Aspergillosis complicating severe influenza infection has been increasingly detected worldwide. Recently, coronavirus disease-associated pulmonary aspergillosis (CAPA) has been detected through rapid ...reports, primarily from centers in Europe. We provide a case series of CAPA, adding 20 cases to the literature, with review of pathophysiology, diagnosis, and outcomes. The syndromes of pulmonary aspergillosis complicating severe viral infections are distinct from classic invasive aspergillosis, which is recognized most frequently in persons with neutropenia and in other immunocompromised persons. Combined with severe viral infection, aspergillosis comprises a constellation of airway-invasive and angio-invasive disease and results in risks associated with poor airway fungus clearance and killing, including virus- or inflammation-associated epithelial damage, systemic immunosuppression, and underlying lung disease. Radiologic abnormalities can vary, reflecting different pathologies. Prospective studies reporting poor outcomes in CAPA patients underscore the urgent need for strategies to improve diagnosis, prevention, and therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As supply chain channels physical, financial, and information flows as well as associated risks, a firm's supply chain information should be helpful in understanding and predicting its credit risks. ...Credit ratings, as an approximate but important measure of corporate credit risks, have been widely used by investors, creditors, and supply chain partners in their decision‐making. This study studies the role of supply chain information in predicting companies’ credit ratings. Using firm‐level supplier–customer linkages and corporate credit rating data, we develop a machine learning framework with gradient boosted decision trees to examine whether and what supply chain features can significantly improve the prediction accuracy of credit ratings, and what types of supply chain links have higher information content that positively affects the predictability of the supply chain features. We construct a firm's supply chain variables from its supplier and customer portfolios. We show that incorporating supply chain features can improve prediction accuracy over the benchmark credit rating model using only the focal firm's features. Moreover, the informativeness of supply chain links in focal credit risk prediction depends on the focal firm's industry sector, the relationship strength of such links, and the switching costs. Finally, we develop a focal credit rating prediction model with a high accuracy level using supply chain factors solely, which can potentially be applied to predict credit risks of small‐ and medium‐sized enterprises (SMEs) and private firms with no public financial information, as long as their supply chain information is available.
Author Video
Abstract
Background
Coronavirus disease 2019 (COVID-19)–associated pulmonary aspergillosis (CAPA) occurs in critically ill patients with COVID-19. Risks and outcomes remain poorly understood.
Methods
...A retrospective cohort study of mechanically ventilated adult patients with COVID-19 admitted to 5 Johns Hopkins hospitals was conducted between March and August 2020. CAPA was defined using composite clinical criteria. Fine and Gray competing risks regression was used to analyze clinical outcomes and, multilevel mixed-effects ordinal logistic regression was used to compare longitudinal disease severity scores.
Results
In the cohort of 396 people, 39 met criteria for CAPA. Patients with CAPA were more likely than those without CAPA to have underlying pulmonary vascular disease (41% vs 21.6%, respectively; P = .01), liver disease (35.9% vs 18.2%; P = .02), coagulopathy (51.3% vs 33.1%; P = .03), solid tumors (25.6% vs 10.9%; P = .02), multiple myeloma (5.1% vs 0.3%; P = .03), and corticosteroid exposure during the index admission (66.7% vs 42.6%; P = .005), and had lower body mass indexes (median, 26.6 vs 29.9 calculated as weight in kilograms divided by height in meters squared; P = .04). Patients with CAPA had worse outcomes, as measured by ordinal severity of disease scores, requiring longer time to improvement (adjusted odds ratio, 1.081.091.1; P < .001), and advancing in severity almost twice as quickly (subhazard ratio, 1.31.82.5; P < .001). They were intubated twice as long as those without CAPA (subhazard ratio, 0.40.50.6; P < .001) and had longer hospital stays (median interquartile range, 41.1 20.5–72.4) vs 18.5 10.7–31.8 days; P < .001).
Conclusion
CAPA is associated with poor outcomes. Attention to preventive measures (screening and/or prophylaxis) is warranted in people with high risk of CAPA.
