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BACKGROUND: Strength and neuromuscular decrements following knee musculoskeletal injury may accelerate knee osteoarthritis development. This study assessed isometric knee extensor and flexor strength and steadiness between individuals with knee injury, i.e., ligament reconstruction, and knee osteoarthritis to healthy age-matched controls. METHODS: Four cohorts (1: knee injury and 2: age-matched controls, and 3: radiographic knee osteoarthritis and 4: age-matched controls) were recruited. Participants performed maximal voluntary isometric knee extensor and flexor contractions. Then, strength (e.g., peak and rate of torque development) and steadiness (e.g., peak power, mean, and median frequency) were derived from each raw torque-time curve and associated power spectral density. A Kruskal-Wallis H test and Spearman's rho correlation analysis assessed cohort differences and association between knee extensor and flexor strength and steadiness. FINDINGS: The young adult control and knee injury cohorts exhibited greater knee extensor and flexor strength than the older, knee osteoarthritis cohort (p < 0.043). The knee injury cohort, despite being as strong as their healthy counterparts, were significantly less steady with a 92% increase in peak power frequency (p = 0.046). The osteoarthritis cohort exhibited 157% less total power compared to the knee injury and young control cohorts (p < 0.019). Knee extensor and flexor peak torque, rate of torque development, and mean torque exhibit a significant, positive relation with total power (p < 0.018). INTERPRETATION: Individuals with knee injury and disease may exhibit weaker or less steady knee musculature, predisposing them to degenerative joint disease. Clinicians may need to restore knee extensor and flexor steadiness to facilitate better joint neuromuscular control.
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Extracellular vesicles (EVs) can transfer antigens and immunomodulatory molecules, and such EVs released by antigen-presenting cells equipped with immunostimulatory functions have been utilized for vaccine formulations. A prior high-throughput screening campaign led to the identification of compound 634 (1), which enhanced EV release and increased intracellular Ca2+ influx. Here, we performed systematic structure-activity relationship (SAR) studies to investigate the scaffold for its potency as a vaccine adjuvant. Synthesized compounds were analyzed in vitro for CD63 reporter activity (a marker for EV biogenesis) in human THP-1 cells, induction of Ca2+ influx, IL-12 production, and cell viability in murine bone-marrow-derived dendritic cells. The SAR studies indicated that the ester functional group was requisite, and the sulfur atom of the benzothiadiazole ring replaced with a higher selenium atom (9f) or a bioisosteric ethenyl group (9h) retained potency. Proof-of-concept vaccination studies validated the potency of the selected compounds as novel vaccine adjuvants.
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Adjuvantes Imunológicos , Tiadiazóis , Relação Estrutura-Atividade , Humanos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/síntese química , Animais , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Camundongos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células THP-1 , Vacinas/imunologia , Vacinas/química , Camundongos Endogâmicos C57BL , Feminino , Vesículas Extracelulares/química , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismoRESUMO
Perceptual success depends on fast-spiking, parvalbumin-positive interneurons (FS/PVs). However, competing theories of optimal rate and correlation in pyramidal (PYR) firing make opposing predictions regarding the underlying FS/PV dynamics. We addressed this with population calcium imaging of FS/PVs and putative PYR neurons during threshold detection. In primary somatosensory and visual neocortex, a distinct PYR subset shows increased rate and spike-count correlations on detected trials ("hits"), while most show no rate change and decreased correlations. A larger fraction of FS/PVs predicts hits with either rate increases or decreases. Using computational modeling, we found that inhibitory imbalance, created by excitatory "feedback" and interactions between FS/PV pools, can account for the data. Rate-decreasing FS/PVs increase rate and correlation in a PYR subset, while rate-increasing FS/PVs reduce correlations and offset enhanced excitation in PYR neurons. These findings indicate that selection of informative PYR ensembles, through transient inhibitory imbalance, is a common motif of optimal neocortical processing.
