetic alterations. In this way, it offers the opportunity to advise the patient, with the aim of carrying out early interventions regarding the prenatal prognosis and postnatal management, even if it is available and for this specific case, the interruption of the pregnancy. (1)(6).This chromosomal abnormality is characterized by a constellation of multiple phenotypic abnormalities that mainly involve craniofacial, central nervous system, cardiovascular, musculoskeletal, and genitourinary abnormalities (1,4,5,7). The main structural anatomical alterations include, for ultrasound screening at 11-13.6 weeks, an increase in the thickness of nuchal translucency (1), then microcephaly and brachycephaly become evident, fontanelles and wide cranial sutures, bulbous nose, lip and cleft palate, short nasolabial fold , hypertelorism, micro-retrognathia, short and wide neck and low implantation of the ears. In the central nervous system, it is common to find associated Dandy Walker Malformation characterized by hydrocephalus, alterations in the development of the cerebellar vermis and ventriculomegaly (4,2). At the cardiovascular level, it is common to find ventricular septal defects, cardiomegaly, valvular dysplasia or even the right aortic arch. Regarding the musculoskeletal system, camptodactyly, clubfoot , hypoplasia or agenesis of the fingers and nails of the hands and feet (4), and dislocation of the hip or knees can be found. In genitourinary organs, horseshoe kidney, renal hypoplasia or dysplasia as well as renal cysts, short penis or bicornuate uterus become evident . Other case reports include abnormal lung lobulation, malrotation, hypoplasia or agenesis of the gallbladder and biliary tract, and hypoplasia of the adrenal gland. In addition, this pathology incorporates within its recognition pattern growth restriction, low birth weight and delayed neurological development. (2,7) Other authors mention that, when faced with elevated serum levels of alpha-fetoprotein in the context of trisomy 9, the finding of spina bifida should be ruled out (1). Serum markers such as the free fraction of BhCG and PAPP-A are found to be decreased in concentration in trisomies 9 and 18. In addition, different abnormal phenotypic findings overlap in both chromosomopathies; however, the genetic study can discern the final diagnosis (1,4).

Ping Jin

and 5 more

Objective: Partial patients diagnosed with CIN2 on biopsy include CIN3 +.To compare the histopathological results before and after conization of CIN2 for exploring stratified management for CIN2 in women aged ≥25 years. Design: A observational retrospective study. Setting: China. Population: 307 women aged 19~40 years diagnosed as CIN2 on biopsy with cervical squamocolumnar junction visible. Methods: Compared immediate conization specimen histopathology with the biopsy histopathology,and explored the risk factors to predict CIN3 + in cone histopathology. Main outcome measures: Cone-histopathology-grading rate of CIN2. Risk factors predicting cone histopathology upgrading. Constructing an individualized algorithm for CIN2 stratified management using risk factors. Results: the cone-histopathology-upgrading rate of CIN2 was 22.5%(including one case of cervical microinvasive squamous cell carcinoma).In univariable analysis: age, HPV16/18, HSIL cytology were high-risk factors of cone histopathology upgrading(CIN3 +)(P<0.05). In multivariable analysis: HPV16/18(OR 2.399,[95%CI 1.326-4.338]) and HSIL cytology(OR 3.295,[95%CI 1.622-6.692]) were independently risk factors. Conclusion: CIN2 patients aged ≥25 years were with a higher proportion of CIN3 + and stratified treatment should be considered.Patients with HPV16/18 infection and HSIL cytology owned the highest rate of CIN3 + in the rest cervix,surgical treatment should be taken. For those with HPV16/18 infecton and ASCUS/LSIL cytology, or other high-risk HPV infection and HSIL cytology were with a relatively higher proportion of CIN3 +, treatment should be individualized. However, for patients with HPV16/18 infection and NILM cytology or other high-risk HPV infection and ASCUS/LSIL cytology, the risk of CIN3 + was relatively low,conservative treatment should be taken.

sheng lu

and 7 more

Understanding the accumulation rule of nutrients is crucial to promote the production of Camellia Oleifera. The stoichiometry of soil microelements is more critical than their content in affecting the growth and yield of plants. However, research on C. Oleifera in these aspects is limited. In this study, we examined microelement content in soil and various parts of the C. oleifera plant and analysed the relationship between the bioaccumulation, distribution, and production of plant trace elements with the stoichiometry of soil trace elements. Our findings indicated that high-yield plants transported more Ca, Mg, and B to the shoot, while low-yield plants stored higher Fe, Zn, and Al in the root. The significantly lower bioaccumulation factor and translocation factor of B and Mg in the high-yield plants highlighted the importance of nutrient storage in promoting C. Oleifera yield. Multiple regression analysis and the Mantel test demonstrated that plant yield and bioaccumulation and transportation of trace elements were more closely correlated with the stoichiometry of trace elements than their content. The significantly different stoichiometry of trace elements in soil of different yields revealed that the stoichiometry of trace elements was more sensitive and reliable in reflecting the balance in soil nutrients of C. oleifera and regulating its growth. This study provides a comprehensive understanding of the balance in soil trace elements and their relationship with the growth of C. oleifera and highlights the critical role of the stoichiometry of soil trace elements in promoting high and stable production of C. Oleifera.

Lulu Li

and 4 more

The rare inverse latitudinal diversity gradient is almost neglected compared with the dominant latitudinal diversity gradient, and the underlying mechanism of this biodiversity pattern remains elusive, especially for invertebrates. Necrophage trogid beetles are a vertebrate-dependent family group that may potentially serve as an environmental indicator, but comprehensive distributional knowledge is lacking. Here, a geographical distribution dataset of 11321 coordinates belonging to 284 species (over 80% of Trogidae) was compiled, and pairwise dependencies of trogids and vertebrates were integrated. The diversity patterns of Trogidae were revealed by calculating species richness and performing endemicity analysis. To further illustrate the underlying richness-variable relationships, the relative effects of environmental factors on the richness of trogids were investigated by random forest analysis. The hotspots of trogid species richness and areas of endemism were both located in temperate zones, together generating a rare inverse latitudinal diversity gradient in which similar height bimodal peaks appeared in the mid-latitude temperate zone (near 30°S and 40°N). Climatic conditions and food availability combined to explain 21.94% of the variance in global trogid richness. This work first reported the global diversity pattern of necrophagous beetles at the specimen grade and supported the ‘resource-dependent hypothesis’. And the case study in trogids provides valuable insights into inverse latitudinal diversity gradient patterns. The loose linkage of trogids and vertebrates is another interesting insight, with implications for carefully using trogids as an indicator of vertebrate distribution.

Isaac W. Park

and 5 more

Forecasting the impacts of changing climate on the phenology of plant populations is essential for anticipating and managing potential ecological disruptions to biotic communities. Herbarium specimens enable assessments of plant phenology across broad spatiotemporal scales. However, specimens are collected opportunistically, and it is unclear whether their collection dates—used as proxies of phenology—are closest to the onset, peak, or termination of a phenophase, or whether sampled individuals represent early, average, or late occurrences in their populations. Despite this, no studies have assessed whether these uncertainties limit the utility of herbarium specimens for estimating the onset and termination of a phenophase. Using simulated data mimicking such uncertainties, we evaluated the accuracy with which the onset and termination of population-level phenological displays (in this case, of flowering) can be predicted from natural-history collections data (in the absence of other biases not evaluated here), and how attributes of the flowering period of a species and temporal collection biases influence model accuracy. Estimates of population-level onset and termination were highly accurate for a wide range of simulated species’ attributes, but accuracy declined among species with longer individual-level flowering duration and when there were temporal biases in sample collection, as is common among the earliest and latest-flowering species. The amount of data required to model population-level phenological displays is not impractical to obtain; model accuracy declined by less than 1 day as sample sizes rose from 300 to 1000 specimens. Our analyses of simulated data indicate that, absent pervasive biases in collection and if the climate conditions that affect phenological timing are correctly identified, then specimen data can predict the onset, termination, and duration of a population’s flowering period with similar accuracy to estimates of median flowering time that are commonplace in the literature.

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Shen Shen

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Optimizing the spatial configuration of diverse best management practices (BMPs) can provide valuable decision-making support for comprehensive watershed management. Most existing methods focus on selecting BMP types and locations but neglect their implementation time or order in management scenarios, which are often investment-restricted. This study proposes a new simulation-optimization framework for determining the implementation plan of BMPs by using the net present value to calculate the economic costs of BMP scenarios and the time-varying effectiveness of BMPs to evaluate the environmental effectiveness of BMP scenarios. The proposed framework was implemented based on a Spatially Explicit Integrated Modeling System and demonstrated in an agricultural watershed case study. This case study optimized the implementation time of four erosion control BMPs in a specific spatial configuration scenario under a 5-year stepwise investment process. The proposed method could effectively provide more feasible BMP scenarios with a lower overall investment burden with only a slight loss of environmental effectiveness. Time-varying BMP effectiveness data should be gathered and incorporated into watershed modeling and scenario optimization to better depict the environmental improvement effects of BMPs over time. The proposed framework was sufficiently flexible to be applied to other technical implementations and extensible to more actual application cases with sufficient BMP data. Overall, this study demonstrated the basic idea of extending the spatial optimization of BMPs to a spatiotemporal level by considering stepwise investment, emphasizing the value of integrating physical geographic processes and anthropogenic influences.

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