A newly emerged coronavirus (COVID-19) seriously threatens human life and health worldwide. In coping and fighting against COVID-19, the most critical step is to effectively screen and diagnose infected patients. Among them, chest X-ray imaging technology is a valuable imaging diagnosis method. The use of computer-aided diagnosis to screen X-ray images of COVID-19 cases can provide experts with auxiliary diagnosis suggestions, which can reduce the burden of experts to a certain extent. In this study, we first used conventional transfer learning methods, using five pre-trained deep learning models, which the Xception model showed a relatively ideal effect, and the diagnostic accuracy reached 96.75%. In order to further improve the diagnostic accuracy, we propose an efficient diagnostic method that uses a combination of deep features and machine learning classification. It implements an end-to-end diagnostic model. The proposed method was tested on two datasets and performed exceptionally well on both of them. We first evaluated the model on 1102 chest X-ray images. The experimental results show that the diagnostic accuracy of Xception + SVM is as high as 99.33%. Compared with the baseline Xception model, the diagnostic accuracy is improved by 2.58%. The sensitivity, specificity and AUC of this model reached 99.27%, 99.38% and 99.32%, respectively. To further illustrate the robustness of our method, we also tested our proposed model on another dataset. Finally also achieved good results. Compared with related research, our proposed method has higher classification accuracy and efficient diagnostic performance. Overall, the proposed method substantially advances the current radiology based methodology, it can be very helpful tool for clinical practitioners and radiologists to aid them in diagnosis and follow-up of COVID-19 cases.

Here, we demonstrate that loss of DRAK2 signaling significantly promotes the acceptance of allogeneic engraftment in two separate transplant models without promoting generalized immunosuppression. Drak2-/- T cells failed to reject allogeneic tumors, and were defective in rejecting Balb/C allogeneic skin grafts on C57BL6/J recipients. A significant fraction of alloreactive Drak2-/- T cells underwent apoptosis following activation, whereas enforced expression of Bcl-xL in Drak2-/- T cells restored allograft rejection. Formation of allogeneic memory was also greatly hampered in T cells lacking the Drak2 gene. Adoptive transfer of memory T cells from Drak2-/- mice failed to promote the rejection of allogeneic tumors, and such cells led to significantly delayed rejection of skin allografts in the Balb/C->C57BL/6J model. Costimulatory blockade by in vivo administration of Cytotoxic T-Lymphocyte Antigen 4 fusion protein (CTLA4-Ig) synergized with the DRAK2 deficiency and led to long-term allogeneic skin graft acceptance. Overall, these results demonstrate that DRAK2 plays an important role in primary and memory T cell responsiveness to allografts. Because previous studies have demonstrated that a loss of DRAK2 does not negatively impact antiviral immunity, the studies here underscore the potential utility of pharmacological blockade of DRAK2 to achieve transplant maintenance without the imposition of generalized immunosuppression.

Background: Aerosol delivery via high-flow nasal cannula (HFNC) has attracted clinical interests in recent years. However, both HFNC and nebulization are categorized as aerosol generating procedures (AGPs). In-vitro studies raised concerns that AGPs had high transmission risk. Very few in-vivo studies examined fugitive aerosols with HFNC and nebulization via HFNC, and effective methods to mitigate aerosol dispersion are unknown.Method: Two HFNC devices (Airvo2 and Vapotherm) with or without a vibrating mesh nebulizer (VMN) were compared; HFNC alone, surgical mask over HFNC interface, and HFNC with face tent scavenger were used in a random order for nine healthy volunteers. Fugitive aerosol concentrations at sizes of 0.3-10 m were continuously measured by particle sizers placed at one and three feet from participants. On a different day, six of the nine participants received six additional nebulizer treatments via VMN or small volume nebulizer (SVN) with mouthpiece with/without an expiratory filter or facemask. In-vitro simulation was employed to quantify inhaled dose with VMN via Airvo2 and Vapotherm.Results: Compared to baseline, neither HFNC device generated higher aerosol concentrations. Compared to HFNC alone, VMN via Airvo2 generated higher 0.3-1.0 m particles (all p<.05) but VMN via Vapotherm did not. Concentrations of 1.0-3.0 m particles with VMN via Airvo2 were similar with VMN and a mouthpiece/facemask but lower than SVN with a mouthpiece/facemask (all p<.05). Placing a surgical mask over HFNC during nebulization reduced 0.5-1.0 m particles (all p<.05) to levels similar to the use of a nebulizer with mouthpiece and expiratory filter. In-vitro the inhaled dose with VMN via Airvo2 was 6 times higher than VMN via Vapotherm.Conclusion: During aerosol delivery via HFNC, Airvo2 generated higher inhaled dose and consequently higher fugitive aerosols than Vapotherm. Simple measures, such as placing a surgical mask over nasal cannula during nebulization via HFNC, could effectively reduce fugitive aerosol concentrations.

