To describe the variability in the availability and price of sugary drinks, low-calorie drinks, and water/seltzer across high- and low-poverty census tracts in the five boroughs of New York City (NYC).Cross-sectional study. Our primary analysis compared the overall sample of beverages. Secondary analyses included tests for differences in the availability of beverage categories by neighborhood poverty level.We collected data from 106 stores  in NYC. Fifty-four stores were located in high-poverty census tracts and 52 were located in low-poverty census tracts.p=0.01) but not different from water/seltzer . Sugary drinks and water/seltzer were available in 91% of retailers, and low-calorie drinks were available in 87% of retailers. There was no statistical difference in availability of sugary drinks compared with low-calorie drinks or water/seltzer overall or within high- or low-poverty census tracts. Analyzed by store type, the mean price per ounce of sugary drinks differed significantly from water/seltzer at convenience stores, pharmacies, and Target stores .The mean Price per 0.03-liter of sugary drinks across the sample was $0.08, which was significantly higher than the price of low-calorie drinks ($0.07, Sugary drinks were available in most food retail settings in NYC, with little variation by census tract poverty level. Interventions that raise the price of sugary drinks to make healthier alternatives, such as water, the more affordable option should be considered. Sugary drinks are linked to weight gain; other associated negative health outcomes include heart disease, type-2 diabetes, and cavities.3–10 Consumption of sugary drinks is both a public health issue and a health equity concern.Sugary drinks are high in calories but have little or no nutritional value, and they represent the largest source of added sugars in the diet of Americans of ages 2 years and older.11 and heavily market sugary drinks to low-income communities12 and communities of color.13 One study found 4.35 higher odds of in-store sugary drink marketing during Supplemental Nutrition Assistance Program (SNAP) benefit issuance days—the first 9 days of the month—compared with other days of the month in census tracts with high percentages of residents who use SNAP.12 These factors, which occur alongside policies and practices based on a history of racism and discrimination in the United States,14 may contribute to higher rates of sugary drink consumption and inequities in rates of diet-related diseases based on income and race.15–20Specifically, beverage companies spend hundreds of millions of dollars on sugary drink promotion21—this is indicative of the key role of retail settings in the consumption of sugary drinks.2 Retail settings influence consumer shopping behavior through practices such as product availability and pricing. These practices, among others, comprise “commercial determinants of health,” defined as “strategies and approaches used by the private sector to promote products and choices that are detrimental to health.”22About 70% of added sugars consumed in the United States are purchased in retail establishments such as supermarkets and convenience stores—compared with 16% in restaurant settingsThis study is the first to assess beverage availability and pricing in a variety of New York City (NYC) retail environments across all five boroughs, and to examine differences by census tract poverty level. Quantified information about the retail beverage landscape may heighten understanding of how to better influence health-promoting consumer behavior and inform public health strategies to address the overconsumption of sugary drinks.23We randomly selected 1 low- and 1 high-poverty census tract in each of the 5 boroughs of NYC, for a total of 10 tracts. In accordance with NYC Department of Health and Mental Hygiene  guidance, low-poverty  tracts were defined as areas where <10% of the population had an income level <100% of the Federal Poverty Level (FPL), and high-poverty  tracts were defined as areas where at least 20% of the population had an income level <100% of the FPL (based on U.S. Census Bureau data).Next, we used data from the New York State (NYS) Department of Agriculture and Markets to randomly select 11 chain and independent food retail outlets in each of the 10 census tracts, for a total of 110 stores. In each tract, three of each of the following outlets were selected: supermarkets ; pharmacies ; and convenience stores .25 The remaining 2 outlet types included chain retailers found in each of the 5 boroughs: 10 Target retail stores and 10 Dollar Tree stores, 1 each in the census tract closest to the randomly selected tracts. These two chains were selected because they are commonly found within all five NYC boroughs , sweetened iced tea, fruit drinks/vitamin-enhanced waters, sports drinks, and energy drinks.For the purposes of this study, five main categories of beverages were defined: sugary drinks, low-calorie drinks, water/seltzer, plain/unsweetened milk, and 100% juice. The analyses presented here focus on sugary drinks, low-calorie drinks, and water/seltzer only. Sugary drinks were broadly defined as products with added caloric sweetener and 24 or more calories per 0.01-liter, which is consistent with how such beverages were defined in a previously proposed sugary drink regulation in NYC.27 Many people report drinking seltzers to complement their low calories or to substitute water when needing hydration.28Low-calorie drinks served as a counterpart to sugary drinks and had low- or no-calorie sweetener and <24 calories per 0.01-liter. Water/seltzer included unsweetened bottled or canned products that could be either plain or flavored. We grouped seltzer and water for the following reasons. Although seltzer can be used as a mixer for hard liquor, it has grown in popularity as a standalone drink over the years, with sales of sparkling mineral water projected to reach $6 billion this year.30 It is designed to evaluate the availability, price, and promotion of different beverage types in food retail stores. We modified the NEMS-B to include beverage choices in groups as already defined. Eighteen data collectors completed the online NEMS training tool provided by researchers at the University of Pennsylvania.The Nutrition Environment Measures Survey for Beverages (NEMS-B) was adapted for use in food retail outlets in this study. NEMS-B was based on similar tools  that are validated observational measures of food retail environments.31 the top two to three highest selling sugary drink brands from each group were selected as target products, as long as the company also sold a low-calorie drink counterpart . The sugary drink category included the following subcategories and brands: (1) carbonated soft drinks: Coke and Pepsi; (2) sweetened iced tea: Snapple and AriZona; (3) energy drinks: Monster and Red Bull; (4) sports drinks: Gatorade and Powerade; and (5) fruit drinks/vitamin-enhanced waters: Fuze, V8 Splash, and Vitamin Water. The low-calorie drinks category included the counterparts to each sugary drink brand.Based on the Rudd Center's 2011 Sugary Drinks FACTS Report,The water/seltzer category included Aquafina for the plain water brand and Poland Spring  for the plain or flavored seltzer brand. A generic or store brand was also included for each beverage category as a mechanism to ensure the sample reflected the true range of pricing among drink categories. For comparability, data collectors prioritized collecting price and availability data for 0.35-liter and 0.59-liter beverage sizes where possible. For brands that did not commonly have 0.35-liter and 0.59-liter size options , data collectors recorded the price and size of other common small and large size options for that brand . In addition, the same brands within each beverage group were used for data collection.After completing the NEMS training, data collectors conducted a pilot test of the survey instrument at five stores in a census tract that was not part of the final sample and completed the modified NEMS-B on tablets. To ensure high-quality data collection across all retail settings, inter-rater reliability was established using this pilot sample of five stores. All raters reached a Krippendorf's alpha level of 0.7 or higher. After establishing reliability of the pilot sample, the stores were divided among the 18 data collectors. For convenience purposes, data collectors were assigned stores that were geographically clustered together. Each store visit lasted ∼1 to 1.5 h. Institutional review board approval was not required, because the study did not involve human participants.32Availability was assessed by noting which of our target products were sold at a given retailer (yes/no). Price was assessed by recording the posted price of target products within stores. The prices of refrigerated beverages were prioritized, but if these were unavailable, prices of unrefrigerated beverages were used instead. When the price was not posted, store personnel were asked the price of each product. After pricing data were collected, NYS sales tax of 8.875% was added to recorded prices of eligible beverages  at stores that utilized barcode scanners.33 Eligible beverages were those sold in sealed glass, metal, and plastic containers smaller than 1 gallon or 3.78 liters. Sales tax and bottle/can deposit were not added to the prices of beverages sold at stores without UPC scanners , since these additional costs are typically built into the posted price and are not added at checkout.A $0.05 bottle/can deposit was also added to eligible beverages sold at stores with scanners.Data collection provided information on a variety of available products, the distribution of which was not necessarily reflective of local purchase and consumption patterns. For example, energy drinks generally cost more per ounce than other types of sugary drinks but are purchased in much smaller volumes. To adjust for this, sugary and low-calorie drink subcategories were weighted by the relative proportion of volume sold in the NYC retail environment using Nielsen sales data from 2015 .34 After weighting, subcategories of beverages were collapsed into three main categories for analyses of availability and price: sugary drinks, low-calorie drinks, and water/seltzer. Price per ounce of 0.35-liter and 0.59-liter drinks of the same beverage category within stores was compared using paired t-tests. No significant differences were found; therefore, both sizes were included in the primary analyses.This strategy is consistent with another recent study of beverage pricing.Availability of beverage categories and subcategories (yes/no) was summarized with frequency counts and percentages. McNemar's test for matched paired data was used to test for differences in the availability of sugary drinks relative to low-calorie drinks and to water/seltzer in the overall sample; and a chi-squared test was to test for differences in the availability of beverage categories by neighborhood poverty level. Pricing data are summarized using means, standard deviations, and ranges. To standardize across potentially varying product sizes, price was analyzed on a per-ounce basis.t-tests were used to test for differences in the mean price of sugary drinks relative to low-calorie drinks and to water/seltzer in the overall sample, and independent samples t-test were used to test for differences in the availability and price of beverage categories by neighborhood poverty level. We also used paired t-tests to test for differences in the mean price of sugary drinks, low-calorie drinks, and water/seltzer within store types, but lacked sufficient variation to estimate differences in presence within store types. All analyses were performed using Stata version 15.0 .Paired The final sample included 106 of the initially sampled 110 stores , of which 54 were in high-poverty census tracts and 52 were in low-poverty census tracts. Four stores were excluded, because store staff asked the researchers to leave the premises, resulting in a 96% completion rate.p=0.47) or low-calorie drinks (p=0.0) by census tract poverty level. The presence of water/seltzer, however, was significantly lower in high-poverty census tracts (84.6%) versus low-poverty census tracts (96.3%) (p=0.04). In all census tracts combined, sugary drinks and water/seltzer were available in 91% of retailers, and low-calorie drinks were available at 87% of retailers. In high-poverty neighborhoods, all three beverage categories were available at >80% of retailers .There were no significant differences in availability of sugary drinks compared with either low-calorie drinks or water/seltzer overall . We alsoIn low-poverty areas, all three categories were available at >90% of retailers . When analyzed by store type, no differences existed in the availability of sugary drinks compared with low-calorie drinks or water/seltzer .p=0.65) and significantly more expensive than the mean price of low-calorie drinks  (p=0.37), low-calorie drinks , or water/seltzer .The mean price per 0.03-liter of sugary drinks across the sample was $0.08, which was similar to the price per ounce of water/seltzer  . There wp=0.03; $0.08 vs. $0.11, p=0.02, respectively) .The mean price per 0.03-liter of sugary drinks versus low-calorie drinks did not significantly differ at Dollar Tree stores, convenience stores, or Target stores . At supectively) . The mea24Our findings show that sugary drinks are pervasive in the NYC retail environment. Nearly all store locations in our sample sold sugary drinks; their ubiquity at pharmacies is especially concerning, given the ostensible purpose of these retailers is one of health promotion. The primary finding from our study is that the availability of water/seltzer is significantly lower in high-poverty areas than in low-poverty areas. Even though the price of beverages is similar, the lower availability of water in high-poverty areas is concerning because equivalent pricing of sugary drinks and water/seltzer may not provide a strong enough incentive toward selecting water or seltzer, as consumers' decision making is impacted by many factors beyond price.35Food and beverage companies tend to employ marketing strategies that capitalize on place, price, product, and promotion—known as the 4 P's of foundational marketing. To drive purchasing and ultimately increase sales, companies use place-based marketing, including offline and online promotion tactics; sell their products for low prices; and develop unique products that appeal to particular groups of consumers.36 If water/seltzer is less available and sugary drink ads are prevalent in high-poverty areas compared with low-poverty areas, residents may be persuaded to purchase sugary drinks, especially if the price is the same.For example, a recent study found that outdoor sugary drink advertising in NYC is prevalent in retail-dense areas, with a higher density of sugary drink ads observed in neighborhoods with a greater percentage of residents who are Black, as well as with higher poverty, and lower education levels.37 Given the lack of consensus on the health impacts of such beverages, pricing schemes that might incentivize consumption of low-calorie drinks over water, which is known to be the healthiest choice, may be seen as problematic.Low-calorie drinks were priced similarly to sugary drinks in both high-poverty and low-poverty census tracts. Compared with sugary drinks, low-calorie drinks do not have as robust an evidence base regarding long-term impacts on health. As such, public health experts acknowledge further research is needed to assess impacts related to low- and no-calorie sweetener consumption, particularly among children.34 who found that sugary drink prices did not vary by income or neighborhood poverty level. However, our findings differed in that the prices of sugary drinks and water/seltzer were similar in most retail outlets in our sample, whereas Lieder and Powell found that water was significantly less expensive than sugary drinks at food stores in four U.S. metro areas. This may be due to potential differences in the price elasticity of bottled water in these metro areas compared with NYC, possibly driven by differences in perceptions of the safety of consuming tap water.38Our findings support those of Leider and Powell,n=8), dollar stores in general have recently gained media attention for serving as the primary food source for many low-income families and predominantly supplying low-quality nutrient-poor highly processed foods.39–41In our study, Dollar Tree stores sold sugary drinks for only five cents/ounce, offering very-low-cost access to these products. Put in perspective, this equates to just $0.60 for a 0.35-liter can or $1.00 for a 0.59-liter bottle. Although we included a small sample of Dollar Trees  are urgently needed to enable families with lower incomes to afford healthy products.Not only do these retailers provide access to inexpensive unhealthy products, their presence may also displace stores with healthier, although market rate, food options.43 A growing body of empirical evidence suggests beverage taxes reduce sugary drink purchases and intake and can increase water consumption,44–49 including among consumers with lower income.50Policy approaches that incentivize price-sensitive consumers to select the healthier of the two beverage options  would be preferable to one where both options are equal. Strategies to increase the relative price of sugary drinks may be particularly effective; for instance, one study showed that a 10% increase in the price of sugary drinks would lead to a 12% decrease in consumption.51 These approaches are as of yet untested for sugary drinks but have been identified by public health experts as innovative policies warranting consideration.51Some price-based policy approaches to reduce sugary drink consumption, including minimum pricing and discount bans, find their roots in the tobacco control policy approaches. Requiring sugary drink retailers to have a license is another public health strategy that may help regulate practices in these spaces.This study had several limitations to note. First, the cross-sectional nature of the survey only allows for presenting data at a single time point. Second, data on availability and prices of specific beverages were taken from only a sample of retailers that do not represent the full scope of where beverages are sold, and a limited number of specific chains  were included. Third, not all retailers were located precisely within sampled census tracts; in these instances, stores in nearby census tracts were used instead.Store environments may play a critical role in short-term consumer purchasing and consumption patterns, which may contribute to longer term negative low-calorie–related health outcomes. The lower availability of water/seltzer in high-poverty areas than in low-poverty areas is concerning given high rates of obesity and diabetes in high-poverty areas. As morbidity and mortality associated with low-calorie–related diseases continue to impact individuals, families, communities, and institutions, public health experts must also continue to explore opportunities to address not only the social, but also commercial, determinants that maintain conditions for poor health.