Aspergillosis occurs at a variable incidence in people with severe coronavirus disease 2019, depending on diagnostic approach and definitions. Associated poor outcomes may be improved with early detection and antifungal therapy, warranting development of better noninvasive diagnostic and prevention strategies.
This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and ...low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota–gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
Abstract
Background
Phase I oncology trials are often regarded as a therapeutic option for patients. However, such claims have relied on surrogate measures of benefit, such as objective response.
...Methods
Using a systematic search of publications, we assessed the therapeutic value of phase I cancer trial participation by determining the probability that patients will receive active doses of treatments that eventually receive FDA approval or a National Comprehensive Cancer Network (NCCN) guideline recommendation for their indication. ClinicalTrials.gov, PubMed, American Society of Clinical Oncology reports, NCCN guidelines, and Drugs@FDA were searched between May 1, 2018, and July 31, 2018. All statistical tests were 2-sided.
Results
A total of 1000 phase I oncology trials initiated between 2005 and 2010 and enrolling 32 582 patients were randomly sampled from 3229 eligible trials on ClinicalTrials.gov. A total of 386 (1.2%) patients received a treatment that was approved by the US Food and Drug Administration for their malignancy at a dose delivered in the trial; including NCCN guideline recommendations, the number and proportion are 1168 (3.6%). Meta-regression showed a statistically significantly greater proportion of patients receiving a drug that was ultimately FDA approved in biomarker trials (rate ratio = 4.49, 95% confidence interval CI = 1.53 to 13.23; P = .006) and single-indication trials (rate ratio = 3.32, 95% CI = 1.21 to 9.15; P = .02); proportions were statistically significantly lower for combination vs monotherapy trials (rate ratio = 0.09, 95% CI = 0.01 to 0.68; P = .02).
Conclusions
One in 83 patients in phase I cancer trials received a treatment that was approved for their indication at the doses received. Given published estimates of serious adverse event rates of 10%-19%, this represents low therapeutic value for phase I trial participation.
The Biology of Aging and Cancer Zhang, Xinwen; Meng, Xin; Chen, Yiyin ...
The cancer journal (Sudbury, Mass.),
7/2017, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Abstract
The majority of patients with common malignancies are older adults. Intrinsic complex biological changes of aging along with inflammation, immunosenescence, age-associated chronic diseases, ...and extrinsic environmental and psychosocial factors have significant impact on not only development and behavior of individual malignancies, but also physiologic reserve and vulnerability of older patients who suffer from them. As a result, clinical practice of geriatric oncology demands integration of careful geriatric assessment and management. This article provides an overview of basic biology of aging and its relationship with cancer. After a brief introduction about the definition and mechanisms of aging, as well as age-related biological and physiological changes, the discussion mainly focuses on recent development and insights into the relationship of frailty, inflammation, and immunity with cancer, highlighting how the new knowledge can help further improve assessment and treatment of older patients with malignancies and promote cancer research.
Copper is both an essential nutrient and potentially toxic metal, and during infection the host can exploit Cu in the control of pathogen growth. Here we describe a clever adaptation to Cu taken by ...the human fungal pathogen Candida albicans. In laboratory cultures with abundant Cu, C. albicans expresses a Cu-requiring form of superoxide dismutase (Sod1) in the cytosol; but when Cu levels decline, cells switch to an alternative Mn-requiring Sod3. This toggling between Cu- and Mn-SODs is controlled by the Cu-sensing regulator Mac1 and ensures that C. albicans maintains constant SOD activity for cytosolic antioxidant protection despite fluctuating Cu. This response to Cu is initiated during C. albicans invasion of the host where the yeast is exposed to wide variations in Cu. In a murine model of disseminated candidiasis, serum Cu was seen to progressively rise over the course of infection, but this heightened Cu response was not mirrored in host tissue. The kidney that serves as the major site of fungal infection showed an initial rise in Cu, followed by a decline in the metal. C. albicans adjusted its cytosolic SODs accordingly and expressed Cu-Sod1 at early stages of infection, followed by induction of Mn-Sod3 and increases in expression of CTR1 for Cu uptake. Together, these studies demonstrate that fungal infection triggers marked fluctuations in host Cu and C. albicans readily adapts by modulating Cu uptake and by exchanging metal cofactors for antioxidant SODs.