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Interneurônios , Neocórtex , Células Piramidais , Animais , Neocórtex/fisiologia , Células Piramidais/fisiologia , Células Piramidais/metabolismo , Interneurônios/fisiologia , Interneurônios/metabolismo , Camundongos , Inibição Neural/fisiologia , Parvalbuminas/metabolismo , Masculino , Potenciais de Ação/fisiologia , FemininoRESUMO
BACKGROUND: Stress fracture is a concern among older adults, as age-related decrements in ankle neuromuscular function may impair their ability to attenuate tibial compressive forces experienced during daily locomotor tasks, such as stair descent. Yet, it is unknown if older adults exhibit greater tibial compression than their younger counterparts when descending stairs. RESEARCH QUESTION: Do older adults exhibit differences in ankle biomechanics that alter their tibial compression during stair descent compared to young adults, and is there a relation between tibial compression and specific changes in ankle biomechanics? METHODS: Thirteen young (18-25 years) and 13 older (>â¯65 years) adults had ankle joint biomechanics and tibial compression quantified during a stair descent. Discrete ankle biomechanics (peak joint angle and moment, and joint stiffness) and tibial compression (maximum and impulse) measures were submitted to an independent t-test, while ankle joint angle and moment, and tibial compression waveforms were submitted to an independent statistical parametric mapping t-test to determine group differences. Pearson correlation coefficients (r) determined the relation between discrete ankle biomechanics and tibial compression measures for all participants, and each group. RESULTS: Older adults exhibited smaller maximum tibial compression (pâ¯=â¯0.004) from decreases in peak ankle joint angle and moment between 17â¯% and 34â¯% (pâ¯=â¯0.035), and 20-31â¯% of stance (pâ¯<â¯0.001) than young adults. Ankle biomechanics exhibited a negligible to weak correlation with tibial compression for all participants, with peak ankle joint moment and maximum tibial compression (râ¯=â¯-0.48⯱â¯0.32) relation the strongest. Older adults typically exhibited a stronger relation between ankle biomechanics and tibial compression (e.g., râ¯=â¯-0.48⯱â¯0.47 vs râ¯=â¯-0.27⯱â¯0.52 between peak ankle joint moment and maximum tibial compression). SIGNIFICANCE: Older adults altered ankle biomechanics and decreased maximum tibial compression to safely execute the stair descent. Yet, specific alterations in ankle biomechanics could not be identified as a predictor of changes in tibial compression.
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Articulação do Tornozelo , Subida de Escada , Tíbia , Humanos , Fenômenos Biomecânicos , Articulação do Tornozelo/fisiologia , Articulação do Tornozelo/fisiopatologia , Masculino , Adulto , Idoso , Feminino , Tíbia/fisiologia , Adulto Jovem , Subida de Escada/fisiologia , Adolescente , Fatores Etários , Envelhecimento/fisiologiaRESUMO
School-based COVID-19 vaccine clinics were more likely to vaccinate children who identified as a racial minority, who lacked a regular source of primary care, and who lacked private insurance compared to those vaccinated in non-school-based community locations.
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Vacinas contra COVID-19 , COVID-19 , Acessibilidade aos Serviços de Saúde , Unidades Móveis de Saúde , Humanos , Estudos Transversais , Vacinas contra COVID-19/provisão & distribuição , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Criança , Adolescente , Masculino , Vacinação , Feminino , SARS-CoV-2/imunologia , Serviços de Saúde EscolarRESUMO
BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4â µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.
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Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Diarilquinolinas/farmacologia , Diarilquinolinas/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Genótipo , Fenótipo , Testes de Sensibilidade MicrobianaRESUMO
INTRODUCTION: In children with myocarditis or dilated cardiomyopathy (DCM) on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock, it is often necessary to decompress the left heart to minimize distension and promote myocardial recovery. We compare outcomes in those who underwent balloon atrial septostomy (BAS) versus direct left atrial (LA) drainage for left heart decompression in this population. METHODS: Retrospective study of the Extracorporeal Life Support Organization (ELSO) multicenter registry of patients ≤ 18 years with myocarditis or DCM on ECMO who underwent LA decompression. Descriptive and univariate statistics assessed association of patient factors with decompression type. Multivariable logistic regression sought independent associations with outcomes. RESULTS: 369 pediatric ECMO runs were identified. 52% myocarditis, 48% DCM, overall survival 74%. 65% underwent BAS and 35% LA drainage. Patient demographics including age, weight, gender, race/ethnicity, diagnosis, pre-ECMO pH, mean airway pressure, and arrest status were similar. 89% in the BAS group were peripherally cannulated onto ECMO, versus 3% in the LA drainage group (p < .001). On multivariable analysis, LA drainage (OR 3.96; 95% CI, 1.47-10.711; p = .007), renal complication (OR 2.37; 95% CI, 1.41-4.01; p = .001), cardiac complication (OR 3.14; 95% CI, 1.70-5.82; p < .001), and non-white race/ethnicity (OR 1.75; 95% CI, 1.04-2.94; p = .035) were associated with greater odds of mortality. There was a trend toward more episodes of pulmonary hemorrhage in BAS (n = 17) versus LA drainage group (n = 3), p = .08. Comparing only those with central cannulation, LA drainage group was more likely to be discontinued from ECMO due to recovery (72%) versus the BAS group (48%), p = .032. CONCLUSIONS: In children with myocarditis or DCM, there was a three times greater likelihood for mortality with LA drainage versus BAS for LA decompression. When adjusted for central cannulation groups only, there was better recovery in the LA drainage group and no difference in mortality. Further prospective evaluation is warranted.