TPE or intravenous immunoglobulins (IVIG) infusions were used in impending/manifested myasthenic crises, especially in patients at high-risk for prolonged invasive ventilation (IMV) and in those tolerating non-invasive ventilation (NIV). The clinical improvement was assessed using the Myasthenia Muscle Score (0–100), with ≥20 increase for responders. The primary outcome measures included the rates of implemented TPE, IVIG, and corticosteroids immunotherapies, NIV/IMV, early tracheotomy, MMS scores, extubation time, neuro-ICU/hospital LOS, complications, and mortality rates. The univariate analysis found that IMV was lower in the nanomembrane-based group (42%) compared to the conventional treatment group (83%) (p = 0.02). The multivariate analysis using binary logistic regression revealed TPE and NIV as independent predictors for short-term (≤7 days) respiratory support . The novel TPE technology moved our clinical practice towards proactive rather than protective treatment in reducing prolonged IMV during MG acute exacerbations.According to the American Academy of Neurology 2011 guidelines, there is insufficient evidence to support or refute the use of therapeutic plasma exchange (TPE) for myasthenia gravis (MG). The goal of this study was to determine whether a novel nanomembrane-based TPE could be useful in the treatment of MG. Thirty-six adult patients, MGFA 4/4B and 5, with acute MG episodes were enrolled into a single-center retrospective before-and-after study to compare a conventional treatment group ( Myasthenia gravis (MG) is well known autoimmune disease in which antibodies bind to the postsynaptic acetylcholine receptors or related molecules in the neuromuscular junction, causing fluctuating muscle weakness ,3,4,5,6.Myasthenic crisis (MC) is a severe presentation of MG in which patients experience a rapid deterioration of muscle control. Some authors use “myasthenic crisis” to refer to any exacerbation of MG which causes or threatens to cause frank respiratory failure . Others The management of MC is challenging because of its fluctuant nature . With imNovel nanomembrane-based technology was approved by the American Society for Apheresis as a minimally invasive treatment. It is characterized by rapid control of quantitative and qualitative abnormalities of plasma and blood components using a semi-permeable nanomembrane that localizes immunologically active compounds on its surface . AccordiWe retrospectively identified all MG patients with impending or manifest MC admitted to an academic neuro-ICU between January 1999 and December 2019. The inclusion criteria were any acute exacerbations of muscle weakness leading to neuromuscular respiratory failure requiring noninvasive (NIV) or invasive (ET-IMV) respiratory support (or both), the presence of severe dysphagia with risk of aspiration, or of walking distance below five meters. Patients with congenital myasthenia, sepsis, renal failure, liver failure, malignancy, or incomplete data were excluded from the study.n = 24), while the other third with a novel nanomembrane-based TPE technology . None of the patients were included in both groups in multiple admissions for MG exacerbations. The standard treatment comprised immunotherapies, including conventional TPE, IVIG, and corticosteroids, as well as symptomatic acute treatments as needed. The nanomembrane-based TPE group patients received the same standard treatment as their conventional treatment group counterparts, with the exception of using the novel nanomembrane-based TPE technology. This consisted of a “Hemophenix” apparatus using the ROSA nanomembrane . The nanomembrane was made of Lavsan film irradiated with accelerated charged argon particles. It has pores with 30–50 nm diameter and can eliminate molecules with weight less than 40 kDa. The device had an internal filling volume up to 70 mL, which can be used even in unstable hemodynamics, and the advantage of a single-needle access using any peripheral vein.Thirty-six consecutive MG patients with acute exacerbations, Myasthenia Gravis Foundation of America (MGFA) Class IV/IVB and Class V, aged ≥18, with 45 episodes of MG acute exacerbations were enrolled into a before-and-after single-center retrospective observational study. Two-thirds of them were treated with conventional treatment , thymectomy, early-onset (<50 years), MGFA class before MC, Myasthenia Muscle Scores (MMS), comorbidities , recurrent MC, rates of intubations and early tracheotomies, non-invasive ventilation (NIV), invasive mechanical ventilation (IMV), time to successful extubation, neuro-ICU Length of Stay (LOS), hospital LOS, complications, and mortality rates were collected accordingly.Primary outcome measures included: (1) changes in the implemented immunotherapies ; (2) changes in the implemented respiratory support rates; (3) changes in the implemented early tracheotomy rates; (4) changes in extubation time; (5) changes in MMS scores; (6) changes in neuro-ICU LOS; (7) changes in hospital LOS; (8) changes in the complication rate directly related to the implemented treatments; (9) changes in mortality rates.Secondary outcome measures included: (1) distribution of potential variables of clinical relevance to the short-term (≤7 days) vs. long-term (≥8 days) respiratory support; (2) calculation of ORs of prognostic variables associated with short-term or long-term respiratory support.2 test or Fisher’s exact test (as appropriate). Continuous variables were compared with the independent samples T-test in normal distribution or the Mann–Whitney U-test for distributions different from the normal (between-group comparisons), and with the paired samples T-test or Wilcoxon signed ranks Z-test, respectively (within-group comparisons). All statistical analyses were performed at ɑ = 0.05. To find independent predictors for short-term or long-term respiratory support, we dichotomized the MG patients into two groups (≤7 days vs. ≥8 days with implemented NIV/IMV or both). The distribution of potential variables of clinical relevance to the respiratory support were compared between the two groups using a univariate analysis. All the variables that achieved statistical significance were selected for the multivariate analysis. Thereafter, the p-values and OR values of the selected variables were calculated using binary logistic regression.Data were analyzed using SPSS v.20 . Categorical data were compared with the χBaseline demographics and clinical and laboratory characteristics of the studied groups were comparable .About 2/3 of the patients were women and 1/3 were men. One of the patients from the before-group had three exacerbations. Eight other patients from the before-group and six patients from the after-group had two exacerbations. The reasons for the worsening were anticholinesterase medication overdose (12.5% of the patients), other change in the treatment algorithm (8% of the patients), concomitant infections (45% of the patients), and surgery and stress (10% of the patients). The reason remained unknown in about 14% of the patients. In another 17% of them, the MC was the first manifestation of MG disease.There were no between-group changes in survival and IVIG consumption, but there was a remarkable increase in the use of TPE (75%), less IMV, more aggressive NIV trials, and a reduction of early tracheotomy by one-half along with shortening the extubation time after the introduction of the novel TPE technology . The onlp = 0.004, same-sex comparisons).The mortality rate was not statistically significant—one patient (4.2%) in the before-group and one patient (8.3%) in the after group—both patients had significant comorbidities . In the p < 0.05). All variables that achieved statistical significance were further investigated using multivariate analysis.Of 36 MG patients with acute exacerbations, 16 (44.4%) received short-term (≤7 days) respiratory support  . By compThe results of the binary logistic regression are shown in No complications from the TPE itself were detected. We did not observe significant changes in blood, biochemical, or hemostaseologic parameters due to the plasmapheresis.Our study has some important caveats. Since we performed a single-center study with a relatively low number of patients, we have more preliminary findings than conclusive ones. Although our sample size was less representative, it corresponded to the observed small single-center study population sample size (13–53 patients) reported by others . AnotherOur primary outcomes  support p = 0.109). Although not statistically significant, our finding could be clinically relevant and suggests the advantages of rapid improvement using more aggressive immunomodulatory therapies, leading to less high-dose corticosteroid exposure.Another aspect of the primary outcome measures included corticosteroid use as a part of our aggressive immunomodulatory approach . A rapidOur data suggest that the novel nanomembrane-based plasma exchange technology (NMBPE) is safe and efficient. It seems superior to the conventional treatment, especially in terms reducing the need for intubation, tracheostomy and the time on artificial ventilation, thus reducing the chance for the ventilator-dependent complications. The last factor was not detected in our study, probably because of the sample size limitation. The after-group was also characterized by increased use of non-invasive ventilation, thus suggesting more preserved swallowing in this group, which was not directly quantified in our study. The patients with NMBPE also had shorter courses of the disease.One of the reasons that nanomembrane-based TPE is safer than the conventional TPE is simpler venous access  and preserved hemodynamic stability of our patients. Of course, peripheral access is acceptable in some forms of conventional TPE as well .Our data support the suggestion that nanomembrane-based TPE can improve outcomes. It can optimize rather than substitute intubation, ventilation, and early tracheostomy in severe MC . HoweverThis pilot study leaves room for further questions. Some of them are connected with the most appropriate protocol for nanomembrane-based TPE. We have 3–5 procedure every other day, while for immunoabsorption and double-filtration plasmapheresis, some authors recommend a daily schedule scheme. They also suggest that the optimal number of sessions is four .Another relevant question is whether the nanomembrane-based TPE would be also effective in other forms of treatments of MG, for example, in preparation for surgery. The clinical response of conventional TPE seems better in patients with higher MG scores , but morAn important research perspective could be to study the best combinations between nanomembrane-based TPE and other treatments. For example, the combination of double-filtration plasmapheresis and rituximab was proven to be effective in treatment of refractory MG , as wereNanomembrane-based TPE is a new and promising type of TPE, which seems to share the basic advantages of the conventional TPE, but probably with less adverse effects. The novel technology has changed our clinical practice towards more proactive rather than protective treatment in reducing prolonged IMV during MG acute exacerbations.


