Characterizing Long COVID: Deep Phenotype of a Complex Condition

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or long COVID ), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FINDINGS: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need

Bioelectrical impedance phase angle as a prognostic indicator in breast cancer

<p>Abstract</p> <p>Background</p> <p>Bioelectrical impedance analysis (BIA) is an easy-to-use, non-invasive, and reproducible technique to evaluate changes in body composition and nutritional status. Phase angle, determined by bioelectrical impedance analysis (BIA), detects changes in tissue electrical properties and has been hypothesized to be a marker of malnutrition. Since malnutrition can be found in patients with breast cancer, we investigated the prognostic role of phase angle in breast cancer.</p> <p>Methods</p> <p>We evaluated a case series of 259 histologically confirmed breast cancer patients treated at Cancer Treatment Centers of America. Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of phase angle independent of stage at diagnosis and prior treatment history. Survival was calculated as the time interval between the date of first patient visit to the hospital and the date of death from any cause or date of last contact/last known to be alive.</p> <p>Results</p> <p>Of 259 patients, 81 were newly diagnosed at our hospital while 178 had received prior treatment elsewhere. 56 had stage I disease at diagnosis, 110 had stage II, 46 had stage III and 34 had stage IV. The median age at diagnosis was 49 years (range 25 – 74 years). The median phase angle score was 5.6 (range = 1.5 – 8.9). Patients with phase angle <= 5.6 had a median survival of 23.1 months (95% CI: 14.2 to 31.9; n = 129), while those > 5.6 had 49.9 months (95% CI: 35.6 to 77.8; n = 130); the difference being statistically significant (p = 0.031). Multivariate Cox modeling, after adjusting for stage at diagnosis and prior treatment history found that every one unit increase in phase angle score was associated with a relative risk of 0.82 (95% CI: 0.68 to 0.99, P = 0.041). Stage at diagnosis (p = 0.006) and prior treatment history (p = 0.001) were also predictive of survival independent of each other and phase angle.</p> <p>Conclusion</p> <p>This study demonstrates that BIA-derived phase angle is an independent prognostic indicator in patients with breast cancer. Nutritional interventions targeted at improving phase angle could potentially lead to an improved survival in patients with breast cancer.</p

Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or long COVID ), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FINDINGS: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411

Market reforms and the limitations of monetary policy : the case of Colombia

In the early 1990s, Colombia moved rapidly to reform its economy including a dramatic opening to foreing trade and capital. This study shows that as a result of this opening, the Colombian economy has become much more economically integrated with that of the rest of Latin America, especially Venezuela and Ecuador

Absolute Quantification of Aldehyde Oxidase Protein in Human Liver Using Liquid Chromatography-Tandem Mass Spectrometry

The function of the enzyme human aldehyde oxidase (AOX1) is uncertain, however, recent studies have implicated significant biochemical involvement in humans. AOX1 has also rapidly become an important drug metabolizing enzyme. Until now, quantitation of AOX1 in complex matrices such as tissue has not been achieved. Herein, we developed and employed a trypsin digest and subsequent liquid chromatography tandem mass spectrometry analysis to determine absolute amounts of AOX1 in human liver. E. coli expressed human purified AOX1 was used to validate the linearity, sensitivity, and selectivity of the method. Overall, the method is highly efficient and sensitive for determination of AOX1 in cytosolic liver fractions. Using this method, we observed substantial batch-to-batch variation in AOX1 content (21-40 pmol AOX1/mg total protein) between various pooled human liver cytosol preparations. We also observed inter batch variation in V max (3.3-4.9 nmol min −1 mg −1 ) and a modest correlation between enzyme concentration and activity. In addition, we measured a large difference in k cat /K m , between purified (k cat /K m of 1.4) and human liver cytosol (k cat /K m of 15-20) indicating cytosol to be 11-14 times more efficient in the turnover of DACA than the E. coli expressed purified enzyme. Finally, we discussed the future impact of this method for the development of drug metabolism models and understanding the biochemical role of this enzyme

Mechanical Implications of Creep and Partial Coupling on the World's Fastest Slipping Low-Angle Normal Fault in Southeastern Papua New Guinea

We use densely spaced campaign GPS observations and laboratory friction experiments on fault rocks from one of the world's most rapidly slipping low-angle normal faults, the Mai'iu fault in Papua New Guinea, to investigate the nature of interseismic deformation on active low-angle normal faults. GPS velocities reveal 8.3 ± 1.2 mm/year of horizontal extension across the Mai'iu fault, and are fit well by dislocation models with shallow fault locking (above 2 km depth), or by deeper locking (from ~5–16 km depth) together with shallower creep. Laboratory friction experiments show that gouges from the shallowest portion of the fault zone are predominantly weak and velocity-strengthening, while fault rocks deformed at greater depths are stronger and velocity-weakening. Evaluating the geodetic and friction results together with geophysical and microstructural evidence for mixed-mode seismic and aseismic slip at depth, we find that the Mai'iu fault is most likely strongly locked at depths of ~5–16 km and creeping updip and downdip of this region. Our results suggest that the Mai'iu fault and other active low-angle normal faults can slip in large (Mw > 7) earthquakes despite near-surface interseismic creep on frictionally stable clay-rich gouges

Mechanical Implications of Creep and Partial Coupling on the World's Fastest Slipping Low‐Angle Normal Fault in Southeastern Papua New Guinea

We use densely spaced campaign GPS observations and laboratory friction experiments on fault rocks from one of the world's most rapidly slipping low-angle normal faults, the Mai'iu fault in Papua New Guinea, to investigate the nature of interseismic deformation on active low-angle normal faults. GPS velocities reveal 8.3 ± 1.2 mm/year of horizontal extension across the Mai'iu fault, and are fit well by dislocation models with shallow fault locking (above 2 km depth), or by deeper locking (from ~5–16 km depth) together with shallower creep. Laboratory friction experiments show that gouges from the shallowest portion of the fault zone are predominantly weak and velocity-strengthening, while fault rocks deformed at greater depths are stronger and velocity-weakening. Evaluating the geodetic and friction results together with geophysical and microstructural evidence for mixed-mode seismic and aseismic slip at depth, we find that the Mai'iu fault is most likely strongly locked at depths of ~5–16 km and creeping updip and downdip of this region. Our results suggest that the Mai'iu fault and other active low-angle normal faults can slip in large (Mw > 7) earthquakes despite near-surface interseismic creep on frictionally stable clay-rich gouges

Mechanical Implications of Creep and Partial Coupling on the World's Fastest Slipping Low-Angle Normal Fault in Southeastern Papua New Guinea

We use densely spaced campaign GPS observations and laboratory friction experiments on fault rocks from one of the world's most rapidly slipping low-angle normal faults, the Mai'iu fault in Papua New Guinea, to investigate the nature of interseismic deformation on active low-angle normal faults. GPS velocities reveal 8.3 ± 1.2 mm/year of horizontal extension across the Mai'iu fault, and are fit well by dislocation models with shallow fault locking (above 2 km depth), or by deeper locking (from ~5–16 km depth) together with shallower creep. Laboratory friction experiments show that gouges from the shallowest portion of the fault zone are predominantly weak and velocity-strengthening, while fault rocks deformed at greater depths are stronger and velocity-weakening. Evaluating the geodetic and friction results together with geophysical and microstructural evidence for mixed-mode seismic and aseismic slip at depth, we find that the Mai'iu fault is most likely strongly locked at depths of ~5–16 km and creeping updip and downdip of this region. Our results suggest that the Mai'iu fault and other active low-angle normal faults can slip in large (Mw > 7) earthquakes despite near-surface interseismic creep on frictionally stable clay-rich gouges