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Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). Left atrial (LA) function is a poorly understood concept in this patient population, and research suggests underlying structural changes that could affect atrial function. Cardiac magnetic resonance (CMR) imaging may provide an important non-invasive approach to evaluating LA function. This study was a single center retrospective review of consecutive CMR studies over a 1 year period comparing LA phasic function within a cohort of DMD patients, and to those with structurally and functionally normal hearts. LA strain measurements including global reservoir, conduit, boost-pump strain, and LA volumes were obtained retrospectively. Spearman correlation analyses were performed on atrial strain measurements. 107 DMD and 79 normal CMR studies were included. The DMD cohort had worse systolic function (p < 0.001), smaller indexed max LA and left ventricular (LV) volumes (p < 0.001), and greater LA emptying fraction (p < 0.001). In the DMD cohort, emptying fraction decreased with advanced patient age (p < 0.001) and diminishing systolic function (p < 0.001). DMD patients with moderate or severe LV dysfunction demonstrated lower LA emptying fraction (p = 0.002), more impaired 2-chamber LA reservoir (p = 0.003), and LA pump (p = 0.006) and conduit strain (p = 0.018). DMD patients with preserved function have lower indexed LA volumes with higher LA emptying fractions than controls. Progression of disease and age is associated with decreased LA emptying fraction with early manifestations in reservoir and conduit strain. These findings suggest that strain markers of LA compliance and early left ventricular relaxation are associated with worsening cardiomyopathy in the DMD population.
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The provision of clinical neuropsychological services has predominately been undertaken by way of standardized administration in a face-to-face setting. Interpretation of psychometric findings in this context is dependent on the use of normative comparison. When the standardization in which such psychometric measures are employed deviates from how they were employed in the context of the development of its associated norms, one is left to question the reliability and hence, validity of any such findings and in turn, diagnostic decision making. In light of the current COVID-19 pandemic and resultant social distancing direction, face-to-face neuropsychological assessment has been challenging to undertake. As such, remote (i.e., virtual) neuropsychological assessment has become an obvious solution. Here, and before the results from remote neuropsychological assessment can be said to stand on firm scientific grounds, it is paramount to ensure that results garnered remotely are reliable and valid. To this end, we undertook a review of the literature and present an overview of the landscape. To date, the literature shows evidence for the reliability of remote administration and the clinical implications are paramount. When and where needed, neuropsychologists, psychometric technicians and examinees may no longer need to be in the same physical space to undergo an assessment. These findings are most relevant given the physical distancing practices because of COVID-19. And whilst remote assessment should never supplant face-to-face neuropsychological assessments, it does serve as a valid alternative when necessary.
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BACKGROUND: There is a lack of randomized controlled trial data regarding differences in immunogenicity of varying coronavirus disease 2019 (COVID-19) mRNA vaccine regimens in CKD populations. METHODS: We conducted a randomized controlled trial at three kidney centers in Toronto, Ontario, Canada, evaluating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody response after third dose vaccination. Participants ( n =273) with CKD not on dialysis or receiving dialysis were randomized 1:1 to third dose 30- µ g BNT162b2 (Pfizer-BioNTech) or 100- µ g mRNA-1273 (Moderna). The primary outcome of this study was SARS-CoV-2 IgG-binding antibodies to the receptor-binding domain (anti-RBD). Spike protein (antispike), nucleocapsid protein, and vaccine reactogenicity were also evaluated. Serology was measured before third dose and 1, 3, and 6 months after third dose. A subset of participants ( n =100) were randomly selected to assess viral pseudovirus neutralization against wild-type D614G, B.1.617.2 (Delta), and B.1.1.529 (Omicron BA.1). RESULTS: Among 273 participants randomized, 94% were receiving maintenance dialysis and 59% received BNT162b2 for initial two dose COVID-19 vaccination. Third dose of mRNA-1273 was associated with higher mean anti-RBD levels (1871 binding antibody units [BAU]/ml; 95% confidence interval [CI], 829 to 2988) over a 6-month period in comparison with third dose BNT162b2 (1332 BAU/ml; 95% CI, 367 to 2402) with a difference of 539 BAU/ml (95% CI, 139 to 910; P = 0.009). Neither antispike levels nor neutralizing antibodies to wild-type, Delta, and Omicron BA.1 pseudoviruses were statistically different. COVID-19 infection occurred in 10% of participants: 15 (11%) receiving mRNA-1273 and 11 (8%) receiving BNT162b2. Third dose BNT162b2 was not associated with a significant different risk for COVID-19 in comparison with mRNA-1273 (hazard ratio, 0.78; 95% CI, 0.27 to 2.2; P = 0.63). CONCLUSIONS: In patients with CKD, third dose COVID-19 mRNA vaccination with mRNA-1273 elicited higher SARS-CoV-2 anti-RBD levels in comparison with BNT162b2 over a 6-month period. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: COVID-19 Vaccine Boosters in Patients With CKD (BOOST KIDNEY), NCT05022329 .