Cerebral venous thrombosis (CVT) is a rare type of stroke that may cause an intracranial hypertension syndrome as well as focal neurological deficits due to venous infarcts. MRI with venography is the method of choice for diagnosis, and treatment with anticoagulants should be promptly started. CVT incidence has increased in COVID-19-infected patients due to a hypercoagulability state and endothelial inflammation. CVT following COVID-19 vaccination could be related to vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare but severe complication that should be promptly identified because of its high mortality rate. Platelet count, D-dimer and PF4 antibodies should be dosed. Treatment with non-heparin anticoagulants and immunoglobulin could improve recuperation. Development of headache associated with seizures, impaired consciousness or focal signs should raise immediate suspicion of CVT. In patients who received a COVID-19 adenovirus-vector vaccine presenting thromboembolic events, VITT should be suspected and rapidly treated. Nevertheless, vaccination benefits clearly outweigh risks and should be continued. Increased intracranial pressure with newly onset headache in 70 to 90% of patients , and lesSeizures, which may affect as much as 34% of patients [Focal neurological deficits ;Encephalopathy or coma, usually in the context of multiple sinus or deep venous occlusions;Specific regional syndromes, including periorbital pain, ocular chemosis, palsies of oculomotor cranial nerves and the ophthalmic division of the fifth cranial nerve (in the case of cavernous sinus thrombosis).Cerebral venous thrombosis (CVT) is an uncommon type of stroke with an incidence around 3–4 cases per million adults, with a predominance in Caucasian females . It may The intracranial hypertension is due to increased venular and capillary pressure as well as decreased cerebrospinal fluid absorption.There are several risk factors associated with CVT, such as pregnancy, postpartum and the use of oral contraceptives . Other cBy May 2022, COVID-19 had infected 513 million people worldwide and had caused over 6.2 million deaths . A retroThe aims of this study, therefore, are to report cases of patients with CVT related to COVID-19 who were hospitalized in the Neurovascular Unit of the Hôpital Fondation Adolphe de Rothschild in Paris and, afterwards, to review the literature concerning the management of CVT in the COVID-19 pandemic context.A retrospective analysis of medical charts of the Neurovascular Unit of Hôpital Fondation Adolphe de Rothschild was performed. The number of hospitalizations due to cerebral venous thrombosis from 2018 to 2020 was compared with the period of 2020 to 2021. Cases in which COVID-19 infection was detected in relation to CVT were described.Descriptive statistics were performed using JASP (JASP Team (2022), Version 0.16.3) (computer software), Eric-Jan Wagenmakers, University of Amsterdam. Amsterdam, The Netherlands.A literature review was developed on the Pubmed database searching for the keywords “cerebral venous thrombosis”, “COVID-19”, “COVID vaccine”, and “vaccine-induced thrombotic thrombocytopenia”.Patients and/or patients’ families consented to the publication of images and data.During the period of 2018–2019, 39 individuals with CVT were hospitalized, while 47 patients were admitted during 2020–2021 (a 1.2-fold increase). However, COVID-19 PCR was positive in only 5 patients out of those 47 (10.6% of cases). Only one case of CVT was possibly related to a COVID-19 vaccine (Johnson & Johnson).2 and had a previous history of five miscarriages, with anti-phospholipid syndrome ruled out.One patient had a history of breast cancer 5 years before evaluation. It was in remission, but still being treated by tamoxifen. Another individual was under oral contraception with an estrogen–progestogen combined pill for the treatment of menorrhagia and had an iron-deficiency anemia with a hemoglobin level of 7 g/dL. One patient was obese, with a Body Mass Index (BMI) of 34 kg/mRegarding neuroimaging features, three of our patients had transverse and sigmoid sinus thrombosis, one of which was also associated with a hemorrhagic venous infarct ; one patA 70-year-old male patient was hospitalized for presenting CVT with involvement of the superior longitudinal sinus and the left transverse sinus . Such evCVT is a rare but potentially severe neurological disorder that may have a wide spectrum of clinical presentations.The method of brain Magnetic Resonance Imaging (MRI) with contrast-enhanced venography is the one most commonly indicated to diagnose CVT. The diversity of radiological signs depends on the delay between symptom onset and MRI, but the typical finding consists of the visualization of the thrombus, a contrast-filling defect (empty delta sign), or the lack of flow signal. Venous strokes appear as an edematous region with mixed infarct, with possible hemorrhage in atypical locations, not compatible with arterial territories. If a venous MRI is not available, or for any reason contraindicated, a Computerized Tomography (CT) scan with venography is an alternative diagnostic modality.Concerning treatment, it should consist of anticoagulation by low-molecular-weight heparin, warfarin or with Direct Oral Anticoagulants (DOACs). The RESPECT-CVT trial, which compared dabigatran versus warfarin in 120 randomized patients, reported no differences in the safety and efficacy between the groups . Yaghi aA randomized trial compared Rivaroxaban versus warfarin or heparin in 114 children with CVT and found decreased bleeding risk with similar low recurrence rates and reduced thrombotic burden .Endovascular treatment is mostly discussed in cases of thrombosis of multiple sinuses associated with severe intracranial hypertension and clinical deterioration. The American Heart Association guidelines recommend endovascular thrombolysis or thrombectomy in refractory patients who deteriorate despite anticoagulant treatment . SystemaHowever, it is worth mentioning that a multicenter, randomized, open-label study (the TO-ACT study) that included 67 patients with CVT and at least one risk factor for poor outcome  showed no difference in disability at 12 months between patients treated by a standard medical treatment versus those who underwent endovascular treatment . The stuDecompressive craniectomy is a controversial procedure that can be performed in life-threatening situations. Two retrospective studies of medical records compared patients with malignant CVT treated by craniectomy versus medical treatment alone, and the results showed that craniectomy decreased mortality and improved functional outcomes ,24. A prAntiepileptic drugs should not be used preventively, and corticoids have no benefit. Acetazolamide could eventually be useful in refractory intracranial hypertension .Considering prognosis, it is largely variable depending on the site of thrombosis, the size of thrombus and also on the delay before clinical diagnosis and the start of treatment. The overall mortality is around 6% while circa 10% have permanent disability after one year of follow-up .The clinical presentation of CVT related to COVID-19 does not seem to be different from CVT which is not COVID-19-related: cephalalgia, seizures, encephalopathy, abducent palsies, papilledema and focal deficits such as hemiparesis or aphasia. In a multicenter study, headache was present in 50% of the cases, decreased level of consciousness in 12.5% and neurological focal deficits in 25% of patients. In another multicentric retrospective cohort, headache was present in 85% of cases. Focal symptoms such as hemiparesis or seizures were present in 42% of cases, and cortical signs such as aphasia or hemianopsia were present in 25% .One study focused on neuro-ophthalmological complications of CVT related to COVID-19. The intracranial hypertension caused by CVT can lead to papilledema and direct ischemic injury of visual pathways and also to ocular motility impairment due to injury of oculomotor and abducent nerves with diplopia. For patients with papilledema and visual impairment, a lumbar puncture can be performed to rapidly lower intracranial pressure. Acetazolamide can also be used in this context. Severe cases should undergo cerebrospinal fluid shunt or optic nerve fenestration .Thromboembolic events related to COVID-19 are frequent and can appear in later stages of infection and even after patients no longer have respiratory symptoms . One stuIt is worthy of mention that even “Long COVID-19 syndrome”—which refers to patients who present long-lasting inflammatory alterations and prolonged persistence of symptoms—can be associated with an increase in prothrombotic state. Some of the patients present persistent high levels of D-dimers with an increased risk of thromboembolic complications .The literature reports 3 to 4 days as the mean time from neurological symptoms onset to CVT diagnosis and 7 to 11 days as the mean time from COVID-19 symptoms onset to CVT diagnosis ,13,27,33In a multicentric study, Abdalkader and colleagues  reportedRegarding neuroimaging features, the transverse sinuses and the superior sagittal were most commonly affected; one patient also had deep venous thrombosis . AccordiAnother case series showed that half of the patients presented multiple sinuses implicated . One revIt has been well established in the literature that infections, in general, increase the risk of CVT, especially those related to the cranium, such as sinusitis, meningitis, mastoiditis, otitis and tonsillitis . Viral iThe mechanisms which lead to the increase in thromboembolic events vary and include endothelial disfunction, cytokine storm, an increase in prothrombotic markers such as D-dimers and fibrinogen, as well as the rise of pro-inflammatory molecules such as interleukin-6 and C Reactive Protein (CRP), which would result in a hypercoagulability state . The sepCOVID-19’s interaction with angiotensin-converting enzyme (ACE) receptors may be the leading cause of endothelial damage, being associated with the coagulopathy caused by the increase in prothrombotic molecules such as D-dimers and fibrinogen, the dysregulation of inflammatory cascades as well as platelet dysfunction. The latter is characterized by increased platelet adherence and aggregation , which iNevertheless, hypoxia, which is frequently present in COVID-19 patients, especially in the intensive care unit setting, is also associated with increased blood viscosity, the activation of genes related to hypoxia that interfere with coagulation and alterations in fibrinolysis .Standard CVT treatment, with LMWH used in most cases, was associated with the treatment of complications, such as antiepileptic drugs when seizures were present or detected in the EEG of comatose patients. Very few patients were treated by endovascular thrombectomy or thrombolysis. A multicentric study already mentioned above recommends intravenous recombinant tissue plasminogen activator (rt-PA) and endovascular treatment as a last resort for refractory cases ,38. One Concerning prognosis, one Asiatic review found a mortality rate in CVT related to COVID-19 as high as 45.5% . CVT morNot only COVID-19 infection