The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-also referred to as Long COVID-have been described, but whether breakthrough SARS-CoV-2 infection ...(BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.
The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national ...healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.
The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively ...characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.
Atherosclerosis (AS) is a major contributor to cardiovascular diseases worldwide, and alleviating inflammation is a promising strategy for AS treatment. Here, we report molecularly engineered M2 ...macrophage‐derived exosomes (M2 Exo) with inflammation‐tropism and anti‐inflammatory capabilities for AS imaging and therapy. M2 Exo are derived from M2 macrophages and further electroporated with FDA‐approved hexyl 5‐aminolevulinate hydrochloride (HAL). After systematic administration, the engineered M2 Exo exhibit excellent inflammation‐tropism and anti‐inflammation effects via the surface‐bonded chemokine receptors and the anti‐inflammatory cytokines released from the anti‐inflammatory M2 macrophages. Moreover, the encapsulated HAL can undergo intrinsic biosynthesis and metabolism of heme to generate anti‐inflammatory carbon monoxide and bilirubin, which further enhance the anti‐inflammation effects and finally alleviate AS. Meanwhile, the intermediate protoporphyrin IX (PpIX) of the heme biosynthesis pathway permits the fluorescence imaging and tracking of AS.
M2 macrophage‐derived exosomes molecularly engineered with the drug hexyl 5‐aminolevulinate hydrochloride (HAL) can actively target and transmigrate to atherosclerotic lesions, wherein the biosynthesis and metabolism of heme induced by HAL produces CO and bilirubin. This, along with the anti‐inflammatory cytokines in exosomes, acts to significantly alleviate atherosclerosis.
The Post-Acute Sequelae of SARS-CoV-2 infection (PASC) have been characterized; however, the burden of PASC remains unknown. Here we used the healthcare databases of the US Department of Veterans ...Affairs to build a cohort of 181,384 people with COVID-19 and 4,397,509 non-infected controls and estimated that burden of PASC-defined as the presence of at least one sequela in excess of non-infected controls-was 73.43 (72.10, 74.72) per 1000 persons at 6 months. Burdens of individual sequelae varied by demographic groups (age, race, and sex) but were consistently higher in people with poorer baseline health and in those with more severe acute infection. In sum, the burden of PASC is substantial; PASC is non-monolithic with sequelae that are differentially expressed in various population groups. Collectively, our results may be useful in informing health systems capacity planning and care strategies of people with PASC.
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Although flavonoid compounds have various pharmacological applications, they generally exhibit low oral bioavailability due to their poor aqueous solubility. To address this problem, ...numerous promising strategies, such as the use of an absorption enhancer, structural transformation (e.g., prodrugs, glycosylation), and pharmaceutical technologies (e.g., carrier complexes, nanotechnology, cocrystals), have been developed and applied to deliver poorly water-soluble flavonoids. These formulation approaches can effectively improve the oral bioavailability of flavonoids by enhancing their solubility, dissolution rate and permeability; preventing their degradation or metabolism in the gastrointestinal tract; and/or delivering them directly to their physiological targets. This review comprehensively summarizes the viable oral delivery systems for insoluble flavonoids to date and discusses their design principles, potential advantages, possible limitations, and oral delivery efficiency, which will provide some useful clues and references to overcome the absorption barrier of these insoluble flavonoids.
Extracellular vesicles (EVs) hold great potential in both disease treatment and drug delivery. However, accurate drug release from EVs, as well as the spontaneous treatment effect cooperation of EVs ...and drugs at target tissues, is still challenging. Here, an engineered self‐activatable photo‐EV for synergistic trimodal anticancer therapy is reported. M1 macrophage‐derived EVs (M1 EVs) are simultaneously loaded with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl) phenyl oxalate (CPPO), chlorin e6 (Ce6), and prodrug aldoxorubicin (Dox‐EMCH). After administration, the as‐prepared system actively targets tumor cells because of the tumor‐homing capability of M1 EVs, wherein M1 EVs repolarize M2 to M1 macrophages, which not only display immunotherapy effects but also produce H2O2. The reaction between H2O2 and CPPO generates chemical energy that activates Ce6, creating both chemiluminescence for imaging and singlet oxygen (1O2) for photodynamic therapy (PDT). Meanwhile, 1O2‐induced membrane rupture leads to the release of Dox‐EMCH, which is then activated and penetrates the deep hypoxic areas of tumors. The synergism of immunotherapy, PDT, and chemotherapy results in potent anticancer efficacy, showing great promise to fight cancers.
Self‐activatable photo‐extracellular vesicles are constructed by loading M1‐macrophage‐derived EVs with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl)phenyl oxalate, chlorin e6, and prodrug aldoxorubicin. These skillfully engineered extracellular vesicles can actively target tumors owing to their inherent tumor‐homing ability, wherein they exhibit potent trimodal therapy effects in an intersynergistic and self‐controllable way, attributed to the interaction between the engineered EV and the special tumor microenvironment.
Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize ...responsive exosome nano‐bioconjugates for cancer therapy. Azide‐modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne‐modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH‐sensitive linkers. After systemic administration, the nano‐bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic‐imine bonds of the nano‐bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished “don't eat me” signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro‐tumoral M2 to anti‐tumoral M1.
Ok, take a bite: Responsive exosome nano‐bioconjugates were constructed by engineering M1 exosomes with aCD47 and aSIRPα linked with a pH‐sensitive bond. After systemic administration, the synergism of specific targeting by aCD47, blocking of “don't eat me” signaling by aCD47 and aSIRPα, and M2 reprogramming by M1 exosomes resulted in a potent anticancer effect.
Kidney Outcomes in Long COVID Bowe, Benjamin; Xie, Yan; Xu, Evan ...
Journal of the American Society of Nephrology,
11/2021, Letnik:
32, Številka:
11
Journal Article
Recenzirano
Odprti dostop
COVID-19 is associated with increased risk of post-acute sequelae involving pulmonary and extrapulmonary organ systems-referred to as long COVID. However, a detailed assessment of kidney outcomes in ...long COVID is not yet available.
We built a cohort of 1,726,683 US Veterans identified from March 1, 2020 to March 15, 2021, including 89,216 patients who were 30-day survivors of COVID-19 and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE). MAKE was defined as eGFR decline ≥50%, ESKD, or all-cause mortality. We used inverse probability-weighted survival regression, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates, including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory.
Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR, 1.94; 95% CI, 1.86 to 2.04), eGFR decline ≥30% (aHR, 1.25; 95% CI, 1.14 to 1.37), eGFR decline ≥40% (aHR, 1.44; 95% CI, 1.37 to 1.51), eGFR decline ≥50% (aHR, 1.62; 95% CI, 1.51 to 1.74), ESKD (aHR, 2.96; 95% CI, 2.49 to 3.51), and MAKE (aHR, 1.66; 95% CI, 1.58 to 1.74). Increase in risks of post-acute kidney outcomes was graded according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared with non-infected controls, 30-day survivors of COVID-19 exhibited excess eGFR decline (95% CI) of -3.26 (-3.58 to -2.94), -5.20 (-6.24 to -4.16), and -7.69 (-8.27 to -7.12) ml/min per 1.73 m
per year, respectively, in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection.
Patients who survived COVID-19 exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should include attention to kidney disease.
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