Analysis of the population genetic structure of microbial species is of fundamental importance to many scientific disciplines because it can identify cryptic species, reveal reproductive mode, and ...elucidate processes that contribute to pathogen evolution. Here, we examined the population genetic structure and geographic differentiation of the sexual, dimorphic fungus Blastomyces dermatitidis, the causative agent of blastomycosis.
Criteria for Genealogical Concordance Phylogenetic Species Recognition (GCPSR) applied to seven nuclear loci (arf6, chs2, drk1, fads, pyrF, tub1, and its-2) from 78 clinical and environmental isolates identified two previously unrecognized phylogenetic species. Four of seven single gene phylogenies examined (chs2, drk1, pyrF, and its-2) supported the separation of Phylogenetic Species 1 (PS1) and Phylogenetic Species 2 (PS2) which were also well differentiated in the concatenated chs2-drk1-fads-pyrF-tub1-arf6-its2 genealogy with all isolates falling into one of two evolutionarily independent lineages. Phylogenetic species were genetically distinct with interspecific divergence 4-fold greater than intraspecific divergence and a high Fst value (0.772, P<0.001) indicative of restricted gene flow between PS1 and PS2. Whereas panmixia expected of a single freely recombining population was not observed, recombination was detected when PS1 and PS2 were assessed separately, suggesting reproductive isolation. Random mating among PS1 isolates, which were distributed across North America, was only detected after partitioning isolates into six geographic regions. The PS2 population, found predominantly in the hyper-endemic regions of northwestern Ontario, Wisconsin, and Minnesota, contained a substantial clonal component with random mating detected only among unique genotypes in the population.
These analyses provide evidence for a genetically divergent clade within Blastomyces dermatitidis, which we use to describe a novel species, Blastomyces gilchristii sp. nov. In addition, we discuss the value of population genetic and phylogenetic analyses as a foundation for disease surveillance, understanding pathogen evolution, and discerning phenotypic differences between phylogenetic species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:There is no consensus guidance on when to reinitiate Pneumocystis jirovecii pneumonia (PJP) prophylaxis in solid organ transplant (SOT) recipients at increased risk. The 2019 American ...Society of Transplantation Infectious Diseases Community of Practice (AST IDCOP) guidelines suggested to continue or reinstitute PJP prophylaxis in those receiving intensified immunosuppression for graft rejection, CMV infection, higher dose of corticosteroids, or prolonged neutropenia.
METHODS:A literature search was conducted evaluating all literature from existence through April 22, 2020 using MEDLINE and EMBASE. (PROSPEROCRD42019134204)
RESULTS:A total of 30 studies with 413 276 SOT recipients were included. The following factors were associated with PJP developmentacute rejection (pooled odds ratio (pOR) = 2.35 (1.69, 3.26), study heterogeneity index (I)= 23.4%), cytomegalovirus (CMV)-related illnesses (pOR = 3.14 (2.30, 4.29), I=48%), absolute lymphocyte count < 500 cells/mm (pOR = 6.293.56, 11.13, I 0%), BK-related diseases (pOR = 2.591.22, 5.49, I 0%), HLA mismatch ≥ 3 (pOR = 1.83 1.06, 3.17, I= 0%), rituximab use (pOR =3.03 (1.82, 5.04); I =0%) and polyclonal antibodies use for rejection (pOR = 3.92 1.87, 8.19, I= 0%). On the other hand, sex, CMV mismatch, interleukin-2 inhibitors, corticosteroids for rejection, and plasmapheresis were not associated with developing PJP.
CONCLUSION:PJP prophylaxis should be considered in SOT recipients with lymphopenia, BK-related infections and rituximab exposure in addition to the previously mentioned risk factors in the AST IDCOP guidelines.
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