but also COVID-19 vaccines were associated with thromboembolic episodes in many reports and reviews. To this date, 11.5 billion doses of COVID-19 vaccines have been administered worldwide , which hThe rapid development of the vaccines was due, partially, to previous research on the technology of adenoviral vectors, which, along with m-RNA technology, accounts for the majority of vaccines that were administered during the pandemic period.One of the most severe adverse effects attributed to the adenovirus-vector COVID-19 vaccine is immune thrombotic thrombocytopenia (VITT), which has already been associated with other adenoviral vector vaccines . This coThe fact that VITT occurs mainly after vaccination with ChAdOx1 suggests that VITT-induced antibodies against PF-4 do not react to the COVID-19 spike protein but probably react to the adenoviral vector .One German multicentric vaccination study group found an incidence of CVT of 0.55/100,000 in patients after taking vaccines. They reported a total of 45 CVT cases within a month after vaccination, as well as nine ischemic strokes and four hemorrhagic strokes. There was a predominance of females (77.8%) and of patients younger than 60 years (80%); 85.5% of events occurred after ChAdOx1 vaccine, 14.5% after BNT162b2 vaccine; and none after mRNA-1273 vaccine. The adjusted incidence for the ChAdOx1 vaccine was 1.52 per 100,000, with an adjusted incidence of 3.14 for women ,44. ThisOne meta-analysis revealed that CVT represented 29% of total thromboembolic events following adenovirus-vector-based vaccination against COVID-19; 28% of patients who had CVT post vaccine died. The mean age of patients who presented CVT post vaccine was 45 years, with 75% of them being women; the mean time from vaccine to symptoms was 10 days, and 68% presented hemorrhagic infarcts [The time of CVT symptoms onset after vaccine ranged from 6 to 15 days after the Ad26.COV2.S vaccine and 5 to 24 days after the ChAdOx1 vaccine . The majOne large cohort study in the UK included 95 patients who presented CVT after COVID-19 vaccines, and it compared the group who fulfilled diagnostic criteria for VITT to the CVT without those criteria. It found that the mean age was lower in the VITT group (47 versus 57). The VITT group had more sinus thrombosed than the non-VITT group, more hemorrhagic infarcts and unfavorable outcomes. Outcomes were better amongst those who received non-heparin anticoagulants and immunoglobulin . AnotherThere were also two cases of CVT reported after BNT162b2 vaccine, but with no evidence of VITT . One of A VITT risk score was developed, adapted from the HIT 4Ts scoring system which considers the number of thrombocytes, the timing post-vaccine, the presence of thrombosis or elevated D-dimers and the presence of other possible causes for thrombosis or thrombocytopenia. In the German study, CVTs with a score higher than two occurred after the ChAdOx1 vaccine, and 44% of these CVTs scored four points, meeting all criteria for likelihood of association with the vaccine . The morClinicians should raise awareness of possible VITT, especially in young female patients presenting with CVT after exposure to COVID-19 vaccines, and they must dose PF4-antibodies if thrombocytopenia, preferentially by ELISA HIT assays (which were shown to have higher sensitivity for detection of these antibodies) . Other tTreatment consists of anticoagulation by non-heparin anticoagulants  and avoiding heparin and heparin products (including prothrombin complex concentrates) . WarfariIntravenous immunoglobulins, at a dose of 1 g/kg for at least 2 days, should be used in refractory cases ,50. For Platelet transfusions could be beneficial before invasive procedures or for patients with a high risk of bleeding . In HIT,The main limitations of this study concern its small number of patients, as well as its retrospective nature. Although we have performed an extensive medical chart review to track patients who presented cerebral venous thrombosis in the context of a COVID-19 infection over the last two years, it is possible that some data are missing. One reason might be faulty medical chart completion. If the study had a prospective nature, medical staff could be made aware of more specific data that should be collected for all possible candidates. It is also possible that we have failed to diagnose COVID-19 in some patients with cerebral venous thrombosis due to fact that in the beginning of the pandemic not all individuals were screened for COVID-19.CVT is a rare yet potentially severe complication of COVID-19 infection and also of COVID-19 vaccination. The development of headaches associated with seizures, impaired consciousness or focal signs should raise immediate suspicion of CVT, and neuroimaging should be obtained as soon as possible. In patients who received an adenovirus-vector vaccine and are presenting with thromboembolic events, platelet count, D-dimer and PF4 antibodies should be dosed, and if there is suspicion of VITT, non-heparin anticoagulation should be started in conjunction with immunoglobulins. Nevertheless, since COVID-19 infection itself is also related to thromboembolic events, the benefits of COVID-19 vaccination outweigh the risk of thrombosis and should not be interrupted ,55. A sp


The relationships between repeated non-fasting triglyceride (TG) measurements and carotid stenosis progression during follow-ups have never been investigated. In 111 consecutive carotid arteries of 88 patients with ≥50% atherosclerotic stenosis on at least one side, who had ≥3 blood samples taken during ≥one-year follow-ups, clinical variables were compared between carotid arteries with and without subsequent stenosis progression. To evaluate non-fasting TG burden, a new parameter area [TG ≥ 175] was calculated by integrating non-fasting TG values ≥ 175 mg/dL  with the measurement intervals (year). Carotid stenosis progression occurred in 22 arteries (19.8%) during the mean follow-up period of 1185 days. Younger age, symptomatic stenosis, higher mean values of TG during follow-ups, the area [TG ≥ 175], mean TG values ≥ 175 mg/dL and maximum TG values ≥175 mg/dL were significant factors related to the progression on univariate analyses. The cut-off value of the area [TG ≥ 175] to discriminate carotid stenosis progression was 6.35 year-mg/dL. Multivariate analyses demonstrated that symptomatic stenosis and the area [TG ≥ 175] ≥ 6.35 year-mg/dL were independently related to carotid stenosis progression. In conclusion, the area [TG ≥ 175] was an independent risk factor for carotid stenosis progression, and this study suggests the importance to continuously control non-fasting TG levels < 175 mg/dL during follow-ups to prevent carotid stenosis progression. Although many types of intervention have been explored to treat dyslipidemia, particularly low-density lipoprotein cholesterol (LDL-C), which is an established risk factor for the development of cardiovascular and cerebrovascular diseases, the diseases have not yet been eradicated. In this context, triglyceride (TG) is attracting more attention as a residual risk factor of atherosclerotic diseases. Recent studies reported that elevated non-fasting TG levels had a marked impact on cardiovascular disease ,2,3 and It is very useful in clinical practice if non-fasting serum TG values can effectively assess a risk of carotid stenosis progression, because postprandial TG measurements would allow clinicians to easily manage TG levels with a minimum of patients’ discomfort. However, there is concern that postprandial TG measurements may vary considerably due to the influence of meals and may be unreliable as an index. Since no study has investigated the relationships between changes or fluctuations in non-fasting TG levels during follow-ups and progression of carotid artery stenosis so far, the present study aimed to examine changes in non-fasting TG levels over time and to find a better influencer related to non-fasting TG that may independently aggravate carotid artery stenosis.The analyzed 111 carotid arteries in eighty-eight patients  had an average age of 70.6 years . During a mean follow-up period of 1185 days, 22 of 111 carotid stenosis (19.8%) suffered stenosis progression: the mean degree of carotid stenosis progressed from 32.2%  at baseline to 72.9%  at the last follow-up on ultrasonography. Among the twenty-two progressively narrowed arteries, three caused ipsilateral ischemic stroke during the follow-up period, and eleven and two underwent CAS and CEA, respectively. The study included two symptomatic carotid stenosis of ≥50%, for which patients consented to neither CAS nor CEA at the initial DSA diagnosis: the carotid artery with symptomatic 60% stenosis progressed to 80% stenosis without ischemic stroke in 390 days and then was treated with CAS, while the other carotid artery with symptomatic 74% stenosis showed no significant progression of stenosis during the 600-day follow-up.Baseline clinical characteristics of 111 carotid arteries were shown and compared between the progression and non-progression groups in p value . Thus, symptomatic carotid stenosis and the area [TG ≥ 175] ≥ 6.35 year-mg/dL were used as candidate variables for multivariate logistic regression analyses. Logistic regression analyses indicated that symptomatic carotid stenosis and the area [TG ≥ 175] ≥ 6.35 year-mg/dL were independent factors associated with carotid stenosis progression , and therefore can be a strong predictor of cardiovascular and cerebrovascular events ,2,3,11. Recently, the level of non-fasting TG is getting more attention as an atherosclerosis promoting factor, and recent guidelines recommend using non-fasting values rather than fasting ones for the screening and management of TGs ,14,15. HThe impact of elevated non-fasting TG levels on carotid artery stenosis can be explained by the following mechanisms ,20. In tThere are some limitations to the present study. First, the present study included patients with well-controlled LDL-C levels but little control of elevated TG levels, which may have biased the results. In patients with carotid artery stenosis with elevated LDL-C levels, it is important to control LDL-C by administering statins as the first choice to prevent the carotid stenosis progression, and the enrolled patients had received the statin-based treatment at the time of the first visit to our hospital. However, patients with elevated TG levels have uncommonly undergone treatments such as fibrate administration, because the combination of statins and fibrates raises the risk of myopathy and rhabdomyolysis, and it remains unclear if TG-lowering therapy suppresses carotid stenosis progression. Based on the results of the present study, we plan to perform TG-lowering therapy using pemafibrate, which is considered to be safer in combination with statins . Second,This was a single-center retrospective study. A total of consecutive eighty-eight patients  were recruited from patients with digital subtraction angiography (DSA) for carotid artery stenosis in our hospital from 1 January 2013 to 31 December 2019. The enrolled patients met the following inclusion criteria: aged 20 years or older at diagnosis, unilateral or bilateral atherosclerotic cervical internal carotid artery stenosis of ≥50% on the initial DSA according to the method used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), follow-up period of more than one year for less severe-side and/or worse-side carotid artery stenosis with no indication for carotid revascularization from the first DSA in our hospital, B-mode and color Doppler ultrasonography or magnetic resonance angiography of the carotid artery one or more times per year from the first DSA, and at least three blood samples taken during the follow-up period. The exclusion criteria were as follows: patients who underwent carotid artery stenting (CAS) or carotid endarterectomy (CEA) for carotid stenosis before 1 January 2013, carotid stenosis caused by dissection, and carotid artery stenosis with less than one-year follow-up from the first DSA to the last ultrasonography or CAS/CEA treatment. CAS or CEA was performed in accordance with the indication of carotid revascularization as described previously , and carWhen patients first visited the outpatient department of our hospital, medical treatment was administered including antiplatelet agents and drugs for hypertension, dyslipidemia and diabetes mellitus if needed, according to the related Japanese guidelines. Routine laboratory data were assessed with non-fasting blood sampling to avoid patient burdens to fast, and the timing of the blood test was decided by the attending physician. The study was conducted to examine the relationships between carotid stenosis progression and each clinical variable, especially focusing on non-fasting TG.The study was approved by the ethical committee of our institute and was performed according to the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000 . For retrospective analyses, the committee waived the need for formal consent.All clinical data were documented by experienced vascular neurosurgeons. The following data were gathered from medical records of 88 patients who underwent the first DSA during the period for extracranial  internal carotid artery stenosis: age, sex, body mass index, hypertension, diabetes mellitus, dyslipidemia, radiation induction, smoking, alcohol consumption, clinical symptoms (symptomatic or asymptomatic), degree of carotid artery stenosis (the NASCET method) on ultrasonography from the time of the first DSA diagnosis to the last follow-up or before CAS or CEA, the signal intensity ratio (SIR) of a carotid plaque on 3-dimensional T1-weighted gradient echo magnetic resonance images , atherosNon-fasting blood sampling was measured within 10 h postprandially, and non-fasting hypertriglyceridemia was defined as non-fasting serum TG levels ≥ 175 mg/dL according to the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine joint consensus initiative . Other cNon-fasting TG levels were measured at least three times at different timing during the follow-up period. In addition to the maximum, minimum, and mean values of non-fasting TG during the follow-up period, the area of TG ≥ 175 mg/dL  was calculated. The area [TG ≥ 175] was defined as the area determined by the time axis (year) and non-fasting TG values more than 175 mg/dL  during the follow-up period .In this case, blood samples were taken five times during the follow-up period and the respective non-fasting TG values were 330 mg/dL on day 0, 169 mg/dL on day 268, 126 mg/dL on day 704, 188 mg/dL on day 732, and 330 mg/dL on day 907. The area [TG ≥ 175] in this case is 95.2 year-mg/dL, based on the following formula:Among 176 enrolled carotid arteries in 88 patients, one carotid artery was excluded because of complete occlusion at the initial DSA. In addition, 64 worse-side carotid arteries had CAS or CEA following the first DSA, and were therefore excluded. Thus, the remaining 111 carotid arteries on the less severe stenosis side and worse stenosis side with no indication for carotid revascularization were analyzed. In the analysis, carotid artery stenosis was divided into two groups, progression and non-progression groups. The progression of carotid artery stenosis was diagnosed only using ultrasonography as previously described  ≥0.4). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and the independence of variables was tested using the likelihood ratio test on reduced models. The receiver operating characteristic (ROC) curves with area under the curve (AUC) for the area [TG ≥ 175] were calculated in the reference population by carotid stenosis progression. p values less than 0.05 were considered significant.All data were analyzed using the SPSS software version 25.0 . Categorical variables were reported as a proportion and were analyzed using chi-square or Fisher’s exact tests, as appropriate. Continuous variables were reported as a mean ± standard deviation (SD) or a median (interquartile range) and were compared using unpaired t or Wilcoxon rank-sum tests between the two groups, as appropriate. The impact of each variable on carotid stenosis progression was determined by multivariate logistic regression analyses using the dichotomous status (progression or non-progression) as the dependent variable. Variables were selected if univariate association was Symptomatic carotid stenosis and the area [TG ≥ 175] were independent risk factors for subsequent progression of carotid artery stenosis in patients with ≥50% carotid artery stenosis at least on one side. The findings suggest the importance of continuous monitoring of non-fasting TG levels to predict the progression of carotid artery stenosis especially in symptomatic cases. Further studies are warranted to explore the impact of non-fasting TG burden during a follow-up on carotid stenosis progression and to investigate the possibility of a TG-lowering therapy to prevent it.


Natural language processing (NLP) of unstructured text from electronic medical records (EMR) can improve the characterization of COVID-19 signs and symptoms, but large-scale studies demonstrating the real-world application and validation of NLP for this purpose are limited.The aim of this paper is to assess the contribution of NLP when identifying COVID-19 signs and symptoms from EMR.This study was conducted in Kaiser Permanente Southern California, a large integrated health care system using data from all patients with positive SARS-CoV-2 laboratory tests from March 2020 to May 2021. An NLP algorithm was developed to extract free text from EMR on 12 established signs and symptoms of COVID-19, including fever, cough, headache, fatigue, dyspnea, chills, sore throat, myalgia, anosmia, diarrhea, vomiting or nausea, and abdominal pain. The proportion of patients reporting each symptom and the corresponding onset dates were described before and after supplementing structured EMR data with NLP-extracted signs and symptoms. A random sample of 100 chart-reviewed and adjudicated SARS-CoV-2–positive cases were used to validate the algorithm performance.A total of 359,938 patients  with confirmed SARS-CoV-2 infection were identified over the study period. The most common signs and symptoms identified through NLP-supplemented analyses were cough , fever , myalgia , and headache . The NLP algorithm identified an additional 55,568 (15%) symptomatic cases that were previously defined as asymptomatic using structured data alone. The proportion of additional cases with each selected symptom identified in NLP-supplemented analysis varied across the selected symptoms, from 29%  of all records for cough to 64%  of all records with nausea or vomiting. Of the 295,305 symptomatic patients, the median time from symptom onset to testing was 3 days using structured data alone, whereas the NLP algorithm identified signs or symptoms approximately 1 day earlier. When validated against chart-reviewed cases, the NLP algorithm successfully identified signs and symptoms with consistently high sensitivity (ranging from 87% to 100%) and specificity (94% to 100%).These findings demonstrate that NLP can identify and characterize a broad set of COVID-19 signs and symptoms from unstructured EMR data with enhanced detail and timeliness compared with structured data alone. COVID-19, the infection caused by the novel coronavirus, SARS-CoV-2 -6. The mSigns and symptoms can be documented in EMR by health care providers in four primary forms, broadly defined as “structured” and “unstructured,” which are as follows: (1) structured COVID-19 lab test order–related questionnaires; (2) structured diagnosis codes; (3) structured clinical notes (which may include self-reported information); and (4) unstructured free-text clinical notes. However, of the few large-scale studies using EMR, most are limited to structured data alone, particularly International Classification of Diseases (ICD) diagnoses, which have demonstrated low concordance with self-reported information due to incomplete documentation during physician visits . NaturalLarge integrated health care systems with access to complete EMR data provide a unique resource to investigate the value of NLP algorithms in the extraction of additional information from unstructured text fields. This paper describes the distribution and time of the onset of COVID-19 signs and symptoms before and after supplementing structured EMR with an NLP algorithm among more than 350,000 members of a large integrated health care system. In addition, we performed a validation substudy to assess the accuracy of the NLP algorithm in identifying COVID-19 signs and symptoms.Kaiser Permanente Southern California (KPSC) is one of the largest integrated health care systems in the United States providing medical services to over 4.7 million members. KPSC’s comprehensive EMR data contains individual-level structured data  and unstructured data  covering all medical visits. Therefore, the EMR represents a standardized data collection method across all health care settings . Care delivered to members outside of the KPSC system is also captured, as outside providers must submit detailed claims to KPSC for reimbursement. KPSC has a diverse member population that is largely representative of all residents in Southern California with health insurance . As of DThis is a retrospective cohort study of KPSC patients of all ages with positive SARS-CoV-2 laboratory tests from March 2020 to May 2021. SARS-CoV-2 tests of all types  across all care settings were included. Participants were included in the analysis if they had at least 6 months of continuous KPSC membership  prior to the date of their first positive COVID-19 test.All EMR records were searched for 12 prespecified signs and symptoms within 30 days prior to and following the positive COVID-19 lab test order date. Signs and symptoms included fever, cough, headache, fatigue, dyspnea, chills, sore throat, myalgia, anosmia, diarrhea, vomiting or nausea, and abdominal pain, consistent with the Centers for Disease Control and Prevention (CDC) definitions ,20. If nAn NLP algorithm was developed to identify signs and symptoms of COVID-19 and to determine their corresponding onset dates from the EMR. The algorithm development process was implemented using a rule-based approach via Python 3.6 (Python Software Foundation). This