Psychosis has been associated with neural anomalies across a number of brain regions and cortical networks. Nevertheless, the exact pathophysiology of the disorder remains unclear. Aberrant visual perceptions such as hallucinations are evident in psychosis, while the occurrence of visual distortions is elevated in individuals with genetic liability for psychosis. The overall goals of this project are to: (1) use psychophysical tasks and neuroimaging to characterize deficits in visual perception; (2) acquire a mechanistic understanding of these deficits through development and validation of a computational model; and (3) determine if said mechanisms mark genetic liability for psychosis. Visual tasks tapping both low- and high-level visual processing are being completed as individuals with psychotic disorders (IPD), first-degree biological siblings of IPDs (SibIPDs) and healthy controls (HCs) undergo 248-channel magneto-encephalography (MEG) recordings followed by 7 Tesla functional magnetic resonance imaging (MRI). By deriving cortical source signals from MEG and MRI data, we will characterize the timing, location and coordination of neural processes. We hypothesize that IPDs prone to visual hallucinations will exhibit deviant functions within early visual cortex, and that aberrant contextual influences on visual perception will involve higher-level visual cortical regions and be associated with visual hallucinations. SibIPDs who experience visual distortions—but not hallucinations—are hypothesized to exhibit deficits in higher-order visual processing reflected in abnormal inter-regional neural synchronization. We hope the results lead to the development of targeted interventions for psychotic disorders, as well as identify useful biomarkers for aberrant neural functions that give rise to psychosis. At present, abnormal neural functions that give rise to psychotic experiences remain poorly understood. As a result, present pharmacological and behavioral interventions remain unguided by etiologic mechanisms ,2. A proLess severe aberrations are often described as visual distortions. Visual distortions are more common than visual hallucinations ; their iThe purpose of the proposed work is to combine measures of scene segmentation and surround suppression behaviors as a measure of perceptual organization in schizophrenia. Surround suppression tasks are thought to (1) involve gain control mechanisms in early visual cortex ; and (2)It has been suggested that early visual processing is partially dependent on local gain control mechanisms ,31, coupSchwartz and colleagues  found thThe primary goals of the proposed work are to use psychophysical tasks and neuroimaging techniques to (1) precisely characterize behavioral and neural abnormalities in individuals with psychotic disorders during visual perception; (2) acquire a mechanistic understanding of these abnormalities through development and validation of a computational model; and (3) determine if said mechanisms mark genetic liability for psychosis .Herein, we propose to examine the neural mechanisms underlying visual hallucinations and distortions in individuals with a psychotic disorder (IPDs) and first-degree biological siblings of individuals with a psychotic disorder (SibIPDs) and healthy controls (HC). The cortical networks underlying vision constitute some of the best-understood mechanisms within cognitive neuroscience—nearly a third of human cortex is devoted to visual processing . PresentBy studying individuals that vary along the psychosis spectrum , as well as individuals with intermediate clinical phenotypes , we can determine how dimensional variation along the psychosis spectrum differentially influences the manifestation of visual hallucinations and visual distortions/illusions. The proposed work has the following specific aims:improved accuracy on a surround suppression task ; H2: Reduced intracortical connectivity within visual cortex , will be reflected in aberrant detection of co-linearity between visual elements and poor suppression of irrelevant elements of a visual scene; H3: Reduced activity in more anterior visual brain regions  and early visual cortex, will be characterized by deviant object identification due to weak use of high-level object templates to identify relevant targets in ambiguous scenes.H1: Individuals prone to visual hallucinations have reduced gain control in neural circuits of early visual cortex , which will be reflected by H4: IPDs prone to visual hallucinations will exhibit stable neural abnormalities in early visual cortex , and will be associated with errors in processing visual elements in simple scenes; H5: Visual hallucinations result in IPDs when long-range influences from “higher-order” brain regions  visual percepts are deviant, and will be reflected by anomalous inter-regional synchronization within theta/gamma frequencies; H6: SibIPDs prone to anomalous visual distortions will share this stable decrement in long-range influences on visual perception reflected in anomalous inter-regional synchronization in theta/gamma frequencies.H7: Reduced surround suppression in IPDs  can be characterized as a reduction in local gain control strength; there will be no contribution of intra-regional coordination; H8) Deficits in attention regulation and perception of complex scenes in IPDs and SibIPDs cannot be explained merely by reduced gain control and require an additional term describing reduced efficacy of long-range  projections.The proposed work has several notable innovations. First, the assessment of early visual processing through behavioral task performance and attentional manipulations in the same individuals within a single study will elucidate the proportional influences of local and long-range mechanisms on self-reported visual hallucinations and distortions. Second, most visual psychophysical tasks employ an adaptive staircase procedure in order to individualize difficulty level to equate performance across subjects; doing so eliminates the generalized deficit confound that would be expected in IPDs (and to some extent SibIPDs), thereby equating true score variance across tasks. Third, combined use of 248-channel MEG and 7T fMRI to derive cortical source signals for retinotopically mapped areas of striate cortex will optimize both spatial and temporal resolution allowing for dynamic comparisons of neural responses across levels of visual processing. Fourth, quantitative modeling will parameterize the determinants of subjects’ visual percepts during specialized psychophysical tasks and allow integration of experimental findings across tasks, groups, and modalities. Fifth, MEG-derived cortical source signals will allow investigation of the interdependence between theta and gamma frequencies in occipital and other cortices during visual processing. Sixth, use of the Reduced Interference Distribution (RID) time frequency (TF) transform will yield a precise characterization of the timing of select frequency band activity ,44; thisThis is an R01 currently in its third year. Dr. Scott Sponheim is the Principal Investigator. There are two sites: the Minneapolis VA Health Care System and the University of Minnesota’s Center for Magnetic Resonance Research (CMRR). Participants are recruited through the Minneapolis VA, and community-based providers in the Twin Cities area. Subjects complete psychophysical tasks, and undergo behavioral, clinical and cognitive assessment at the Minneapolis VA. Subjects undergo magneto-encephalography (MEG) scans while completing psychophysical tasks within the Brain Sciences Center at the VA. Participants undergo 7T MRI scanning at the CMRR, in addition to completing additional psychophysical tasks. In order to assess the role of altered visual perception in psychotic symptomatology, IPDs will have 4- and 8-month follow-up appointments for both MEG and MRI. Dr. Cheryl Olman oversees both 7T fMRI analyses, including retinotopic mapping of visual cortex and functional localization of other visual regions , as well as the implementation of psychophysical tasks and neural network models. Dr. Seung Suk-Kang oversees both MEG analyses, and the derivation of cortical source signals using Ti-weighted structural scans. Dr. Nathaniel Helwig will oversee statistical analyses, and provide consultation on quantitative methods related to MRI and MEG analyses.Total study enrollment will include 150 subjects total: 50 IPDs who are receiving outpatient or community-based mental health services, 50 SibIPDs, and 50 HCs. All participants will complete a clinical assessment protocol that will document current and lifetime symptomatology as well as perceptual illusions. For In order to assess symptom domains in IPDs, SibIPDs, and HCs, a trained and supervised research staff, a clinical psychology doctoral student, or a doctoral-level psychologist, completes the Structured Clinical Interview for DSM-IV  for eacBased on the SCID, chart information, study staff complete initial ratings of symptomatology using the Scale for the Assessment of Negative Symptoms (SANS: ) and theBecause the proposed work focuses on hallucinatory phenomena and includes individuals with intermediate levels of symptomatology  we will also rely on dimensional measures that span from health to disorder . While current measures of psychotic