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Older adults often suffer an accidental fall when navigating challenging surfaces during common locomotor tasks, such as walking and ascending stairs. This study examined the effect of slick and uneven surfaces on lower limb joint work in older and younger adults while walking and ascending stairs. Fifteen young (18-25 years) and 12 older (>65 years) adults had stance phase positive limb and joint work quantified during walking and stair ascent tasks on a normal, slick, and uneven surface, which was then submitted to a two-way mixed model ANOVA for analysis. The stair ascent required greater limb, and hip, knee, and ankle work than walking (all p < 0.001), with participants producing greater hip and knee work during both the walk and stair ascent (both p < 0.001). Surface, but not age, impacted positive limb work. Participants increased limb (p < 0.001), hip (p = 0.010), and knee (p < 0.001) positive work when walking over the challenging surfaces, and increased hip (p = 0.015), knee (p < 0.001), and ankle (p = 0.010) work when ascending stairs with challenging surfaces. Traversing a challenging surface during both walking and stair ascent tasks required greater work production from the large proximal hip and knee musculature, which may increase the likelihood of an accidental fall in older adults.
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Background Digoxin prescription in patients with single-ventricle physiology after stage 1 palliation is associated with reduced interstage death. Prior literature has primarily included patients having undergone the Norwood procedure. We sought to determine if digoxin prescription at discharge in infants following hybrid stage 1 palliation was associated with improved transplant-free interstage survival. Methods and Results A retrospective multicenter cohort analysis was conducted using data from the National Pediatric Cardiology Quality Improvement Collaborative registry data from 2008 to 2021. Infants with functional single ventricles and aortic arch obstruction discharged home after the hybrid stage 1 palliation hospitalization were included. Patients were excluded if they had supraventricular tachycardia or conversion to Norwood operation. The primary outcome was transplant-free survival. Multivariable logistic regression analysis including a propensity score for digoxin use identified associations between digoxin use and interstage death or transplant. Of 259 included infants from 45 sites, 158 (61%) had hypoplastic left heart syndrome. Forty-nine percent had a gestational age ≤38 weeks, 18% had a birth weight <2.5 kg, and 58% had a preoperative risk factor. Of the 259 subjects, 129 (50%) were discharged on digoxin. Interstage death or transplant occurred in 30 (23%) patients in the no-digoxin group compared with 18 (14%) in the digoxin group (P=0.06). With multivariate analysis, discharge digoxin prescription was associated with a lower risk of interstage death or transplant (adjusted odds ratio, 0.48 [95% CI, 0.24-0.93]; P=0.03). Conclusions In infants with single-ventricle physiology who underwent hybrid stage 1 palliation, digoxin prescription at hospital discharge was associated with improved interstage transplant-free survival.
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Síndrome do Coração Esquerdo Hipoplásico , Procedimentos de Norwood , Coração Univentricular , Humanos , Lactente , Digoxina/uso terapêutico , Ventrículos do Coração/cirurgia , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Cuidados Paliativos/métodos , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Protein arginine methylation is a widespread post-translational modification (PTM) in eukaryotic cells. This chemical modification in proteins functionally modulates diverse cellular processes from signal transduction, gene expression, and DNA damage repair to RNA splicing. The chemistry of arginine methylation entails the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet, SAM) onto a guanidino nitrogen atom of an arginine residue of a target protein. This reaction is catalyzed by about 10 members of protein arginine methyltransferases (PRMTs). With impacts on a variety of cellular processes, aberrant expression and activity of PRMTs have been shown in many disease conditions. Particularly in oncology, PRMTs are commonly overexpressed in many cancerous tissues and positively correlated with tumor initiation, development and progression. As such, targeting PRMTs is increasingly recognized as an appealing therapeutic strategy for new drug discovery. In the past decade, a great deal of research efforts has been invested in illuminating PRMT functions in diseases and developing chemical probes for the mechanistic study of PRMTs in biological systems. In this review, we provide a brief developmental history of arginine methylation along with some key updates in arginine methylation research, with a particular emphasis on the chemical aspects of arginine methylation. We highlight the research endeavors for the development and application of chemical approaches and chemical tools for the study of functions of PRMTs and arginine methylation in regulating biology and disease.
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This paper describes the structure and creation of Blackfoot Words, a new relational database of lexical forms (inflected words, stems, and morphemes) in Blackfoot (Algonquian; ISO 639-3: bla). To date, we have digitized 63,493 individual lexical forms from 30 sources, representing all four major dialects, and spanning the years 1743-2017. Version 1.1 of the database includes lexical forms from nine of these sources. This project has two aims. The first is to digitize and provide access to the lexical data in these sources, many of which are difficult to access and discover. The second is to organize the data so that connections can be made between instances of the "same" lexical form across all sources, despite variation across sources in the dialect recorded, orthographic conventions, and the depth of morpheme analysis. The database structure was developed in response to these aims. The database comprises five tables: Sources, Words, Stems, Morphemes, and Lemmas. The Sources table contains bibliographic information and commentary on the sources. The Words table contains inflected words in the source orthography. Each word is broken down into stems and morphemes which are entered into the Stems and Morphemes tables in the source orthography. The Lemmas table contains abstract versions of each stem or morpheme in a standardized orthography. Instances of the same stem or morpheme are linked to a common lemma. We expect that the database will support projects by the language community and other researchers.
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Purpose: To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence. Design: Interreader agreement study. Participants: Twelve readers from 6 reading centers. Methods: All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image. Main Outcome Measures: Interreader agreement, as assessed by Gwet's first-order agreement coefficient (AC1). Results: When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30). Conclusions: There was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.
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Acute respiratory distress syndrome is characterized by non-cardiogenic pulmonary edema, decreased pulmonary compliance, and abnormalities in gas exchange, especially hypoxemia. Patients with acute respiratory distress syndrome (ARDS) who receive support with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) usually have severe lung disease. Many patients with ARDS have associated pulmonary vascular injury which can result in elevated pulmonary vascular resistance and right heart dysfunction. Since V-V ECMO relies upon preserved cardiac function, right heart failure has important implications for patient evaluation, management, and outcomes. Worsening right heart function complicates ARDS and disease processes. Given the increasing use of ECMO to support patients with ARDS, an understanding of right ventricular-ECMO and cardiopulmonary interactions is essential for the clinician. A narrative review of the manifestations of right heart dysfunction, as well as diagnosis and management strategies for the patient with ARDS on ECMO, is provided.
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SARS-CoV-2 has caused a global pandemic with significant humanity and economic loss since 2020. Currently, only limited options are available to treat SARS-CoV-2 infections for vulnerable populations. In this study, we report a universal fluorescence polarization (FP)-based high throughput screening (HTS) assay for SAM-dependent viral methyltransferases (MTases), using a fluorescent SAM-analogue, FL-NAH. We performed the assay against a reference MTase, NSP14, an essential enzyme for SARS-CoV-2 to methylate the N7 position of viral 5'-RNA guanine cap. The assay is universal and suitable for any SAM-dependent viral MTases such as the SARS-CoV-2 NSP16/NSP10 MTase complex and the NS5 MTase of Zika virus (ZIKV). Pilot screening demonstrated that the HTS assay was very robust and identified two candidate inhibitors, NSC 111552 and 288387. The two compounds inhibited the FL-NAH binding to the NSP14 MTase with low micromolar IC50. We used three functional MTase assays to unambiguously verified the inhibitory potency of these molecules for the NSP14 N7-MTase function. Binding studies indicated that these molecules are bound directly to the NSP14 MTase with similar low micromolar affinity. Moreover, we further demonstrated that these molecules significantly inhibited the SARS-CoV-2 replication in cell-based assays at concentrations not causing cytotoxicity. Furthermore, NSC111552 significantly synergized with known SARS-CoV-2 drugs including nirmatrelvir and remdesivir. Finally, docking suggested that these molecules bind specifically to the SAM-binding site on the NSP14 MTase. Overall, these molecules represent novel and promising candidates to further develop broad-spectrum inhibitors for the management of viral infections.
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COVID-19 , Infecção por Zika virus , Zika virus , Humanos , Metiltransferases/genética , Metiltransferases/metabolismo , SARS-CoV-2/genética , Ensaios de Triagem em Larga Escala , Proteínas não Estruturais Virais/metabolismo , Zika virus/genética , Zika virus/metabolismo , Sítios de Ligação , Capuzes de RNA/química , Capuzes de RNA/genética , Capuzes de RNA/metabolismo , Polarização de Fluorescência , RNA Viral/genéticaRESUMO
BACKGROUND: The simplified frailty index (sFI) is a commonly used instrument to estimate postoperative risk, but its correlation with phenotypic frailty has been questioned. This study evaluates the relationship between sFI and phenotypic frailty, as measured by the Sinai Abbreviated Geriatric Evaluation (SAGE). METHODS: Charts were retrospectively reviewed from patients ≥75 years old who underwent surgery between 2012-2022. The sFI score was calculated by adding 1 point for hypertension, COPD, congestive heart failure, functional dependence, and diabetes (score 0-5). SAGE was calculated by adding 1 point for normal gait speed, normal Mini-Cog©, and independent activities of daily living (ADL) (0-3). Spearman rank correlation was used to test the relationship between sFI and SAGE. SAGE components were used as binary-dependent outcomes in covariate-adjusted logistic regression modeling to evaluate associations with sFI scores while adjusting for potential confounders. RESULTS: 334 patients were assessed, with a mean age of 84.0. SAGE and sFI scores were significantly associated, with a modest inverse relationship (r=-0.24, p<0.0001). Each 1-point increase in sFI score was associated with increased odds of ADL deficit (OR 2.3, 95%CI [1.5-3.8], p<0.0001) and abnormal gait speed (OR 1.9, 95%CI 1.2-3.0, p<0.01). The sFI score was not associated with deficits in the Mini-Cog (OR 1.5, 95%CI [0.96-2.3], p=0.07). CONCLUSION: Higher sFI was significantly associated with increased phenotypic frailty, particularly with the loss of physical condition and function but not associated with cognitive deficit. Therefore, sFI may not be an appropriate tool to estimate postoperative complications related to cognition, such as delirium risk.
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Disfunção Cognitiva , Fragilidade , Humanos , Idoso , Idoso de 80 Anos ou mais , Idoso Fragilizado , Atividades Cotidianas , Estudos Retrospectivos , Disfunção Cognitiva/complicações , Avaliação GeriátricaRESUMO
OBJECTIVES: Convenience sampling is an imperfect but important tool for seroprevalence studies. For COVID-19, local geographic variation in cases or vaccination can confound studies that rely on the geographically skewed recruitment inherent to convenience sampling. The objectives of this study were: (1) quantifying how geographically skewed recruitment influences SARS-CoV-2 seroprevalence estimates obtained via convenience sampling and (2) developing new methods that employ Global Positioning System (GPS)-derived foot traffic data to measure and minimise bias and uncertainty due to geographically skewed recruitment. DESIGN: We used data from a local convenience-sampled seroprevalence study to map the geographic distribution of study participants' reported home locations and compared this to the geographic distribution of reported COVID-19 cases across the study catchment area. Using a numerical simulation, we quantified bias and uncertainty in SARS-CoV-2 seroprevalence estimates obtained using different geographically skewed recruitment scenarios. We employed GPS-derived foot traffic data to estimate the geographic distribution of participants for different recruitment locations and used this data to identify recruitment locations that minimise bias and uncertainty in resulting seroprevalence estimates. RESULTS: The geographic distribution of participants in convenience-sampled seroprevalence surveys can be strongly skewed towards individuals living near the study recruitment location. Uncertainty in seroprevalence estimates increased when neighbourhoods with higher disease burden or larger populations were undersampled. Failure to account for undersampling or oversampling across neighbourhoods also resulted in biased seroprevalence estimates. GPS-derived foot traffic data correlated with the geographic distribution of serosurveillance study participants. CONCLUSIONS: Local geographic variation in seropositivity is an important concern in SARS-CoV-2 serosurveillance studies that rely on geographically skewed recruitment strategies. Using GPS-derived foot traffic data to select recruitment sites and recording participants' home locations can improve study design and interpretation.