Deep-learning techniques have led to technological progress in the area of medical imaging segmentation especially in the ultrasound domain. In this paper, the main goal of this study is to optimize a deep-learning-based neural network architecture for automatic segmentation in Ultrasonic Computed Tomography (USCT) bone images in a short time process. The proposed method is based on an end to end neural network architecture. First, the novelty is shown by the improvement of Variable Structure Model of Neuron (VSMN), which is trained for both USCT noise removal and dataset augmentation. Second, a VGG-SegNet neural network architecture is trained and tested on new USCT images not seen before for automatic bone segmentation. Therefore, we offer a free USCT dataset. In addition, the proposed model is implemented on both the CPU and the GPU, hence overcoming previous works by a value of 97.38% and 96% for training and validation and achieving high segmentation accuracy for testing with a small error of 0.006, in a short time process. The suggested method demonstrates its ability to augment USCT data and then to automatically segment USCT bone structures achieving excellent accuracy outperforming the state of the art.

BACKGROUND Limited data guide the prediction of weight loss success or failure after bariatric surgery according to presurgery factors. There is significant variation in weight change after bariatric surgery and much interest in identifying preoperative factors that may contribute to these differences. This report evaluates the associations of a comprehensive set of baseline factors and 3-year weight change. SETTING Ten hospitals in 6 geographically diverse clinical centers in the United States. METHODS Adults undergoing a first bariatric surgical procedure as part of clinical care by participating surgeons were recruited between 2006 and 2009. Participants completed research assessments utilizing standardized and detailed data collection on over 100 preoperative and operative parameters for individuals undergoing Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). Weight was measured 3 years after surgery. Percent weight change for RYGB or LAGB from baseline to 3 years was analyzed as both a continuous and dichotomous outcome with cut points at 25% for RYGB and 10% for LAGB. Multivariable linear and logistic regression models were used to identify independent baseline predictors of the continuous and categorical outcomes, respectively. RESULTS The median weight loss 3 years after surgery for RYGB (n = 1513) participants was 31.5% (IQR: 24.6%-38.4%; range, 59.2% loss to .9% gain) of baseline weight and 16.0% (IQR: 8.1%-23.1%; range, 56.1% loss to 12.5% gain) for LAGB (n = 509) participants. The median age was 46 years for RYGB and 48 years for LAGB; 80% of RYGB participants and 75% of LAGB participants were female; and the median baseline body mass index (BMI) was 46 kg/m(2) for RYGB and 44 kg/m(2) for LAGB. For RYGB, black participants lost 2.7% less weight compared with whites and participants with diabetes at baseline had 3.7% less weight loss at year 3 than those without diabetes at baseline. There were small but statistically significant differences in weight change for RYGB in those with abnormal kidney function and current or recent smoking. For LAGB participants, those with a large band circumference had 75% greater odds of experiencing less than 10% weight loss after adjusting for BMI and sex. CONCLUSIONS Few baseline variables were associated with 3-year weight change and the effects were small. These results indicate that baseline variables have limited predictive value for an individual's chance of a successful weight loss outcome after bariatric surgery. TRIAL REGISTRATION NCT00465829, ClinicalTrials.gov.

Background A high proportion of COVID-19 patients develop acute liver dysfunction. Early research has suggested that pre-existing fatty liver disease may be a significant risk factor for hospitalisation. Liver fat, in particular, is a modifiable parameter and can be a target for public health policy and individual patient plans. In this study we aimed to assess pre-existing liver disease as a risk factor for developing symptomatic COVID-19. Methods From 502,506 participants from the UK Biobank, 42,146 underwent MRI (aged 45-82), and had measures of liver fat, liver fibroinflammatory disease and liver iron. Patients were censored on May 28th to determine how many had tested for COVID-19 with symptomatic disease. UK testing was restricted to those with symptoms in hospital. COVID-19 symptoms included fever, dry cough, sore throat, diarrhoea and fatigue. Univariate analysis was performed on liver phenotypic biomarkers to determine if these variables increased risk of symptomatic COVID-19, and compared to previously described risk factors associated with severe COVID-19, including to age, ethnicity, gender and obesity, Findings Increased liver fat was associated with a higher risk for symptomatic confirmed COVID-19 in this population in univariate analysis(OR:1.85, p=0.03). In obese participants, only those with concomitant fatty liver([]10%) were at increased risk(OR:2.96, p=0.02), with those having normal liver fat (<5%) showing no increased risk(OR:0.36, p=0.09). Conclusions UK Biobank data demonstrated an association between pre-existing liver disease and obesity with severe COVID-19, with higher proportions of liver fat in obese individuals a likely risk factor for symptomatic disease and severity. Public policy measures to protect patients with liver disease who may have almost double the risk of the general population should be considered, especially as dietary and pharmacological strategies to reduce body weight and liver fat already exist. Funding University of Oxford, Innovate UK, UK Biobank. Authors are employees of Perspectum Ltd.

The origin and spread of current novel coronavirus had raised serious concerns among stakeholders around the globe Different speculations that may unfold the mystery in the future are taking roots, but now there is no globally acceptable opinion about the origin and spread of this novel coronavirus It is reported that Wuhan city of Hubei Province of central China was the epicenter of this outbreak of novel coronavirus However, initial inadequate preventive measures allowed the infection to cross the borders of China and that pulls the world into drastic public health and economic crisis This coronavirus disease now named as COVID-19 by World Health Organization (WHO) and the responsible coronavirus is named as "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) " The spread of SARS-CoV-2 is alarming even after 5 months of inception and WHO further warns the world to be prepared for more intense spread of COVID-19 Different diagnostic tools to detect SARS-CoV-2 are being used around the globe, but the identification of asymptomatic carriers of the disease is a serious challenge in countering the COVID-19 pandemic There is no specific treatment available, only preventive, symptomatic, and supportive treatments are being used for clinical management of COVID-19 The available knowledge is limited, therefore, any escalation of information on the disease will help to combat this global challenge of COVID-19 In this review, we have discussed and summarized the available multi-factorial information and recent updates on the SARS-CoV-2 which can help support future research and may help in the strategic management of the current COVID-19 pandemic The articles available online before June 30, 2020, on bioRxiv, medRxiv, ChemRxiv, Google Scholar, and PubMed have been assessed for the compilation of this review Information on the official portal of WHO, CDC, ICMR, etc , were also assessed and used with due credit

COVID-19 is a new disease which mainly presents with respiratory symptoms, however can present with a multitude of signs and symptoms affecting various body systems. Several oral manifestations related to COVID-19 have also been reported. We carried out a systematic review to explore the types of oral mucosal lesions that have been reported in COVID-19 related literature up to the date of 25th of March 2021. A structured electronic databases search using Medline, Embase and CINAHL as well as gray literature search using Google Scholar revealed a total of 322 studies. After removal of duplicates and the primary and secondary filtering process, 12 studies were included for final appraisal. We have identified several different types of oral mucosal lesions in patients with COVID-19 infection, present at various locations within the oral cavity. Most of the studies appraised in this review were of high risk of bias according to the Joanna Briggs Institute checklist. The current published literature does not allow differentiation as to whether the oral lesions are caused by the viral infection itself or instead related to oral manifestations secondary to existing patient comorbidities or treatment instigated to combat the disease. It is important for healthcare professionals to be aware of the possible link between COVID-19 and oral mucosal lesions, and we hereby discuss our findings.

Plasma membranes fulfil many physiological functions. In polarized cells, different membrane compartments take on specialized roles, each being allocated correct amounts of membrane. The Drosophila tracheal system, an established tubulogenesis model, contains branched terminal cells with subcellular tubes formed by apical plasma membrane invagination. We show that apical endocytosis and late endosome-mediated trafficking are required for membrane allocation to the apical and basal membrane domains. Basal plasma membrane growth stops if endocytosis is blocked, whereas the apical membrane grows excessively. Plasma membrane is initially delivered apically and then continuously endocytosed, together with apical and basal cargo. We describe an organelle carrying markers of late endosomes and multivesicular bodies (MVBs) that is abolished by inhibiting endocytosis and which we suggest acts as transit station for membrane destined to be redistributed both apically and basally. This is based on the observation that disrupting MVB formation prevents growth of both compartments.

There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HtAEC) and human small airway epithelial cells (HsAEC) grown at the air-liquid interface (ALI). These cultures were infected at the apical side with one of two different SARS-CoV-2 isolates. Each virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35 C than 37 C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. Remdesivir, GS-441524 (the parent nucleoside of remdesivir), EIDD-1931 (the parent nucleoside of molnupiravir) and IFN (?1 and &#955;1) all resulted in dose-dependent inhibition of viral RNA and infectious virus titers collected at the apical side. However, AT-511 (the free base form of AT-527 currently in clinical testing) failed to inhibit viral replication in these in vitro primary cell models. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.

OBJECT Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain. METHODS This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy. RESULTS For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 0.3 vs 7.8 0.6 mm, respectively; p = 0.27) and unruptured (3.4 0.2 vs 3.2 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 296.4 vs 2910.5 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% 1.0% vs 98.2% 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% 1.1% vs. 104.1% 5.2%, respectively; p < 0.01). CONCLUSIONS For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.

? During COVID-19 lockdown, the number of radiotherapy treatments had to be reduced. ? Given number of delayed treatments, the post-crisis period should be anticipated. ? Data visualization software allowed to predict when peak activity would happen.

This study investigates the nature and magnitude of abuse in the Paycheck Protection Program (PPP or the Program) using PPP loans made to 2,999 investment advisory firms registered with the U.S. Securities and Exchange Commission (SEC). The data suggest that PPP abuse was relatively widespread as approximately 25% of firms receiving PPP loans indicated they would retain more jobs in their loan application than the number of employees they disclosed on their most recent regulatory filing (Form ADV). We show an existing model of investment advisor fraud predicts the most egregious PPP loans at a rate similar to actual cases of fraud. Investment advisors abusing the Program were significantly more likely to disclose a history of past fraud and other legal and/or regulatory misconduct. Using a conservative approach, we estimate that more than 6% of the $590 million in PPP funds received by SEC registered investment advisors consisted of overallocations to firms abusing the Program. We test a variety of hypotheses to shed further light on the nature of PPP abuse.

BACKGROUND Hyperpigmentation conditions can affect all skin types but occur more frequently in darker skin. Because many factors have been implicated in the etiologies of these disorders, multi-targeted approaches may be required to achieve a better overall outcome in a diverse patient population. AIMS The purpose of this study was to investigate the safety and efficacy of a combination regimen of a comprehensive cosmetic brightening agent (LYT2) with a broad blend of antioxidants (LVS) to reduce hyperpigmentation and improve overall skin appearance. METHODS The combination of LYT2 and LVS, in addition to a basic skincare routine, was evaluated in subjects of either Caucasian or Asian (a majority of whom were Indian) descent, presenting with moderate to severe hyperpigmentation. Efficacy evaluations consisted of investigator clinical grading of overall hyperpigmentation, skin-tone evenness, and radiance, as well as subject self-assessment questionnaires. RESULTS Immediate and progressive improvement was noted by the investigators for all assessed parameters. At the end of the 12-week study, investigators observed a 45% mean decrease from baseline for overall hyperpigmentation. In addition, a 50% improvement in skin tone evenness and a 58% increase in radiance was observed. These investigator assessments were matched by good patient scores for self-perceived efficacy parameters and high overall satisfaction. One patient (7%) showed a treatment-related adverse event. CONCLUSION A combination skincare regimen that combines the pigmentation control of LYT2 with the broad antioxidant defense of LVS is a well-tolerated and effective treatment option to improve the appearance of facial hyperpigmentation and make skin more radiant.

INTRODUCTION: It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporter substrates, it is expected that drug-drug interactions would not result in any changes in volume of distribution. METHODS: An evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug-drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms. RESULTS: Seventy-two metabolic drug interaction studies were identified where volume of distribution at steady-state (Vss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). Changes in exposure (area under the curve) up to 5.1-fold were observed; however, ratios of Vss changes have a range of 0.70-1.26, with one outlier displaying a Vss ratio of 0.57. DISCUSSION: These results support the widely held founding tenant of pharmacokinetics that clearance and Vss are independent parameters. Knowledge that Vss is unchanged in metabolic drug-drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. As Vss remains unchanged for intravenous metabolic drug-drug interactions, following oral dosing changes in Vss/F will reflect changes in F alone. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug-drug interactions are interpreted from drug development and regulatory perspectives.

In this study we argue that parasite-host infections are a major research topic because of their implications for human health, agriculture and wildlife. The evolution of infection mechanisms is a research topic in areas such as virology and ecology. Mathematical modelling has been an essential tool to obtain a better systematic and quantitative understanding of the processes of parasitic infection that are difficult to discern through strictly experimental approaches. In this article we review recent attempts using mathematical models to discriminate and quantify these infection mechanisms. We also emphasize the challenges that these models could bring to new fields of study such as social sciences and economics.

BACKGROUND: Digital technology uses in cardiology have become a popular research focus in recent years. However, there has been no published bibliometric report that analyzed the corresponding academic literature in order to derive key publishing trends and characteristics of this scientific area. OBJECTIVE: We used a bibliometric approach to identify and analyze the academic literature on digital technology uses in cardiology, and to unveil popular research topics, key authors, institutions, countries, and journals. We further captured the cardiovascular conditions and diagnostic tools most commonly investigated within this field. METHODS: The Web of Science electronic database was queried to identify relevant papers on digital technology uses in cardiology. Publication and citation data were acquired directly from the database. Complete bibliographic data were exported to VOSviewer, a dedicated bibliometric software package, and related to the semantic content of titles, abstracts, and keywords. A term map was constructed for findings visualization. RESULTS: The analysis was based on data from 12,529 papers. Of the top 5 most productive institutions, 4 were based in the United States. The United States was the most productive country (4224/12,529, 33.7%), followed by United Kingdom (1136/12,529, 9.1%), Germany (1067/12,529, 8.5%), China (682/12,529, 5.4%), and Italy (622/12,529, 5.0%). Cardiovascular diseases that had been frequently investigated included hypertension (152/12,529, 1.2%), atrial fibrillation (122/12,529, 1.0%), atherosclerosis (116/12,529, 0.9%), heart failure (106/12,529, 0.8%), and arterial stiffness (80/12,529, 0.6%). Recurring modalities were electrocardiography (170/12,529, 1.4%), angiography (127/12,529, 1.0%), echocardiography (127/12,529, 1.0%), digital subtraction angiography (111/12,529, 0.9%), and photoplethysmography (80/12,529, 0.6%). For a literature subset on smartphone apps and wearable devices, the Journal of Medical Internet Research (20/632, 3.2%) and other JMIR portfolio journals (51/632, 8.0%) were the major publishing venues. CONCLUSIONS: Digital technology uses in cardiology target physicians, patients, and the general public. Their functions range from assisting diagnosis, recording cardiovascular parameters, and patient education, to teaching laypersons about cardiopulmonary resuscitation. This field already has had a great impact in health care, and we anticipate continued growth.

The first mitigation response to the Covid-19 pandemic was to limit person-to-person interaction as much as possible. This was implemented by the temporary closing of many workplaces and people were required to follow social distancing. Networks are a great way to represent interactions among people and the temporary severing of these interactions. Here, we present a network model of human-human interactions that could be mediators of disease spread. The nodes of this network are individuals and different types of edges denote family cliques, workplace interactions, interactions arising from essential needs, and social interactions. Each individual can be in one of four states: susceptible, infected, immune, and dead. The network and the disease parameters are informed by the existing literature on Covid-19. Using this model, we simulate the spread of an infectious disease in the presence of various mitigation scenarios. For example, lockdown is implemented by deleting edges that denote non-essential interactions. We validate the simulation results with the real data by matching the basic and effective reproduction numbers during different phases of the spread. We also simulate different possibilities of the slow lifting of the lockdown by varying the transmission rate as facilities are slowly opened but people follow prevention measures like wearing masks etc. We make predictions on the probability and intensity of a second wave of infection in each of these scenarios.

The COVID-19 pandemic has brought challenges that sparked a multitude of research questions at the Institutes of Family Medicine in Geneva and Lausanne This article presents a synthesis of these questions, and the research projects that have resulted from them

This positioning paper is informed by our judgment that the mainstream research on business marketing and marketing in general is losing its relevance and vigor because it views business environments as narrow markets and focuses primarily on dyadic business relationships and their management Sticking to this limited, economics-driven market view has detached the discipline from major real-world phenomena, leaving it with scant understanding of the contemporary environmental context of marketing and business strategy Based on a focused reading of literature on business fields, business networks, business ecosystems, and market systems, we venture our own comprehensive theoretical framing of complex business environments summarized in two frameworks In the pursuit of relevance our integration is avowedly simplifying as we strive for parsimony Key points explicate the nested, multi-layered, multimodal, transitional and conditioned character of the business environment, and the dynamics, phases and processes of the evolution of that nested environment We use the frameworks constructed, which form an initial theory of complex business environments, to supply a research agenda for business marketing and offer brief managerial conclusions