symptomatology are derived from clinician-ratings , lifetime symptomatology is characterized with the Operational Criteria Checklist  informeAlthough the primary focus of the work is the dimensional assessment of psychotic symptomatology, diagnoses will secondarily be assigned according to DSM criteria through a consensus process involving at least two trained advanced degree clinical psychology students, or doctoral level psychologists, and include the review of a subject’s interview, symptom ratings, chart review, and informant information whenever possible. The diagnostic method will approximate the best-estimate approach as articulated by Leckman et al. . Dr. SpoWe will include a small set of measures to assess general cognitive functioning and test for select deficits in IPDs and SibIPDs. Intellectual ability will be estimated from the Wide Range Achievement Test III , and perThe task has been described previously ,63. BrieFor a detailed description of the task, please see Nuechterlein & Asarnow . The tasIn order to characterize basic visual functions in IPDs, SibIPDs, and HCs, we measure contextual modulation of perceived contrast of naturalistic textures . ParticiThe development of the FAOT is detailed in Olman et al. . The tasy is self-reported visual distortions , “contrast” represents the performance on BBSS, and both scene statistics , and “object identity”  are indicative of performance on FAOT. f is the unknown function linking the perceptual task performance to the self-reported visual hallucinations and distortions—the function estimated from the data—and e is the model error term. Using these methods, we can determine how individual and group differences in self-reported visual misperceptions relate to differences in laboratory-based tasks without a priori assumptions about the nature of the relationship. We will complement these analyses with the Simultaneous Component Analysis (SCA) model, which will allow us to capture both intraindividual and interindividual differences across numerous observations .MEG data is being collected at 1017 Hz using a 248-sensor axial gradiometer MEG system , located within an electromagnetically-shielded room in the Brain Sciences Center at the Minneapolis VA Medical Center. Environmental noise will be removed from the data by relating signals from separate reference channels to cortical channels. Eye movements are at the same sampling rate using horizontal and vertical electrooculograms  for later artifact removal. Sensor configuration and head position are obtained using a spatial digitizer. The MEG is equipped with a calibrated projector and accompanying screen to present visual stimuli.MEG data processing and analysis procedures will be conducted using custom Matlab scripts . In order to remove slow artifacts related to slow-drift noise, high-pass filtering with a cut-off of .1 Hz will be applied to the data. MEG signals will be segmented into trial periods defined in relation to task timing and trial parameters . Independent component analysis (ICA) using the Fast ICA algorithm in a custom pipeline will be used to remove additional signal artifacts . Noisy sIn order to obtain an optimal ICA decomposition and prevent underfitting or over-fitting of the 248-sensor data, dimensionality will be estimated using the Bayesian information criterion . PrinciProcedures to compute cortical source signals are summarized in the left panel of To solve the inverse problem as part of computing source signals, the leadfield matrix relating sensor space (MEG) to cortical source space (fMRI) will be created using the BrainStorm program. The inverse operator W  transmit, 32-channel receive head coil is used to acquire functional data. Anatomical reference data will be acquired in a separate scanning session at 3 Tesla. The scanner is equipped with a calibrated projector for display of visual stimuli and MR-compatible button boxes for subject response collection. Eye-tracking equipment is available and are used to verify fixation stability. Functional data are acquired with 2 s temporal resolution and 1.6 mm isotropic spatial resolution, using multiband and parallel imaging strategies to accelerate acquisition in the through-slice as well as phase-encode direction . PE-revep < 0.01. These regions of interest will be seeds for task-dependent connectivity  analyses , and FreeSurfer . The majority of the analysis will focus on ROI-based analyses in predetermined ROIs in visual cortex , in order to mitigate the multiple comparisons problem. Posterior ROIs  to asseTime-domain analysis reliably delineates neural responses that are consistently timed with a stimulus. To account for the possibility that individuals with psychosis show variability in evoked activity, we will characterize changes in frequency across time. We will use a RID algorithm to resolve time-frequency elements in EEG signals. Dr. Kang has expertise in generating RID waveforms.Statistical tests of TF energy for MEG-derived cortical source signals of functionally localized ROIs will be carried out to describe neural activity associated with regulation of early visual processes that to the formation of visual percepts, and to test whether anomalous neural responses evident in IPDs and SibIPDs predict self-reported visual hallucinations and illusions. In order to ensure that we capture effects not predicted by the proposed computational model in The model that will be used to interpret behavioral and neuroimaging data is adapted from one developed by Schwartz and colleagues, . It has Eg|c,s) and one that does not (Eg|c):iE is the channel (orientation column) tuned to the ith orientation, and p is the probability that the classical receptive field and the extraclassical receptive field belong to the same object. Thus, the p term reflects learned scene statistics encoded by extrastriate neuronal populations [p parameter as well as the gain control terms that determine Eg|c,s,  and Eg|c .Neuronal responses in primary visual cortex are estimated as a mixture of two separate neuronal populations, one of which experiences surround suppression : a scalar that reflects the size of the extra-classical receptive field, and a scalar that reflects the relative strength of local inhibition. Three additional parameters regulate the grouping probability (p): a term that represents sensitivity to relative orientation, a term that represents sensitivity to higher-order scene statistics, and a term that represents object detection. The model can be used to predict 7 experimental outcomes: suppression of perceived contrast by parallel and orthogonal similar and dissimilar textures (4), fMRI response suppression by parallel vs. orthogonal similar vs. dissimilar textures (2), and VI response modulation by object recognition (1).Two parameters regulate the local response term , and task-dependent connectivity analysis has revealed that IPD and HC differ in the relative strength of the interaction between VI and pre-frontal cortex. Thus, we will also correlate task-dependent connectivity measures from the two tasks against appropriate components of the long-range connectivity term (p) in the model to verify model estimates of the strength of the long-range grouping terms, to test the hypothesis that alterations in long-range (excitatory) neural mechanisms are altered in SibIPDs.Eg|c,s and Eg|c based on our previous findings that differences in orientation tuning of surround suppression are evident in IPDs [Classical multivariate statistics (MANOVA) will be used to assess group differences in relative fit of the model parameters. Group by term interactions of interest involve parameters  in IPDs . We willd = 0.66). From this, we estimate that group sizes of 38 with α = 0.05 and power = 0.8 would be sufficient to detect effects employing 2-tailed tests. Considering multiple regression analyses will be extensively used, the observed associations in pilot data for R2 < 0.49) were used to estimate sample size. Given that f2=R2/(1 – R2) [Preliminary studies provide data from which to estimate required sample sizes. For behavioral tasks in (1 – R2) , sample The precise etiology of hallucinations and visual distortions in psychosis is unknown. By combining psychophysical tasks, functional neuroimaging, and a computational model, this project has the potential to yield a mechanistic understanding of visual hallucinations and distortions in subjective visual experience seen across the psychosis spectrum. By including first-degree relatives, we can determine if more subtle alterations in visual experience specifically reflect genetic contributions. As a result, this study will allow ascertainment of how visual perception varies across dimensional phenotypes of psychosis noted in schizophrenia spectrum disorders and bipolar affective disorder. The knowledge derived from this research will facilitate an understanding of neural mechanisms that give rise to psychotic symptoms, and the associated functional impairments of the disorder. Our hope is that the results can be used to formulate novel targeted treatments for psychosis, develop screening tools to help predict who is likely to convert to a psychotic disorder, and guide attempts to mitigate the risk for conversion, thereby reducing the prevalence and substantial disease burden of psychosis on society.


The evidence regarding the safety and efficacy of nonoperative management is growing. However, the best treatment strategy for acute complicated appendicitis remains controversial. We aimed to evaluate the cost-effectiveness of treatment strategies for complicated appendicitis patients. This study sought to determine the most cost-effective strategy from the health care-payer’s perspective.The primary outcome was an incremental cost effectiveness ratio (ICER) using nonoperative management with or without interval laparoscopic appendectomy (ILA) as the intervention compared with operative management with emergency laparoscopic appendectomy (ELA) alone as the control. Model variables were abstracted from a literature review, and from data obtained from the hospital records of Tochigi Medical Center. Cost-effectiveness was evaluated using an ICER. We constructed a Markov model to compare treatment strategies for complicated appendicitis in otherwise-healthy adults, over a time horizon of a single year. Uncertainty surrounding model parameters was assessed via one-way- and probabilistic-sensitivity analyses. Threshold analysis was performed using the willingness-to-pay threshold set at the World Health Organization’s criterion of $107,690.Three meta-analysis were included in our analysis. Operative management cost $6075 per patient. Nonoperative management with interval laparoscopic appendectomy (ILA) cost $984 more than operative management and produced only 0.005 more QALYs, resulting in an ICER of $182,587. Nonoperative management without ILA cost $235 more than operative management, and also yielded only 0.005 additional QALYs resulting in an ICER of $45,123 per QALY. Probabilistic sensitivity analysis with 1000 draws resulted in average ICER of $172,992 in nonoperative management with ILA and $462,843 in Nonoperative management without ILA. The threshold analysis demonstrated that regardless of willingness-to-pay, nonoperative management without ILA would not be most cost-effective strategy.Nonoperative management with ILA and Nonoperative management without ILA were not cost-effective strategies compared with operative management to treat complicated appendicitis. Based on our findings, operative management remains the standard of care and nonoperative management would be reconsidered as a treatment option in complicated appendicitis from economic perspective. Appendicitis is one of the most common acute abdominal diseases and emergency surgeries . AppendePatients with complicated appendicitis undergoing immediate surgery might require larger colonic resection and have higher complication risk and longer hospital stay  5] 6]. [6].5] [. [6].5] Therefore, in Japan, there is ongoing debate over the management of complicated appendicitis, and clinicians continue to use both operative and nonoperative treatment strategies. For comparison of competing management strategies in the setting of clinical complexity, the cost-effectiveness analysis is particularly useful to assess which treatment strategy is more effective relation to its cost. To date, and to our knowledge, no study has examined the cost effectiveness of treatment strategies in patients with complicated appendicitis in Japan. Using the technique, we performed a cost-effectiveness analysis of operative management with emergency laparoscopic appendectomy (ELA) alone as the first-line therapy in patients with complicated appendicitis in a municipal hospital in Japan.For our analysis, the reference case was an adult diagnosed with complicated appendicitis with confirmatory abdominal imaging. The patient was > 18 years of age without comorbidities that would substantially increase their risk of complications from laparoscopic appendectomy and image-guided drainage. Complicated appendicitis was defined as appendiceal inflammation with the presence of appendiceal abscess, cellulitis, or extraluminal air on initial abdominal computed tomographic images.We compared the cost-effectiveness of the three following treatment strategies from a health-care payer’s perspective in Japan : (1) operative management with elective ELA, (2) initial nonoperative management with interval laparoscopic appendectomy (ILA) at 2 months, and (3) nonoperative management without ILA. Nonoperative management entailed hospitalization for 5 days with intravenous cefmetazole as a 3-day course of antibiotics. Computed tomography-guided percutaneous abscess drainage was performed if necessary. All nonoperative treatment failures regardless of the specific indication  required delayed laparoscopic appendectomy in the same hospitalization. Failures occurring after discharge were considered recurrent appendicitis, and patients with recurrent appendicitis underwent ELA.For decision analytical modeling, we used a Markov model to simulate costs, health outcomes, and cost savings while comparing the three treatment strategies Fig. . Given tProbabilities of clinical events were abstracted from a literature review Table  4] 11] [11]4] [ [11]4] . The litCosts were estimated from a health-care payer’s perspective; therefore, only direct medical costs were included. The cost of laparoscopic appendectomy is an unexplored field. Thus, careful attention was paid to the costing methodology because there is no gold standard. Therefore, for cost analysis, we used a micro-costing method in which the actual monetary health care costs are categorized within the main category: Diagnostic procedures, drugs, ward care, and operating room cost  14]. Da. Da14]. The primary measures of effectiveness in the present analysis were quality- adjusted life years (QALY) gained. To estimate total QALYs in the Markov model, QALYs were calculated by multiplying the health care-related quality of life (HRQoL) score of a disease state by the duration of time a patient spent in that disease state. We obtained the HRQoL factors from our literature review, and data are shown in Table Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio (ICER). In this analysis, we defined the willingness-to-pay (WTP) threshold based on the criterion of the World Health Organization that states that an intervention is considered cost-effective if the ICER for QALY is 1–3-fold the gross domestic product per capita . In thisWe performed several sensitivity analyses to evaluate the uncertainty and robustness of the model. For these sensitivity analyses, we selected the parameters that covered all potential areas of uncertainty, such as the probabilities, clinical costs, and health-related utility values. One-way sensitivity analyses assessed the effects of varying key model parameters on the ICER. The variation ranges were established based on the analyzed studies. For costs, we allowed values to vary by ±50% of the index value; variations in sensitivity analysis results are listed in Tables This study was approved by the local Ethics Committee on December 3rd, 2018 (number 2018110501).Compared with operative management, results showed that nonoperative management with ILA cost $984 more and yielded 0.005393 additional QALYs, resulting in an ICER of $182,587 per QALY. Similarly, Nonoperative management without ILA cost $235 more than operative management and yielded 0.00521 additional QALYs, resulting in an ICER of $45,123 per QALY. Table The tornado diagram Fig.  graphicaMonte Carlo probabilistic sensitivity analysis showed average ICERs of $172,992 per QALY for nonoperative management with ILA and $462,843 per QALY for NOM without ILA, both of which were above the threshold of $113,880 Table . Our resUncertainty regarding the cost-effectiveness results also appeared in the cost-effectiveness acceptability curve seen in Fig. In our analysis, neither nonoperative management with ILA nor nonoperative management without ILA were more cost-effective strategies in the treatment of complicated appendicitis compared with operative management, at the set threshold. Nonoperative management, with and without ILA, provide a minimal incremental benefit at a high ICER compare to operative management. Base case results demonstrated that nonoperative management without ILA was the most cost-effective strategy compared with operative management. However, probabilistic sensitivity analysis showed that nonoperative management without ILA was not a cost-effective strategy among the simulated cases. In contrast, nonoperative management with ILA was the most effective strategy, but also the most costly. Given these findings, we suggest that operative management remains the cost-effective and standard therapeutic strategy, and nonoperative management without ILA and nonoperative management with ILA may not be recommended routinely in the management of complicated appendicitis. To our knowledge, ours is the first study performing an economic analysis comparing the costs of different treatment strategies for complicated appendicitis in the Japanese public health-care system.Because of continued improvements in the quality and accessibility of computed tomography, the efficacy and feasibility of performing nonoperative management, including targeted intra-abdominal drainage, have increased. In uncomplicated appendicitis, previous studies reported that nonoperative management is successful compared to operative management. Moreover, a recent cost-effective analysis found nonoperative management without interval appendectomy was the most cost-effective strategy for acute uncomplicated appendicitis . HoweverIn complicated appendicitis, it is important to note that several studies reported higher rates of recurrence after nonsurgical treatment of up to 38% within 1 year  23]. Th. Th23]. Sensitivity analyses in our study indicated that variation in the probability and HRQoL factors for ELA with perioperative complications for complicated appendicitis had a significant influence on outcomes for both nonoperative management with ILA and nonoperative management without ILA. Therefore, we suggest that ELA and its perioperative complications is an important factor in choosing a therapeutic strategy for complicated appendicitis. Randomized control trials have reported postoperative complications following laparoscopic appendectomy for complicated appendicitis, including surgical site infections and intra-abdominal abscess, which are the most common complications following appendectomy  28]. Re. Re28]. It should be noted that no consensus exists regarding the threshold for acceptable cost per QALY ratios in Japan’s national health policy. Therefore, we adopted the World Health Organization’s WTP recommendation for ICER threshold, in our model. This metric is meant to be used solely as a common cognitive anchor rather than as a method of dictating clinical decision-making. Nevertheless, we consider our conclusions in this study robust based on the results of the sensitivity analyses. An acceptability curve showed that the probability of nonoperative management with ILA being the most cost-effective strategy was approximately 50% when WTP was $180,000. Additionally, the possibility of nonoperative management without ILA being the most cost-effective strategy was always < 20% regardless of WTP, demonstrating that both nonoperative management strategies were not cost-effective over a pragmatic range of values for Japanese health care payers. Therefore, operative management remains a standard strategy, and a price reduction would be necessary for nonoperative management strategies to be considered cost-effective.This study has several limitations. First, because we focused on cost-effectiveness for a relatively short duration, we did not consider the risk of appendiceal cancer. Some authors recommend routine interval appendectomy to rule out the possibility of malignancy rather than to avoid the risk of recurrence  32] [33 [3332] . The rolThe study concluded that nonoperative management with ILA and nonoperative management without ILA were more costly and gained slight additional utility compared with operative management in the treatment of complicated appendicitis, at the set threshold. The results of the current study support cost-effectiveness of operative management with laparoscopic appendectomy in complicated appendicitis patients.


Equitable access to healthy food is a critical challenge in urban Asia. Food safety governance promotes modern supermarkets over more traditional markets, but supermarkets are associated with unequal access to food. This study investigates how retail policies driven by food safety impact the diets of the urban poor in Hanoi, Vietnam. We do this by linking food retail infrastructures with the food shopping practices and measured dietary intake of 400 women. Our results reveal sub-optimal dietary diversity and reliance on foods sourced through traditional markets, which do not provide formal food safety guarantees. Modern channels supply formal food safety guarantees, but are mainly frequented for purchasing ultra-processed foods. The paper uncovers a conflicting duality governing food security and suggests that the public responsibility for ensuring access of the poor to nutritious and safe foods requires a more diverse retail policy approach. I“Of course, it is important for me to eat nutritious foods, but what is the point when they are not safe for consumption?”This quote illustrates a prevalent dilemma in food health behaviour among urban low-income consumers in Asia. Over the past few decades there have been two notable shifts in the debate on food security. First, the focus has moved from quantity (mainly sufficient food energy) to the inclusion of quality in terms of safety, nutrition and  preferences.Food safety concerns are impacting food retailing policies. Over recent decades, economic development, accelerated by the influx of foreign direct investment (FDI), has resulted in the supermarketization of food retail systems across Southeast Asia (SEA). This stimulates modern supermarket development at the expense of traditional food vending structures such as informal vending and wet markets. The proliferation of modern retail outlets is, however, also associated with food access inequality. While policies that create incentives for private investments in supermarkets are partly framed as food safety efforts, they also contribute to broader processes of gentrification.Ensuring food security for urban low-income groups is among the toughest challenges confronting policymakers globally today. It is well recognized that lower-income groups in urban Asia are food and nutrition-insecure. Micronutrient deficiencies  and the nutrition transition (increasing rates of overweight and obesity) are prevalent problems, requiring food-based strategies in response.Food and nutrition security of the growing number of low-income citizens depends on decisions for food system transformation made in urban planning. However, particularly for emerging economies, there is no well-developed evidence-based policy on how to adequately accommodate the needs of low-income groups. In Asia, there is a critical knowledge gap on the implications of food safety policies for the everyday diets of low-income consumers. Building on the case of Hanoi, this paper aims to understand how the food retail environment impacts food choice and dietary intake of low-income consumers, and to evaluate whether and in what way retail provisioning policies driven by food safety jeopardize the diets of food-vulnerable low-income consumers.This paper continues with an introduction to the case of Hanoi (Section II), followed by a brief overview in Section III of the debate on whether food environments affect the diet quality of low-income consumers. Section IV presents the methods applied, and the results are presented in Section V. After the discussion in Section VI, we conclude with a summary of our findings and argue for the need to consider actual shopping practices when considering transformations of the (urban) food environment.II“People should buy food from supermarkets, malls or reputed shops to ensure food safety and hygiene.”Our research focuses on Hanoi, the capital of Vietnam, which serves as an illustration for comparable Asian contexts regarding the food and nutrition security implications of rapid urban population growth, food system transformations and subsequent nutrition transitions. In Vietnam, a country listed among the world’s fastest-growing economies, the national urban population is expected to increase. Specifically, the population of Hanoi is projected to grow from about 7.5 million in 2015 to 9 million in 2030 and over 10 million in 2050.Nevertheless, in preparing for the expected urban expansion, Hanoi authorities developed a master plan to transform Hanoi into a modern metropolis, including a transformation of the local food environment.The policy interventions to reduce the role of traditional markets in food retailing include: (i) restriction of the construction of new traditional markets; (ii) upgrading and renovation of markets; and (iii) transformation of markets into supermarkets. The development of new markets will be restricted in the sense that they are not included in the urban planning of new suburban residential areas. Policy interventions aimed at stimulating modern retail development include: (i) the development of supermarkets in office buildings and apartment complexes; (ii) suburban supermarket development; (iii) chain convenience store development; and (iv) establishment of supermarkets in department stores. Besides these policies aimed at the transformation of the formal food retail system, the modernization includes a more active repression of informal street vending practices, which range from ambulant vending to informally organized street markets.These policies are reinforced by serious public health concerns regarding the agrochemical and bacteriological safety of the most commonly consumed fresh foods,Food safety is both a real problem and a perceived problem. Over the last decade in Vietnam, there has been an alarming increase in the inappropriate use of chemicals in agriculture.Ensuring healthy and safe food access together with food and nutrition security among poorer populations is a critical challenge for Vietnamese policymakers. As is evident in the recent trend towards supermarketization as a remedy for recurrent food safety incidents, food safety is being prioritized at the cost of traditional wet markets for fresh food. These developments make Hanoi an interesting case for studying the impact of retail transformation on the quality of the diets of low-income urbanites.IIIMultiple studies have addressed the relation between dietary intake and disparities in local food environments.Along with these supply-driven considerations, the socioeconomic dimensions of accessing food are now also receiving considerable attention. Limited access to healthy foods is associated with socioeconomically disadvantaged populations that are disproportionately affected by NCDs.However, most studies have been oriented to the global North, while the urbanization of poverty and the challenge of food equity in the context of food retail transitions are most prominent in the global South. Furthermore, most studies define a healthy diet and food environment in terms of nutritional quality and diversity,In this study we strive:to enhance the body of evidence beyond the global Northto combine nutritional and food safety aspects in the notion of dietary health (diet diversity and food safety); andto link dietary intake with the food retail environment, time–spatial accessibility and socioeconomic affordability outcomes.In this paper, household food shopping and consumption, and thus dietary intake, are approached as being embedded in the organization of everyday life. We take a novel practice-oriented perspective by including the habitual nature of food consumptionIVaWith dietary intake as an indirect dependent variable of food retail provisioning, we defined our target population, low-income urbanites, as households with an income of up to US$ 5/person/day. Next, we selected two urban districts in Hanoi with a relatively high percentage of poor households, while excluding the most recently developed suburban areas to avoid a rural or peri-urban bias (see S1 in the online supplementary information for the poverty definition and sampling plan). The study specifically targeted women of reproductive age, since women are primarily responsible for household food purchasing and preparation and are often more nutritionally vulnerable within the household. Being responsible for caring for their families, women often prioritize diet quality for others over themselves, and as a result their diets are likely to be of the lowest quality within a household.bTo develop a stratification based on food retail environment, we started with a census of food retail outlets, conducted through a street-by-street mapping of commercial food outlets. Each outlet was categorized according to a retail typology , which dConvenience food retail requires some further explanation as Vietnam’s retail modernization policy promulgates the development of chain-based convenience stores. A convenience store carries a limited selection of everyday items, ranging from groceries to drugstore items, like a small version of a supermarket with extended opening hours. Our census distinguishes between modern chain-based convenience stores and more traditional mom-and-pop convenience stores, usually family-owned and typically not franchised. Within the informal food retail system our census also made a distinction between street markets and “street stalls”. The difference is mainly related to whether vendors sell their products collectively (markets) or individually .For each outlet, the health dimension of the food assortment available was assessed based on (i) the level of processing of the available foods,In addition to the census, during five consecutive weeks, the price data of a preselected basket of 20 commonly consumed vegetables were collected within the selected districts. These spanned the five different types of retail channels: supermarket, formal wet market, informal street market, chain-based convenience store, and safe vegetable specialty store (S2).cFollowing the census, we deployed a sample stratification strategy based on the availability of hyper-/supermarkets and formal wet markets within walking distance of 300 metres from respondents’ homes . We stradA quantitative household survey was conducted that delivered data on household food shopping practices and preferences, food selection processes, vegetable food safety risks and trust perceptions. This included sociodemographic parameters such as age, education, income, household composition and whether the respondent was caring for elderly people and/or children. (See S3 [Survey questionnaire] in the online supplement.) The GPS coordinates of each sampled household were also documented and used to verify the accuracy of stratum allocation . The perFollowing the survey of food shopping practices, a 24-hour diet recallFor the data interpretation we mainly used descriptive statistics, first subjecting the individual datasets to frequency and cross-strata analyses, followed by the combined analysis of datasets and outcome triangulation. VBelow we present the results along the conceptual framework . We starahttp://freshstudio.vn/index.php/rd4ddmap for the interactive census map). First, the census confirmed the uneven geographical distribution of the various retail outlets, used to determine the inclusion criteria for stratification. Wet markets are geographically more evenly distributed across the districts, compared to hyper- and supermarkets. Second, the census demonstrated that supermarkets offer a similar assortment of fresh fruits and vegetables to traditional (in)formal markets, but with the difference that the vegetables in supermarkets are offered with visual food safety claims and certificates, which were not observed in the traditional (in)formal markets. However, supermarkets were demonstrated to also offer a wider selection of less healthy ultra-processed foods as defined by Monteiro et al.The census captured the existing diversity in food retailing (see bAll women included in our sample were of reproductive age (20–50 years old), with 50 per cent aged between 40 and 50. In terms of their final educational qualification, the large majority of respondents (89 per cent) had completed high school (47.3 per cent) or higher . The average household size was 4.2 people. 30 per cent of the households had a multigenerational structure that included elderly people (parents or parents-in-law aged 60+); 75 per cent of households had children (36.3 per cent had children aged 0–4 and 54 per cent had children aged 5–12). We only selected households with a per-capita income of US$ 5/ day or less. cThere was an 87 per cent follow-up response rate to the dietary intake survey , with hoNearly all the women (96 per cent) had consumed meat, poultry or fish and nearly 80 per cent had consumed dark green leafy vegetables in the previous 24 hours. Fruit consumption was quite high (84 per cent); however, less than 2 per cent of the women had consumed a vitamin A-rich fruit. Women who reached MDD were more likely to have consumed legumes (seven times), nuts and seeds (five times), dairy (four times), fruits (1.7 times) and vitamin A-rich foods (1.3 times) than those below MDD.Our results reveal that only 8 per cent of the foods consumed were sourced from supermarkets. Traditional (in)formal markets were the most important source of food (48 per cent), followed by convenience stores (23 per cent), specialty single-item stores (15 per cent) and supermarkets (8 per cent). Only 2 per cent of foods consumed were homegrown and 4 per cent were obtained from alternative sources outside of the Hanoi food retail environment, including via contacts who enabled foods to be sourced directly from the rural production areas. There was no significant difference between strata regarding where women sourced foods except for own production, where Stratum 4 (who had no wet market close by) sourced more (3 per cent) and Stratum 1 (who lived close to wet markets) sourced less (1 per cent). Most of the ultra-processed foods consumed were purchased from convenience stores (67 per cent), predominantly mom-and-pop stores, followed by supermarkets (17 per cent), traditional wet and street markets (7 per cent) and specialty stores (6 per cent). There was no significant difference in ultra-processed food consumption between strata.dWe correlated dietary intake with the food retail environment mediated through food shopping practices along two dimensions: (i) time–spatial and (ii) quality–affordability.The comparable diet diversity observed across strata is explained by the similar food shopping patterns, regardless of proximity to supermarkets or wet markets. The dominant food shopping practice entails shopping daily (92 per cent) in the morning (55 per cent before 8 am / 90 per cent before 11 am) at traditional (in)formal markets (88 per cent), mostly accessed on foot (67 per cent) or by motorbike (27 per cent). Whether respondents reported shopping at formal wet markets or informal street markets was clearly geographically defined. For the strata that had a wet market within 300 metres of the home (Strata 1 and 3), 60 per cent purchased most of their foods at the formal wet market and 38 per cent at a nearby informal street market. In comparison, in Strata 2 and 4, which had no wet market close by, 80 per cent of foods were purchased from an informal street market, and 18 per cent at a formal wet market. Retail outlet proximity thus influences food shopping practices, but this does not include supermarkets, which were not widely utilized by the sample . Only 7 The results indicate that low-income consumers in Hanoi do not frequent supermarkets for their main food shopping, even when these are located close to their home or when they are not close to a traditional retail outlet. Of all 179 households with a supermarket within walking distance (Strata 1 and 2), none reported supermarkets as their main source of food. Overall, 98 per cent of respondents reported shopping primarily at (in)formal markets, which account for only 6 per cent of total food retail outlets within the local food environment and 23 per cent of total food retail outlets offering fresh vegetables in the census.We also assessed the preferences in food shopping. The preferences corresponded – with only a slight difference – to the aforementioned practice of shopping every day (preferred by 94 per cent) in the morning (preferred by 93 per cent) at traditional (in)formal markets .The primary reasons for shopping at traditional (in)formal markets were habit (100 per cent), the wide assortment offered (99 per cent), the convenient close-to-home location (98 per cent) and the enjoyment of shopping at the market (97 per cent). Further reasons included the availability of a wide variety of fresh nutritious foods (86 per cent), the low selling price (80 per cent), and trusted food safety (77 per cent), in which food safety is ensured by choosing seasonal products that look fresh, followed by knowing where the vegetables were produced. Personal contact with the vendor (66 per cent) and a convenient location “on the way” from home to work/school (60 per cent) appeared less important. These percentages refer to the total study population as we did not measure significant differences across the strata. Only 4 per cent (N=16) of the respondents reported preferring to shop in hyper-/supermarkets, compared to 56 per cent at informal street markets .The mean household income was calculated at US$ 3.64/person/day (median US$ 3.67/person/day).To assess the quality–affordability dimension of accessing food and dietary intake, we zoomed in on the category of vegetables. Although vegetables are not the most expensive ingredient of a daily meal, they are nevertheless reported to make up a substantial part of the total food expenditure.The household survey uncovered a preference across strata that food should be affordable and provide good value for money, but for the large majority, “cheap” was not an important selection criterion. However, at the same time, nearly 86 per cent of the respondents considered the prices of safe food too high. When further exploring the affordability dimension, we combined reported income and food budget with cross-channel price indexation. We calculated the effects of vegetable price differences across channels as a percentage of the food budget.The main price/quality differentiator across retail channels was food safety. The census uncovered that formal food safety guarantees were most commonly found in modern retail channels, whereas (in)formal markets did not provide for food safety certification, labelling or branding . Nearly Although 98 per cent of the respondents were concerned about the safety of vegetables, and 61 per cent believed that vegetables offered in supermarkets could generally be considered safer than the vegetables offered in wet markets, vegetables were predominantly purchased at traditional (in)formal markets. Buying at supermarkets was considered “rather safe” (67.5 per cent), but was also considered expensive (85.1 per cent). On the other hand, 62 per cent of respondents disagreed with the statement that shopping at wet markets was expensive, and reported being confident in their ability to avoid food safety risks as they trusted their own risk-mitigation strategies/capabilities, including vendor selection, product selection and food cleaning practices.Along with safety, “freshness” was regarded as an important food quality indicator. Vegetables sold through modern channels were considered less “fresh” than vegetables purchased at (in)formal markets.The level of food processing was also considered an indicator of food quality. Our research uncovered that modern retail outlets not only offered a higher percentage of ultra-processed foods than traditional (in) formal markets (>60 compared to <25 per cent), but that these channels were mainly frequented for purchasing such foods, with 92 per cent of the respondents who shopped less than once a week at supermarkets primarily visiting these outlets to purchase processed foods, like snacks and sweets. The 24-hour dietary recall further uncovered that although only a limited amount of food (19 per cent) was purchased in supermarkets and convenience stores, these outlets contributed to 84 per cent of the ultra-processed foods consumed. In contrast, traditional (in)formal market channels, which were frequented on a daily basis, contributed only 7 per cent of the less healthy ultra-processed food category .VIThe survey uncovered that 94 per cent of the foods consumed were obtained through retail channels, which justified our focus on food shopping practices. Our results demonstrate that supermarkets do not (yet) contribute to more healthy diets for low-income urbanites. When formal wet markets are absent, informal vending structures, most importantly informal street markets, are preferred over supermarkets. Our 24-hour diet recall confirmed this preference for traditional (in)formal markets, as Stratum 1, which had both wet markets and supermarkets within walking distance, sourced 6 per cent more foods from informal street markets than the average of the other three strata. These shopping practices resulted in diets that still strongly reflected Vietnamese food culture, containing relatively high quantities of fresh fruits and vegetables when compared to global and regional averages, but with increasing quantities of animal-sourced foods.Our study uncovers how the impact of food retail modernization on the diets of low-income urbanites is mediated through the everyday shopping practices in which time–spatial and quality–affordability dimensions exclude modern store-based alternatives. This is explained by the convenience of open-air (in)formal markets in the routine of early-morning, everyday fresh food shopping close to the home. The importance of considering food affordability, and the subsequent impact on household expenditure of changing access to certain retail outlets, was indicated by the significant differences in vegetable prices measured across retail outlets. The affordability dimension requires further research as the current measurements included only a limited number of outlets.This paper demonstrates the complexity of development effects. Policymakers are confronted with the social justice dilemma of improving food safety without jeopardizing a traditionally healthy and diverse diet. Based on our results, we suggest that the dual public responsibility for ensuring continued access to nutritious and safe foods requires a more diverse retail approach than that planned under the current supermarketization policies. An obvious benefit of the promotion of modern retail chains is their strong and demonstrated interest in promulgating safe foods. However, our results also demonstrate how retail modernization currently plays out negatively for low-income urbanites, highlighting the current incompatibility of aiming for improved food safety and diet quality through these modern channels, potentially at the cost of traditional outlets.In preventing the creation of nutrition deserts or mirages for low-income consumers, food safety policies should recognize the importance of allowing for a versatile and hybridized food retail environment to evolve. On the one hand, policy should focus on how to mitigate the undesirable dietary effects of supermarketization, which lead to the increased prevalence of NCDs. Although low-income consumers in Hanoi are not yet widely utilizing modern retail outlets, in their well-established shopping practices the relatively high contribution of supermarket and convenience outlets to the consumption of ultra-processed foods hints at a potential health risk. The proliferation of transnational retail corporations is strongly associated with increased availability of ultra-processed foods.Instead of depriving low-income consumers of traditional fresh food vending infrastructure, policy should look for ways to renovate and upgrade existing facilities and (in)formal organizational structures with deficient food safety standards. A study in Thailand uncovered that frequent market shopping was associated with increased vegetable intake, whereas frequent shopping at supermarkets and convenience stores was associated with the consumption of six “problem foods”: soft drinks, snack foods, processed meats, Western-style bakery items, instant foods and deep-fried foods.It is important to highlight that the effects of retail modernization policies on dietary diversity are contextual. Supermarket-based food provision is demonstrated to play out differently for low-income populations in different contexts, with disparate associations of supermarket shopping with obesity between Western and developing-country contexts.Our research provides insights into how increasing retail modernization does not yet influence diet diversity and shopping practices in the specific context of low-income consumers in Hanoi, Vietnam. In reconciling the apparently competing priorities of food safety and nutrition for low-income consumers, there is a need for intervention studies that consider dynamic societal interactions. These should allow for co-creation that actively involves consumers, producers, retailers and policymakers within the local food business ecosystem, to develop tailored retail intervention strategies that consider the multiple foodways – cultural, social and economic food practices and preferences – of low-income populations. Currently, there is little to no evidence available on actual levels of food safety or toxicity that would allow for a comparison between different retail outlet typologies. Biochemical analysis of foods from different retail outlets would allow for a more nuanced understanding of how the urban poor’s perception of food safety in modern vs. traditional retail outlets measures up with reality. These data would be useful to better inform both policymakers and consumers.This paper reflects the first results from an ongoing research project exploring drivers of food choice of low-income consumers in Hanoi, based on a stratification defined by home locations and retail proximity. However, neighbourhood definitions of the food environment are crude measures that might be misaligned with broader lifestyle patterns. Although we included transportation modes, shopping frequency, time of shopping and other convenience indicators, this patterned approach does not yet capture the heterogeneity in wider daily activities, let alone future lifestyle changes that are expected with continued urbanization and modernization of Asian cities. It was difficult to discern drivers of access and utilization of supermarkets because only a small number of households actually accessed these modern retail outlets. However, we did find that supermarket distance from the home appeared not to be the most relevant indicator of accessibility. Ongoing research seeks to further deepen our understanding of access to safe and healthy foods by capturing lifestyle dynamics, including intra-household dynamics and generational shifts over time, in order to inform socially just policies.VIIFood retail modernization is not (yet) utilized in the well-established shopping practices of low-income consumers in Hanoi. Our results demonstrate that from both time–spatial and quality–affordability perspectives, supermarkets do not contribute to more healthy diets for low-income urbanites. Our initial hypothesis about the impact of the food retail modernization on the dietary intake, in terms of dietary diversity, proved negative. Distance to supermarkets did not change shopping practices. Although the census provided insights on the uneven distribution of supermarkets across all strata, the foods consumed mainly originated from traditional outlets. In the absence of formal wet markets, dietary diversity was maintained through close-to-home informal vending structures. As such, it was not surprising to find that households’ distance to either supermarkets or wet markets did not influence diet diversity – no significant difference was found between strata in either DDS or MDD. Supermarket shopping is not only considered inconvenient and time consuming, but the safe foods offered are also considered rather expensive and less fresh. Supermarkets currently contribute mainly to the consumption of ultra-processed foods.This study unpacks the competing priorities of nutrition and food safety in governing food security for low-income urbanites. On the one hand, the results confirm the effective direction of the dominant food safety-oriented retail modernization policies. Our research demonstrates that food safety guarantees are indeed omnipresent in modern retail channels; all hyper- and supermarkets and nearly all convenience chain stores offer vegetables with visual food safety guarantees. Moreover, the results show that these outlets offer a similar assortment of fresh vegetables to traditional outlets.However, the findings also demonstrate that low-income urbanites rarely frequent these modern retail channels, even when a supermarket is very close to their home. Traditional food retail structures, in the form of (in)formal markets, appear crucial in maintaining a minimally adequate diverse diet, although they do not provide general or formalized food safety guarantees. When formal wet markets are absent, supermarket proximity is shown to have no impact on diet diversity because informal street markets act as fill-ins for similar foods.The women in our study were from low-income households and were prevented in practical terms from purchasing fresh foods with formal food safety guarantees. Supermarkets presented multiple access barriers  and thus barely contributed to their daily diet. Given this reality, the presence (or absence) of supermarkets and their food assortment do not yet seem to have direct effects on diet quality of low-income consumers in Hanoi. However, this may change in the future when traditional market vending is further reduced, and especially when informal street vending is more forcefully repressed by supermarketization policy.The struggle of low-income urbanites with food safety is a well-recognized problem in Vietnam and affects people throughout Asia. Although it is not contested that traditional markets are often less hygienic than supermarkets and lack adequate control mechanisms, this research demonstrates the limits to pushing modernization by banning traditional vending structures as a remedy for recurrent food safety incidents. Our research demonstrates that these one-dimensional ideal-type policies have limited success in improving access to certified-safe foods among low-income residents, or for improving diet diversity. They fail to produce socially inclusive food retail infrastructure. Moreover, our study provides a hint at how these policies, when successful, might jeopardize dietary quality for low-income urbanites through two pathways: depriving them of access to nutritious foods and stimulating less healthy diets by increasing consumption of ultra-processed foods. Thus, transforming the food environment without considering the food shopping practices, especially of low-income citizens, might result in unwanted outcomes in terms of dietary intake.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.


Here, we assess how COVID-19 may have influenced this apparent decline in cardiac care. We also consider how clinicians can optimize the diagnostic process to provide appropriate and timely patient care in the setting of increased uncertainty regarding the etiology of acute cardiovascular disease. This process is dynamic and will necessitate adaptive strategies over time, particularly as many hospitals, states and countries transition slowly toward the re-escalation of standard operations while being mindful of COVID-19 resurgence.Coronavirus disease 2019 (COVID-19) was first identified in December 2019, yet within months it had spread to pandemic levels with critical global health implications to the clinical practice of all specialties. In cardiology, COVID-19 has imposed an unfortunate conundrum: the disease is significantly associated with death in patients with pre-existing cardiovascular disease, . This crbona fide reduction in the incidence of ACS in the general population due to the imposed lockdown is possible, such as reduced work-related stress, decreased physical stressors and possible environmental factors such as air pollution reduction, we suspect these factors to be minor. Conversely, pandemic-induced stress and economic stress from unemployment can negatively impact cardiovascular health [In spite of numerous mechanisms that may increase the likelihood or severity of cardiovascular disease in COVID-19, many centers have thus far reported a decline in the number of patients admitted for the acute coronary syndrome (ACS). A recent report from the British Heart Foundation revealed that the patient footfall seeking medical attention for myocardial infarction, which is defined as myocardial cell death due to prolonged ischemia, was essentially halved in March 2020, compared with the same period a year ago in England . This wor health .What is far more concerning, however, is that patients may avoid seeking treatment despite serious cardiovascular symptoms due to fear of nosocomial COVID-19 infection or concerns of adding to the overflowing workload at hospitals. Furthermore, the way in which certain centers approach the diagnosis of ACS or myocardial infarction in COVID-19 patients may have contributed to the decline in the apparent incidence of ischemic heart disease. For instance, some have advocated measuring cardiac enzymes only when the patients exhibit specific cardiac symptoms including chest pain, dyspnea and palpitations . While tde novo thrombotic events and the precipitation of subclinical coronary artery disease. The presence of acute respiratory distress syndrome and hypoxemia could exacerbate the oxygen demand-supply mismatch that leads to a type 2 myocardial infarction. For those with pre-existing atherosclerotic plaque, SARS-CoV-2 may predispose to increased atherosclerotic plaque instability and coagulopathy, which are increased in the setting of cytokine storm and may manifest as thromboembolic occlusion of the coronary artery [cor pulmonale, which can also result in cardiac damage and cardiac enzyme release. These latter diagnoses are corroborated by recent autopsy series of COVID-19 patients demonstrating that venous thromboembolism and pulmonary embolism are frequent and often considered the immediate cause of death [In spite of the broad etiologic differential for cardiac enzyme elevation, ACS remains highly likely and should always be considered, given the critical implications of a timely diagnosis. Several aspects of COVID-19 may increase the likelihood of ACS above baseline risk, both via y artery . Similary artery . Furtherof death . While tof death , the ratof death .The differential etiology for cardiac enzyme elevation is broad, even in the absence of viral infection, and this uncertainty is further compounded by COVID-19. Up to 40% of COVID-19 patients with ST-elevation myocardial infarction (STEMI) taken to diagnostic coronary angiogram have had no identifiable culprit occlusion . Thus, wde novo left bundle branch block and pathological Q waves; chest pain consistent with ischemia; imaging evidence showing new regional wall abnormalities or infarct; and angiographic evidence of coronary occlusion [Given the importance of timely management of myocardial infarction in COVID-19 patients, clinicians must be able to distinguish true ACS from ACS mimics among these patients. The mainstay of ACS diagnosis is a raised troponin (above 99th percentile of the upper reference range limit) and at least one other sign including ECG changes such as ST-elevation, T-wave changes, cclusion . Patientcclusion . These tcclusion .Currently, the prevalence of myocardial infarction and its mimics among COVID-19 patients remains unclear. Certain initiatives have been made to study the epidemiology of ischemic heart disease in the SARS-CoV-2 infection;  and othe


Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding has been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens. Immune complexes (IC) are formed naturally when antibodies are generated and bind to their specific antigens. An IC may be made of a single antibody targeting an antigen or many antibodies binding simultaneously to an antigen or antigens on the surface of a microbe. The presence of multiple antibodies on an immune complex promotes their avidity for Fc receptors and enables the cross-linking of these receptors on B cells, dendritic cells, follicular dendritic cells, natural killer (NK) cells, macrophages, neutrophils, or other types of immune cells. The Fc receptor engagement by ICs triggers a cascade of intracellular signals critical for Fc-mediated effector functions against microbes, such as antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) A.There are five major antibody isotypes, IgM, IgG, IgA, IgD, and IgE, which are classified based on their unique Fc fragments and each of which interacts with distinct Fc receptors (FcRs). IgG, the most abundant antibody in the blood, is further divided into four subtypes, IgG1, IgG2, IgG3, and IgG4, while IgA consists of two subtypes, IgA1 and IgA2. The Fc receptors are categorized into type I and type II, which bind the Fc domain at different interaction sites, conformation states, and stoichiometry . The typIn addition to direct pathogen-killing actions described above, ICs serve as a bridge between innate and adaptive immune cells to boost the induction of the adaptive humoral and cellular immune responses against microbes. By engaging Fc receptors on antigen-presenting cells (APCs) such as dendritic cells and macrophages B, ICs faWorking through the complement system, ICs are also integral to the host mechanisms of clearing or retaining microbes and microbial antigens. The binding of C1q to Fc fragments on ICs activates the downstream complement cascade resulting in the deposition of C3 and C4 degradation products, leading to the generation of C5 convertase and the assembly of the membrane-attack complex for initiating complement-mediated lysis A. AdditiInterestingly, on follicular dendritic cells (FDCs), C3-coated ICs are not cleared but accumulate, mainly through CR1, although CR2 and FcgRIIB also contribute to some degrees  Figure B. FDCs aWhile the immune functions of ICs are ascribed customarily to their Fc contribution, the Fab-mediated effects are important to consider as well C. IndeedSince ICs retained on FDCs provide sampling of antigens to B cells, antibodies on ICs influence the accessibility of B cell epitopes on the bound antigens through steric or allosteric effects. Indeed, pre-existing antibodies from maternal–fetal transmission or through previous antigen exposures have been demonstrated to modulate the immunogenicity of live attenuated viral vaccines or viral vaccine vectors . In addiGiven the capacity of ICs for enhancing antigen uptake, MHC presentation, and APC maturation, ICs have been investigated and developed as vaccine immunogens in order to improve the immunogenicity and efficacy of vaccines against several human and animal pathogens. To this end, these IC vaccines primarily take advantage of the Fc immunomodulatory functions, yielding varying degrees of success. Among human vaccines, the IC vaccine that has advanced to human clinical trials is the hepatitis B virus (HBV) vaccine to treat chronically infected patients. Since HBV viral antigens do not elicit effective immune responses capable of clearing the virus in HBV-infected patients, it was postulated that immunization with viral antigens complexed with antibodies would lead to enhanced antigen uptake by APCs via the Fc receptor to result in improved antigen presentation and more effective induction of T cell responses . To thisIn the subsequent Phase IIa trial with HBeAg-positive hepatitis B patients, five of ten participants who received the YIC experienced a marked decrease in viral load and development of antibodies against HBeAg, two of whom also developed antibodies against HBsAg and four of whom showed Th1/Th2 cytokine secretion. Four of the five responders also developed alanine aminotransferase (ALT) flares between 4 and 12 weeks after immunization, which the authors attributed to vaccine-induced cytolytic response, although two of the ten participants who received the placebo also developed ALT flares. In addition, incubation of patient peripheral blood mononuclear cell (PBMC)-derived dendritic cells with YIC resulted in the expression of functional and maturation markers , indicating the capacity of YIC to stimulate dendritic cell maturation and enhance their antigen presentation potential . A phaseTo assess the therapeutic efficacy of the YIC vaccine and the potential of increasing the YIC dosage, a phase III trial was conducted, with 303 HBsAg- and HbeAg-positive patients receiving twelve injections, compared to six in the phase IIb trial. Only 14.0% of the immunized patients achieved HBeAg seroconversion, a marked decrease from the phase IIb trial results. Furthermore, YIC immunization decreased IL-17A expression in patients throughout the study, indicating the lowered therapeutic efficacy of twelve YIC doses, compared to six, attributed to immune fatigue . This ph®) is commercially available for protecting chickens from infectious bursal disease virus (IBDV) infection . T. T42]. TSeveral other labs have also explored the IC vaccine strategies by exploiting the Fab specificity to direct the induction of antibody responses against broadly neutralizing epitopes that are poorly immunogenic . Chen etA similar study in guinea pigs tested IC vaccines made of cross-linked gp120 proteins of clade B BaL or 89.6 strains with mAb A32 against a CD4-induced epitope in the inner domain of gp120 , which sIn the past decade, the use of native-like trimeric Env vaccines, rather than monomeric gp120 immunogens, has been advocated as a rational pathway to induce bNAbs, as these antibodies target epitopes present or accessible only on the functional trimeric Env spikes expressed on the virions. However, because the near-native Env immunogens such as the BG505 SOSIP.664 trimer display immunodominant strain-specific epitopes in a glycan-devoid region around positions 241 and 289 (“the glycan hole”), which elicit autologous neutralizing antibody responses, mAbs have been used to conceal this glycan hole in the constructed IC vaccines . ImmunizOne strategy may be to construct IC vaccines with a combination of mAbs: mAbs imposing steric blockage against undesired dominant epitopes plus mAbs triggering allosteric alterations to augment the exposure and stability of the desired bNAb epitopes. Moreover, instead of aiming to induce solely bNAb-like responses, it would be more practical to utilize IC vaccines to stimulate cross-reactive multifunctional antibodies capable to mediate an array of antiviral activities that are characteristic of polyclonal vaccine-induced responses. For examples, the IC strategy may be employed to improve upon a number of trimeric Env vaccines reported to elicit neutralizing antibodies that are not as broad and potent as any of the bNAbs but were effective against some tier 2 heterologous viruses . The appThe IC vaccine studies described above demonstrate the prominent Fab-dependent steric and allosteric effects that modulate IC-induced antibody responses toward or away from HIV-1 Env regions of interest. Our own gp120 IC experiments provide clear evidence for the importance of the Fab fragment and specificity used to form the ICs in altering the antigenic and immunogenic properties of V1V2 and V3. However, improved V1V2 and V3 immunogenicity detected upon IC immunization in our studies may also be attributed to the Fc function, even though evidence for this phenomenon is still developing. Our early study examining different types of APCs treated with ICs versus un-complexed gp120 did not show the influence of Fc-enhanced uptake ,72,73. RThe immunomodulatory potential of ICs has also been alluded to in antibody passive transfer studies, which point to the “vaccinal effect” of ICs formed by the exogenous antibodies on endogenous T cell and antibody responses . An earlIn developing IC-based vaccines, a number of significant challenges must be addressed. For our IC vaccine studies, the steric and allosteric effects on Env antigenicity and immunogenicity depend greatly on the stability of ICs, requiring high-affinity mAbs and precluding low-affinity mAbs. Nonetheless, the long-term stability of these ICs must be assessed, as well as the influence of adjuvant, an essential component for vaccine formulation ,79,80. CFinally, the potential adverse effects of ICs should be considered in the development of any IC-based vaccines, as ICs have been shown to cause immune dysregulation in chronic infectious and autoimmune diseases. IC formation and accumulation have led to the prolonged engagement of FcγR signaling and aberrant antibody responses, triggering sustained inflammatory responses in autoimmune, neoplastic, or infectious etiologies . IC-mediIC vaccine strategies offer promising results to improve and fine-tune the induction of antibody responses against various pathogenic microbes via Fab- and Fc-mediated immunomodulatory activities. By engaging Fc and complement receptors, ICs can bridge the innate and adaptive immune system to augment the elicitation of antibody and cellular immune responses. Fab-mediated steric and allosteric effects, on the other hand, can alter the fine specificities, affinities, and effector functions of IC-induced antibody responses. IC strategies have been tested in human vaccine trials against HBV and used for veterinary vaccines in chickens against IBDV and in pigs against PPV. IC vaccines have also been tested in animal models to direct the antibody responses toward or away from distinct epitopes on the HIV envelope glycoprotein, with varying degrees of success. While there remain significant challenges to be overcome, accumulating data from IC vaccine studies reveal important lessons that can inform the development of more effective vaccines and treatment modalities against infectious diseases.


This cohort study examines whether communities in Medicare’s Comprehensive Care for Joint Replacement (CJR) Model are representative of others nationwide with respect to residents’ socioeconomic status. Among metropolitan statistical area (MSA) markets with above-average episode spending (196 of 384 MSAs), Medicare randomly selected 67 for inclusion.4 This advantage can also enhance generalizability of program results, but only if regions in the program do not differ greatly from those not included. However, it remains unclear whether communities in CJR are representative of others nationwide with respect to residents’ SES.One key advantage of mandatory over voluntary programs is mitigating physician or hospital self-selection that could lead to the exclusion of patients with low socioeconomic status (SES).STROBE) reporting guideline.This cohort study was approved by the University of Pennsylvania institutional review board with a waiver of informed consent because of the infeasibility of obtaining consent from a large retrospective claims data set. Our analysis followed the Strengthening the Reporting of Observational Studies in Epidemiology , which are collections of zip codes whose residents receive the majority of hospitalizations from hospitals in that area, as communities within MSAs. We then measured community-level dual-eligibility share, which is the proportion of dual-eligible individuals in HSAs.6 The HSA-level dual-eligibility share was clustered at the MSA level, an approach that reflects the fact that although CJR participation was determined at the MSA level, the program incentivized care changes more narrowly among hospitals.We measured low SES using Medicaid and Medicare dual eligibility, which federal policy makers consider the most reliable measure of social risk among Medicare beneficiaries.We compared dual-eligibility share and other characteristics between CJR and non-CJR markets using Wilcoxon rank sum tests. We evaluated the association between dual-eligibility share, categorized into quartiles to allow for nonlinear associations, and CJR market status using multivariable linear regression on HSA-level data, controlling for market characteristics . Statistical tests were 2-tailed and significant at α = .05. Data analysis was performed from October 2020 to January 2021.Our sample consisted of 67 CJR markets containing 389 HSAs and 306 non-CJR markets containing 915 HSAs . The meaP = .02) and quartile 3 . An increase from the lowest to highest quartile (quartile 4) of dual-eligibility share was associated with a −14.1 percentage point probability of being a CJR market .In multivariable analysis, market-level dual-eligibility share was inversely associated with the likelihood of being a CJR market . The proMarkets that were more likely to have a higher burden of adverse outcomes through social risk factors were less likely to be selected for CJR. A limitation of this study is the observational design; however, this study underscores the need to ensure that expanded or additional market-level mandates do not inadvertently perpetuate SES disparities. Policy makers should urgently address this concern by directly considering community social factors when selecting markets in forthcoming mandatory bundled payment programs.


A 39-year-old man presented to the ophthalmology emergency room complaining of decreased visual acuity and metamorphopsia on his left eye after undergoing Nd:YAG facial hair epilation without wearing proper eye protection. Fluorescein angiography showed a foveal staining initially, with an increase in foveal leakage over late phases. On optical coherence tomography, a subfoveal retinal pigment epithelial detachment with associated subretinal fluid and no signs of choroidal neovascularization or cystoid macular edema was observed. Observation with monthly follow-ups was adopted. By the fourth month, the subretinal fluid had already disappeared and visual acuity had returned to 20/20. Over one-year follow-up, the retinal pigment epithelial detachment experienced a decrease in its size. Conservative management may be a valid option in assessing accidental foveal photocoagulation when choroidal neovascularization or cystoid macular edema is absent. The use of wavelength specific goggles is mandatory for the patient and the aesthetician operating the cosmetic laser, especially when operating on the face or around the eyes.Abbreviations: Nd:YAG = neodymium-doped yttrium aluminium garnet, OCT = optical coherence tomography, PED = pigment epithelial detachment, CME = cystoid macular edema When not complying with safety measures, the eyes may be harmed during the laser operation.Laser depilation has become extremely popular in the last years, due to the beauty canon change and the cheapening and greater availability of aesthetic lasers. Facial laser depilation is a very common procedure realized in many beauty clinics. The most widely used lasers for aesthetic purposes, deliver energy under a wavelength of 700-1200 nm: alexandrite laser (755 nm), diode laser (800-810 nm), neodymium-doped yttrium aluminium garnet (Nd:YAG) laser (1064 nm) and intense pulsed light lasers (590-1200 nm)  about ocular injuries secondary to face aesthetic laser treatments, the patients were found to experience a broad spectrum of eye globe injuries such as superficial punctate keratitis, iris atrophy, iris transillumination defects, anterior uveitis [3], pupillary distortion, posterior synechia or retinal burns [4] causing field defects and preretinal hemorrhages. In 62% of the cases, eye protection was not worn at the moment of laser application [2]. A literature review regarding the adherence to optical safety guidelines for laser hair depilation found that 72,3% of the cosmetic centers had a lack of non-reflective floors and 59,6% of the providers did not instruct patients not to look into the laser beam or its reflection even while wearing protection goggles [5].In a 21 case reports review . In both of them, the operator was either not wearing eye protection at all [6] or wearing regular sunglasses [7]. The most common way of protecting the eyes is by wearing wavelength-specific spectacles by both patient and the operating cosmetician. Laser-impenetrable metal corneal shields can be fit as contact lenses over the patient’s corneas but they do not exempt the operator of wearing laser goggles. Two case reports of retinal injuries produced by Nd:YAG laser affecting the operating aesthetician have been published so far [8] or ranibizumab [9] has been used with excellent anatomical and visual outcomes. Cystoid macular edema (CME) has also been described as a complication of macular photocoagulation. When present, treatment with oral, retrobulbar or intravitreal steroids is recommended [10]. Our patient was not wearing any kind of ocular protection. The laser beam reached the subfoveal RPE producing its detachment and fluid exudation into the subretinal space. Choroidal neovascularization was not observed in the follow-up but it has been described in the first three weeks after foveal exposure to laser beams. When present, treatment with 1 to 5 doses of intravitreal bevacizumab [11].Regarding our patient, we opted for close follow-ups without treatment, given the absence of choroidal neovascularization or CME. Subretinal fluid slowly reabsorbed by itself with recovery of 20/20 visual acuity. Moreover, the RPE detachment experienced a reduction in its size during the one-year follow-up. Fortunately, our patient fully recovered his visual acuity, only complaining of mild scotoma at near vision. Recently, a case of macular burn has been published, following alexandrite laser epilation, leading to permanent scotoma and psychological depression and requiring prescription of antidepressant medication and psychotherapy [There is a risk of accidental foveal photocoagulation associated to the use of cosmetic Nd:YAG laser for facial hair epilation, which increases when safety-operating measures are not followed. Conservative management could be a valid option to assess accidental macular photocoagulation, particularly when there are no choroidal neovascularization or CME associated. The use of wavelength specific goggles by the patient and the operator and the instruction of the patient not to stare into the laser beam or any of its reflections even when wearing eye protection, are mandatory safety measures to follow when utilizing aesthetic lasers in the facial and periocular areas.Compliance with ethical standardsAn informed consent was obtained from the patient included in the Case Report.AcknowledgmentsNone.Sources of FoundingNone.DisclosuresNone.