Factors Associated with Long COVID Recovery among US Adults.

BACKGROUND: While factors associated with long COVID (LC) continue to be illuminated, little is known about recovery. This study used national survey data to assess differences between adults in the United States with LC and those who recovered. METHODS: We used COVID-19 and LC data from the 2022 National Health Interview Survey, a cross-sectional sample of non-institutionalized US adults. Survey analysis was used to account for oversampling and nonresponse bias and to obtain nationally representative estimates. A multivariable logistic regression model was used to identify potential predictors of LC recovery. RESULTS: Among the study sample, 17.7% or an estimated 17.5 American adults reported ever having LC, and among those with LC, 48.5% or an estimated 8.5 million reported having recovered. Multivariable logistic regression analysis showed that Hispanic adults were significantly more likely than White adults to report recovery from LC. At the same time, those with severe COVID-19 symptoms and those who had more than a high school degree, were aged 40 years or older, or were female were less likely to report recovery. CONCLUSION: Significant variations in LC recovery were noted across age, sex, race/ethnicity, and education independent of the severity of COVID-19 symptoms. Further work is needed to elucidate the causes of these differences and identify strategies to increase recovery rates.

Long COVID Characteristics and Experience: A Descriptive Study from the Yale LISTEN Research Cohort.

OBJECTIVE: To describe the experience of people with long COVID symptomatology and characterize the psychological, social, and financial challenges they experience. BACKGROUND: The experience of people with long COVID needs further amplification, especially with a comprehensive focus on symptomatology, treatments, and impact on daily life and finances. METHODS: We collected data from individuals aged 18 and older reporting long COVID as participants in the Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study. The sample population included 441 participants surveyed between May 2022 and July 2023. We evaluated their demographic characteristics, socioeconomic and psychological status, index infection period, health status, quality of life, symptoms, treatments, pre-pandemic comorbidities, and new-onset conditions. RESULTS: Overall, the median age of the participants with long COVID was 46 years (IQR: 38 to 57 years); 74% were women, 86% were Non-Hispanic White, and 93% were from the United States. Participants reported low health status measured by the Euro-QoL visual analogue scale, with a median score of 49 (IQR: 32 to 61). Participants documented a diverse range of symptoms, with all 96 possible symptom choices being reported. Additionally, participants had tried many treatments (median number of treatments: 19, IQR: 12 to 28). They were also experiencing psychological distress, social isolation, and financial stress. CONCLUSIONS: Despite having tried numerous treatments, participants with long COVID continued to experience an array of health and financial challenges-findings that underscore the failure of the healthcare system to address the medical needs of people with long COVID. These insights highlight the need for crucial medical, mental health, financial, and community support services, as well as further scientific investigation, to address the complex impact of long COVID.

Factors Associated With Long COVID: Insights From Two Nationwide Surveys.

BACKGROUND: Long COVID is a multisystemic condition that affects the lives of millions of people globally, yet factors associated with it are poorly defined. Our purpose in this study was to identify factors associated with long COVID. METHODS: This cross-sectional study used data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and the 2022 National Health Interview Survey (NHIS). We restricted the sample to individuals aged 18 and older who reported a positive COVID-19 test or doctor's diagnosis. Individuals who reported symptoms of at least 3 months were assumed to have long COVID. We identified demographic and clinical characteristics associated with long COVID, in unadjusted and adjusted analyses. RESULTS: The study included 124,313 individuals in the BRFSS cohort and 10,131 in the NHIS cohort who reported a COVID-19 infection, with 26,783 (21.5%) and 1797 (17.7%) reporting long COVID, respectively. We found middle age, female sex, lack of a college degree, and severity of acute COVID-19 infection to be associated with long COVID. In contrast, non-Hispanic Asian and Black Americans were less likely to report long COVID compared with non-Hispanic White individuals. These findings were consistent across datasets. CONCLUSIONS: Several demographic features were associated with long COVID, which may be the result of social, clinical, or biological influences.

Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs.

Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization.

Introduction: A chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized. Methods: We included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience. Results: The median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition. Conclusions: In this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

Combination of precipitation and size exclusion chromatography as an effective method for exosome like extracellular vesicle isolation from pericardial fluids.