was an iterative process in which the developed algorithm was refined to align with the reference standards derived through medical chart review and adjudication. The stages of NLP algorithm development are described below and summarized in Clinical notes and structured data (diagnosis codes and symptom related questionnaires) within 30 days prior to or following the order date of the positive SARS-CoV-2 lab test were extracted from the KPSC EMR system. The extracted clinical notes were preprocessed through letter lowercase conversion, misspelled word correction, abbreviated word standardization, sentence separation, and tokenization  .lack of signs or symptoms or a historical medical event or indicate that signs or symptoms were experienced by someone else). A complete list of predefined sentence exclusion scenarios as well as “Yes” criteria for all signs and symptoms are provided in Table S2 in Patients were categorized as “Yes” for a particular symptom of interest under a set of prespecified situations . Keywords and phrases related to the 12 symptoms of interest were compiled by searching additional diagnosis terms and ontologies in the Unified Medical Language System  and wereFor each instance of identified signs or symptoms, the corresponding onset date was determined as either the clinical note date or by extracting the date from clinical notes under prespecified conditions, for example, where a date was detected with the symptom or followed with a phrase of “symptom (first) started,” “Date of symptoms (onset):,” “symptom onset date:,” and “onset:” in unstructured notes. Specific examples of prespecified conditions are included in Table S2 and Table S3 in F score for each preselected sign or symptom of interest [A sample of 100 randomly selected patients was used to assess the accuracy of the NLP algorithm in identifying each of the 12 signs or symptoms from unstructured EMR data, excluding patients used for the original algorithm development. Information on the presence or absence as well as the onset date of signs or symptoms were abstracted from EMR by trained chart abstractors using an abstraction manual. Patients for whom the sign or symptom complaint or onset date could not be clearly determined by the abstractors were further reviewed and adjudicated by a collaborating research physician. For this validation substudy, the manual chart review plus adjudicated results were deemed as the reference standard. The proportions of true positive, false positive, true negative, and false negative patients were used to estimate the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and overall interest .F score for each comparison was calculated as (2 × PPV × sensitivity) / (PPV + sensitivity).Sensitivity was defined as the proportion of patients correctly classified by the computerized NLP algorithm as experiencing the symptom of interest among patients identified with the sign or symptom by manual chart review. Specificity was the proportion of patients correctly classified as not experiencing the sign or symptom among individuals identified as not experiencing the sign or symptom according to chart review. PPV was the proportion of patients correctly classified as experiencing the sign or symptom of interest among those who were classified as experiencing the sign or symptom based on the NLP algorithm. Negative predictive value was the proportion of patients correctly classified as not experiencing the sign or symptom of interest among patients classified as not experiencing the sign or symptom based on the NLP algorithm. The We described patient characteristics and COVID-19 symptoms by mean, SD, median, and quartiles for continuous variables, and by frequency and percentage for categorical variables. Proportions of each symptom reported using structured EMR data were compared against proportions of each symptom identified through NLP-supplemented methods. Signs and symptoms were grouped into the following four categories according to the affected body system: respiratory , systemic , gastrointestinal , and neurologic (headache and anosmia). We assessed the association between characteristics of interest and inconsistencies between traditional EMR analysis using structured data and NLP supplemented analysis. All analyses were performed using Python version 3.6 and SAS statistical software version 9.4 (SAS Institute).The study was reviewed by the CDC and was conducted consistent with applicable federal law and CDC policy—45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq. The study protocol was reviewed and approved by the KPSC Institutional Review Board (#12395) with a waiver of requirement for informed consent. Only authorized persons were provided access to individual-level patient data.The study cohort included 359,938 patients with a positive SARS-CoV-2 laboratory test during March 2020-May 2021. Most patients were Hispanic , the mean age was 40.1 (SD 19.2) years, and approximately half  were female participants . The mosSupplementing structured EMR data with unstructured EMR data identified 55,568 additional symptomatic infections that were previously defined as asymptomatic based on structured data alone, representing 15.4%  of all infections. This proportion of additional identified symptomatic infections did not vary substantially by sex, age group, or race and ethnicity  to 69.4% , systemic symptoms from 44.4%  to 68.9% , neurological symptoms from 29.5%  to 52.1% , and gastrointestinal symptoms from 14.8%  to 31.4%  were not identified as symptomatic at any point over the study period based on the 12 preselected symptoms used in NLP-supplemented analyses . Among aNLP-supplemented analyses also increased the number of signs or symptoms identified per individual, often across multiple body systems. The proportion of patients reporting greater than 4 symptoms more than doubled in NLP-supplemented analysis compared to structured data alone, from 25.1%  to 53.1%  of all cases . SimilarF scores ranged from 0.86 to 1.00, with the majority being over 0.90. Regarding validation of onset time, 87% of onset dates identified by NLP were within +/- 3 days of those found by chart review; 70% were the same date . Sensitivity ranged from 87% for nausea or vomiting to 100% for cough, fever, anosmia, and abdominal pain . SpecifiAmong more than 350,000 patients, this paper demonstrates that NLP algorithms can be used to extract unstructured data from EMR on COVID-19 signs and symptoms with enhanced detail and timeliness compared with structured data alone. To the authors’ knowledge, this analysis represents the largest population study to date using NLP-based methods for identification and characterization of COVID-19 signs and symptoms.Overall, we observed that up to 60% of information on signs and symptoms may only be documented in the clinical narrative; however, this proportion varied widely between the conditions studied. Hence, previous real-world population studies that were limited to classical epidemiological methods  may have underestimated the complexity and diversity of COVID-19 symptoms. This finding has important implications for patient care by improving our understanding of the whole spectrum and pathophysiology of COVID-19. This appeared particularly relevant for respiratory and gastrointestinal symptoms, whereby our data indicate that a significant proportion of symptomatic patients  are overlooked when data are limited to structured components alone.Prior studies have noted similar improvements in COVID-19 case detection when clinical notes, ICD-10 diagnosis codes, and temperature fields have been used together, particularly for gastrointestinal conditions, rash or fever, and influenza-like illness syndromes, reporting almost double the sensitivity of detection ,24. The Compared to a systematic review including EMR and self-reported symptom data pooled from 24,410 cases across 148 studies in 9 countries , and anoThe observed discrepancies between this paper and prior evidence may be the direct result of the contribution of NLP algorithms when identifying COVID-19 signs and symptoms from EMR in this study, whereas prior studies have relied on structured components of EMR alone, such as ICD-10 diagnosis codes . Among sTogether, the findings presented here demonstrate the complexity of COVID-19, which often manifests as multiple diverse signs or symptoms across different body systems. With most prior large-scale real-world studies lacking unstructured EMR data, this observation may have been overlooked previously. As well as informing clinicians to guide patient care, understanding the complete array of signs or symptoms associated with COVID-19 could enhance population-level screening efforts. In addition, we found that NLP-supplemented analyses identified an earlier date of onset of potential COVID-19 signs and symptoms compared to traditional structured EMR data. Importantly, most of the transmission occurs within the first 5 days after symptom onset . TherefoF statistics, and PPV values to previously developed algorithms for symptom identification and COVID-19 characterization [This study has at least 5 limitations, some of which are ubiquitous and unavoidable in observational research. First, while we capture symptoms occurring within 30 days of a COVID-19–positive test, it is possible that the reported symptoms detected in the EMR were due to other causes. However, chart review verified that the identified symptoms occurring within 20 days of testing were attributable to COVID-19 in the overwhelming majority of cases. Nevertheless, a comprehensive assessment of the overall usefulness of NLP would have involved a comparison with symptom reports in a SARS-CoV-2–negative population. Second, SARS-CoV-2 diagnostic tests were restricted to certain populations at differing points over the study period corresponding to periods of limited availability. As such, our estimates largely represented patients with symptomatic COVID-19 who sought medical care, and therefore it is likely that asymptomatic individuals were underrepresented in our analysis. Third, we defined symptomatic COVID-19 according to 12 conditions established as signs or symptoms of COVID-19 in the scientific literature; hence, it is possible that symptomatic cases reporting conditions outside of this established list are not counted as symptomatic. Fourth, the validation data set used in this paper included a relatively small sample size, which may have led to spurious findings. However, despite the small sample, the NLP algorithm performed well when identifying COVID-19 symptoms, producing similar sensitivity, rization ,36,37. LThis paper demonstrates that NLP can identify and characterize a broad set of COVID-19 signs and symptoms from medical records, with enhanced detail and timeliness, compared with prior EMR-based studies. These findings provide clear evidence that structured EMR data alone are incomplete for symptom capture, and NLP can enhance our understanding of the whole spectrum of disease pathophysiology. Further, as a scalable and timely method for disease characterization, NLP could strengthen COVID-19 surveillance beyond conventional surveillance systems.


Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known pathogenic/likely pathogenic mutations in LDLR and one in PCSK9; all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in LDLR. In addition, we identified 18 highly penetrant possibly pathogenic variants, of which 5 were Qatari-specific, in LDLR, APOB, PCSK9 and APOE, which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH.Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known  Familial hypercholesterolemia (FH) is a common autosomal disease characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), leading to an increased risk of atherosclerosis and premature coronary heart disease (CHD) . The preLDLR, APOB and PCSK9 account for most FH cases and have been reported in both HoFH and HeFH. These three genes are members of the low-density lipoprotein receptor (LDL-R) pathway, which is responsible for maintaining healthy levels of plasma and intracellular cholesterol in the body. The vast majority of LDLR variants are deleterious (79%), affecting the splicing or regulatory aspects of early transcription or alternatively, leading to a defective receptor function  (Mutations in function . Owing tspecific . Less stulations . MutatioFH cases . Less coia (ARH) . Interesia (ARH) . Furtheria (ARH) . Notablyia (ARH) .The most widely accepted guidelines for the diagnosis of FH include the Simon-Broome Register criteria , the DutLDLR  in neighboring Gulf countries  was estimated at 1:232  and subsLDLR . Notablyt for FH . Moreovet for FH , specifit for FH . Therefon = 13,808). We sought to decipher mutations in genes previously linked with FH pathogenicity and identify highly penetrant Qatari-specific variants. Our findings have the potential to empower the current diagnostic approaches by allowing targeted genetic screening of high-risk individuals and cascade screening of suspected FH cases.In this study, we estimated the prevalence of FH in Qatar, while uncovering the mutational spectrum and penetrance of population-specific FH-related monogenic variants using whole-genome sequencing of the population-based cohort of Qatar biobank  study  and was p value for Hardy-Weinberg equilibrium <1 × 10−10, or those with a depth of coverage <10X were removed, while only variants with minor allele frequency <0.005 were included in the analysis, calculated based on estimating FH prevalence of ∼1 in 200. Subjects with excess heterozygosity, gender ambiguity, or with call rate <95% were also excluded. The final study cohort comprised 13,808 subjects with both whole-genome sequence data and complete phenotype data.Whole-genome sequencing of the cohort was available through the Qatar Genome Program (QGP) and was performed as previously described . BrieflyLDLR, APOB or PCSK9 genes, xanthomas and corneal deposits of fat, and evidence of coronary and vascular disease in subjects and their close relatives for diagnosing FH  genes (pathogenic/likely pathogenic or disease-causing mutation (DM) or likely disease-causing mutation (DM?) by at least two of the databases described earlier. We assessed the penetrance of genetic variants using two approaches; the first was based on the DLCN score (DLCN-penetrance), which takes into consideration multiple phenotypic variables related to FH risk as described earlier. Using this approach, penetrance was defined as the proportion of mutation carriers with a DLCN score ≥3. The second approach was based on LDL-C and self-reported HC (HC-penetrance) by which penetrance was defined as the proportion of mutation carriers with LDL-C > 3.3 mmol/L, or taking cholesterol-lowering medication, or self-reported HC. For variants of uncertain significance (VUS), we considered them possibly pathogenic if their HC-penetrance value was >50% and their predictive combined annotation dependent depletion (CADD) (We used the bcftools software (version 1.10.2) to extract records of variants located in selected FH genes from the variant calling format (VCF) genotype file. The selection of FH genes was based on a literature search and included S) genes . VariantS) genes  utilizinS) genes , ClinVarS) genes , Human GS) genes  and LeidS) genes . Variantn (CADD)  score wapathogenic/possibly pathogenic variants detected in each gene into a single burden variable, and in this analysis model, we adjusted for age, sex, genomic kinship and the first four population principal components.The Hardy-Weinberg equilibrium of genotypes was evaluated by χ2 tests. Unpaired Student’s t test was used for comparison between individuals with definite, probable, and possible FH relative to those with unlikely FH. The prevalence of each definition of FH was estimated as a percentage for all study subjects. Fisher’s exact test was used to compare the frequency of factors among the definitions of FH. A gene-based burden test was performed using SAIGE-Gene  by collap = 0.06).This study was based on phenotypic and genotypic data from 13,808 individuals. However, the analysis cohort comprised 13,677 subjects since LDL-C profiling measurements were not available for 107 subjects, while additional 24 subjects with hypothyroidism were removed from the analysis . We firsLDLR, APOB and PCSK9 genes. To this end, variants were scrutinized for their pathogenicity using ClinVar, LOVD3 and HGMD significance terms to identify previously reported pathogenic variants in the Qatari population. Our search for variants covered 11 FH-related genes (refer to methods). We detected 17 variants that were reported as pathogenic/likely pathogenic or DM/DM? by at least two of the ClinVar/LOVD3/HGMD databases (LDLR (n = 13), followed by rs771019366  and rs747507019 , while one mutation was located in PCSK9 . Moreover, the majority of these were missense mutations, which lead to specific protein changes while others were splice variants or associated with regulatory regions. Most mutations showed high DLCN-penetrance (>50%) and the majority had complete HC-penetrance (100%). We did not detect any previously reported pathogenic mutations in APOB, APOE, LDLRAP1, CYP7A1, STAP1, ITIH4, EPHX2, GHR, or PPP1R17.Applying the DLCN criteria for FH diagnosis entails the identification of functional mutations in atabases ; all as es (LDLR  with rs1possibly pathogenic variants as those which were predicted to be in the top 1% of most deleterious mutations in the human genome (CADD score >20) and their HC-penetrance is ≥50% , and were considered to be Qatari-specific. The most common possibly pathogenic variants were located in APOB . Overall, the majority of mutations observed were missense, while one stop-gain was detected in PCSK9. Notably, rs1230170597 is located 169 bp upstream of the coding region of LDLR and overlaps LDLR-AS1, an antisense non-coding RNA predicted to downregulate production of the LDL-R. However, these possibly pathogenic mutations were not used in DLCN classification because functional validation will be required to confirm their pathogenicity. Gene-based burden test LDL-R for the pathogenic and possibly pathogenic variants detected in our cohort showed significant associations with HC for LDLR  = 3.2; standard error (SE) = 0.52), PCSK9 , and APOB  but not for APOE (p = 0.303). Genetic variations that fit the “possibly pathogenic” criteria were not detected in the other FH-related genes: LDLRAP1, CYP7A1, STAP1, ITIH4, EPHX2, GHR, or PPP1R17.We identified 18  is ≥50% . These mn = 8), possible FH (n = 14) and unlikely FH (n = 10) subjects were re-classified as definite FH because they were found to carry one of the known pathogenic mutations listed in Assessment of QBB study participants using DLCN criteria after adding information from genotypes and known FH-pathogenic mutations revealed 52 subjects as definite cases of FH . Moreovepathogenic FH variants. Combined these definite FH cases accounted for 52 subjects and yielded an overall prevalence of 0.38% (∼1 in 263) for definite FH  when these mutations are included in the estimation of the prevalence. However, due to the lack of evidence on the pathogenicity of these variants, further investigations are required to incorporate them in the assessment of population-based FH prevalence. In addition, we did not detect any homozygous FH or autosomal recessive mutations in our study cohort, indicating their low prevalence in our study population.Of the total 13,677 subjects used in this study, we identified 109 as definite or probable cases of FH based on the fulfillment of the DLCN criteria . Based oinite FH . In contThis study provides the first reliable estimate of the prevalence of FH in the Qatari population and presents a comprehensive survey of population-specific monogenic FH variants in a considerably large population-based cohort. Combining FH-related phenotypes with whole-genome sequence data revealed a prevalence of definite and probable FH cases in Qatar of ∼1 in 125, which puts Qatari subjects at a higher risk of FH than the global average of 1:250, previously determined from a meta-analysis of 19 published studies , but at pathogenic, out of which 16 were located in LDLR. Notably, 6 of these variants in LDLR were previously reported in ∼6000 subjects from Qatar but without any phenotypic associations with FH  in two subjects with definite FH. This variant was detected in South African FH patients and was found to be pathogenic by functional studies (Subjects carrying any of the known ce sites . Notablymutation , however studies .Our study highlighted the importance of genetic testing to confirm FH diagnosis since only 19 subjects were classified as definite FH based on phenotype data while additional 33 subjects were considered definite FH when genetic testing was taken into consideration.possibly pathogenic variants in LDLR, APOB, PCSK9 and APOE in our study subjects which were not previously confirmed in the literature as disease-causing mutations. These variants, however, were predicted to be among the top 1% of most deleterious mutations in the human genome and showed high penetrance for HC in our study. These variants could be presented as novel variants related to FH, however, further functional investigations are warranted for their validation. Notably, all variants detected in APOB were point mutations that could lead to defects in lipid hemostasis. Point mutations in APOB have been reported to cause FH by affecting its affinity for the LDL-R, which causes disruptions in LDL clearance via LDL-R-mediated internalization (APOB associated with hypobetalipoproteinemia. However, further functional investigations are warranted to confirm their pathogenicity in FH. Notably, five of the possibly pathogenic variants were novel and appear to be predominant in the Qatari population. Novel Qatari-predominant loci have been identified for many clinically relevant traits in a recent GWAS study of the QBB study participants (pathogenic and possibly pathogenic variants in LDLR, PCSK9 and APOB confirmed the association of these variants with HC. However, the gene-based burden test was not significant for APOE possibly because of the small number of pathogenic variants detected in our cohort. Overall, our findings reiterate that mutations in LDLR are the most common cause of FH in the Qatari population.We also detected several lization . These micipants . A gene-possibly pathogenic variants was 1:351 and if future functional studies confirm the pathogenicity of these variants, the overall prevalence of FH will be 1:92 which is higher than our original estimate of 1:125 based on known pathogenic variants. We did not detect any cases of HoFH in our study cohort which indicates that HoFH is extremely rare in Qatar, as estimated in many European populations, but a larger sample size would be required to accurately estimate the prevalence of HoFH. However, one key limitation of our data collection was the lack of phenotypic data related to xanthomas and arcus cornealis for subjects or their first-degree relatives in our cohort. In addition, we did not investigate structural variants in FH-related genes, however, FH is predominantly caused by point mutations and a small fraction of FH cases are attributed to structural variants in FH-related genes. Overall, we detected 17 known pathogenic mutations in FH subjects and identified further 18 possibly pathogenic variants as novel candidates for FH. However, further functional investigations are warranted to investigate their pathogenicity. Overall, the clinical translation of FH-related variants reported herein may be explored further to design FH diagnostic tools.In this study, a substantially large cohort of 13,677 was used to achieve a reliable estimate for the prevalence of definite and probable cases of FH in the Qatari population, which was approximated to 1 in 125. The prevalence of subjects with