Extracellular vesicles (EVs), such as exosomes, are nanovesicles that have received significant attention due to their ability to contain various molecular cargos. EVs found in biological fluids have been demonstrated to have therapeutic potential, including as biomarkers. Despite being extensively studied, a significant downfall in EV research is the lack of standardised protocol for its isolation from human biological fluids, where EVs usually exist at low densities. In this study, we tested two well-established EV isolation protocols, precipitation, and size exclusion chromatography (SEC), to determine their efficiency in isolating EVs from the pericardial fluid. Precipitation alone resulted in high yields of low-purity exosomes as tested by DLS analysis, transmission electron microscopy, immunogold labelling and western blotting for the exosomal surface proteins. While EVs isolated by SEC were pure, the concentration was low. Interestingly, the combination of precipitation followed by SEC resulted in high EV yields with good purity. Our results suggest that the combination method can be adapted to isolate EVs from body fluids which have low densities of EV.

Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432.

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

Do Patient-Reported Quality-of-Life (QoL) Scales Provide an Adequate Assessment of Patients with Cryptoglandular Anal Fistulae? A Systematic Review of Measurement Instruments and Their Content Validity.

BACKGROUND: Cryptoglandular anal fistulae can significantly affect patient quality of life (QoL), making it essential to ensure that any study of fistula treatment assesses the impact on QoL. The aim of this systematic review was to evaluate the content validity of Patient-Reported Outcome Measures (PROMs) that assess QoL in patients with a fistula. METHODS: MEDLINE, EMBASE, PsycINFO, and Scopus were searched and studies assessing the content validity of patient-reported QoL measurement instruments, or PROM development studies in patients with cryptoglandular anal fistulae, were included. Data were extracted from eligible studies to determine the instruments' relevance, comprehensiveness, and comprehensibility, and their quality was assessed according to COnsensus-based Standards for the Selection of health Measurement Instruments (COSMIN). RESULTS: Two PROM development studies were identified, both of which described the development of a disease-specific QoL measurement instrument for patients with cryptoglandular anal fistulae. The overall content validity of these instruments was inconsistent and supported by very low-quality evidence. There were no studies assessing the content validity of established QoL measurement instruments in patients with fistulae. CONCLUSIONS: This systematic review could not establish the content validity of the available QoL PROMs for patients with anal fistulae, due either to the absence of designated content validity studies or a lack of comprehensiveness of the available PROMs. This highlights an important gap in the literature that needs to be addressed to ensure high-quality outcome assessment in patients with fistulae.

Access to Urological Care for Medicaid-Insured Patients at Urology Practices Acquired by Private Equity Firms.

OBJECTIVE: To characterize appointment access for Medicaid-insured patients seeking care at urology practices affiliated with private equity firms in light of the recent national trends in practice consolidation. METHODS: We identified 214 urology offices affiliated with private equity firms that were geographically matched with 231 non-private equity affiliated urology offices. Using a standardized script, researchers posed as an adult patient with either Medicaid or commercial insurance in the clinical setting of new onset, painless hematuria. The primary outcome was whether the patient's insurance was accepted for an appointment. The secondary outcome was appointment wait time. RESULTS: We conducted 815 appointment inquiry calls to 214 private equity (PE) and 231 non-PE-affiliated urology offices across 12 states. Appointment availability was higher for commercially-insured patients (99.0%; 95% CI: 98.1%-99.9%) vs Medicaid-insured patients (59.8%; 95% confidence interval [CI]: 55.0%-64.6%) (P < .0001). Medicaid acceptance was higher at non-PE affiliated (66.8%; CI 60.4%-73.2%) than PE-affiliated practices (52.1%; 95% CI 45.0%-59.2%) (P = .003). On multivariable logistic regression analysis, state Medicaid expansion status (odds ratio [OR] 2.20; CI 1.14-4.28; P = .020) was independently associated with Medicaid appointment availability, whereas PE-affiliation (OR 0.55; CI 0.37-0.83; P = .004) was independently associated with lower Medicaid access. Appointment wait times did not differ significantly for commercially-insured vs Medicaid patients (19.2 vs 20.1 days; p = .59), but PE-affiliated practices offered shorter mean wait times than non-PE offices (17.5 vs 21.4 days; P = .017). CONCLUSION: Access disparities for urologic evaluation in patients with Medicaid insurance at urology practices and were more pronounced at private equity acquired practices.

Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.

Multimodal small-molecule screening for human prion protein binders.

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) NMR spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mm), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Whereas orthogonal binder discovery methods could yield high-affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs.

PROTACs have recently emerged as a novel paradigm in drug discovery. They can hijack existing biological machinery to selectively degrade proteins of interest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins. The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over Von Hippel-Lindau (VHL) and Cereblon (CRBN) PROTACs. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAK degradation was both IAP- and proteasome-dependent.

Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants-A comprehensive review.

Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward.