Patients infected with the SARS-CoV-2 virus can present with a wide variety of symptoms including being entirely asymptomatic. Despite having no or minimal symptoms, some patients may have markedly ...reduced pulse oximetry readings. This has been referred to as “silent” or “apathetic” hypoxia (Ottestad et al., 2020 1). We present a case of a 72-year-old male with COVID-19 syndrome who presented to the emergency department with minimal symptoms but low peripheral oxygen saturation readings. The patient deteriorated over the following days and eventually died as a result of overwhelming multi-organ system failure. This case highlights the utility of peripheral oxygen measurements in the evaluation of patients with SARS-CoV-2 infection. Self-monitoring of pulse oximetry by patients discharged from the emergency department is a potential way to identify patients needing to return for further evaluation.
The rapid expansion of Indian cities, their economic development and increasing concerns for the segregation of Municipal Solid Waste (MSW) lead towards more production of Organic Fraction of ...Municipal Solid Waste (OFMSW) in most cities of developing nations. Organic Fraction of Municipal Solid Waste is the most favorable substrate in meeting goals of waste to energy in recent times using anaerobic digestion. The bio-flocculated sludge produced in Secondary Settling Tank (SST) (used from post UASB) can be a potential co-substrate for the co-digestion of OFMSW, against its independent disposal system in a conventional sewage treatment plant. The majority of Indian states have favorable meteorological conditions (20–40 °C for 9 to 10 months of a year) for anaerobic digestion. Various mixing ratios of OFMSW: Bio-flocculated sludge from SST at 50:50, 75:25, 90:10, 0:100, and 100:0 (% wet weight) are used in the current anaerobic batch reactor study. Co-digestion exhibits a quick phase of acclimatization and raises methane production. With anaerobic co-digestion, the maximum specific methane gas yield is 369.28 ± 55.51 L/kgVS
added
against 167.78 ± 16.45 L/kgVS
added
in batch research mono-digestion of OFMSW. The results of a kinetic analysis using the Modified Gompertz model and Logistic Function model for methane production demonstrate the acceptance of the experimental methane yield. The lab-scale process employed in this study is having the advantage of simplicity & economic affordability for replicating its use in large scale plants in developing nations like India.
Graphical Abstract
Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis ...may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.
University of Maryland School of Medicine Parker, Donna L; Martinez, Joseph P; Shah, Nirav G
Academic medicine,
2020-September, Letnik:
95, Številka:
9S A Snapshot of Medical Student Education in the United States and Canada: Reports From 145 Schools
Journal Article
The p38 MAPK family is composed of four kinases of which p38α/MAPK14 is the major proinflammatory member. These kinases contribute to many inflammatory diseases, but the currently available p38 ...catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity. We reasoned that the failure of catalytic p38 inhibitors may derive from their activity against noninflammatory p38 isoforms (e.g., p38β/MAPK11) and loss of all p38α-dependent responses, including anti-inflammatory, counterregulatory responses via mitogen- and stress-activated kinase (MSK) 1/2 and Smad3. We used computer-aided drug design to target small molecules to a pocket near the p38α glutamate-aspartate (ED) substrate-docking site rather than the catalytic site, the sequence of which had only modest homology among p38 isoforms. We identified a lead compound, UM101, that was at least as effective as SB203580 in stabilizing endothelial barrier function, reducing inflammation, and mitigating LPS-induced mouse lung injury. Differential scanning fluorimetry and saturation transfer difference-nuclear magnetic resonance demonstrated specific binding of UM101 to the computer-aided drug design-targeted pockets in p38α but not p38β. RNA sequencing analysis of TNF-α-stimulated gene expression revealed that UM101 inhibited only 28 of 61 SB203580-inhibited genes and 7 of 15 SB203580-inhibited transcription factors, but spared the anti-inflammatory MSK1/2 pathway. We provide proof of principle that small molecules that target the ED substrate-docking site may exert anti-inflammatory effects similar to the catalytic p38 inhibitors, but their isoform specificity and substrate selectivity may confer inherent advantages over catalytic inhibitors for treating inflammatory diseases.
OBJECTIVE:Clinicians caring for patients with intracerebral hemorrhage must often discuss prognosis and goals of care with their patients’ surrogate decision makers, and may make numeric estimates of ...likelihood of survival and functional independence, informed by validated prediction models. Surrogates’ prognostic estimates are often discordant with physicians’, suggesting that physicians’ numeric statements may not be accurately interpreted. We sought to assess the relationship between numeracy and interpretation of prognostic estimates in intracerebral hemorrhage among surrogate decision makers. We also assessed surrogates’ application of prognostic estimates to decisions regarding goals of care.
DESIGN:Single-center, survey-based, cross-sectional study.
SETTING:Twenty-two–bed neurologic ICU at an urban, academic hospital.
SUBJECTS:Surrogate decision makers for patients admitted to the neurologic ICU.
INTERVENTIONS:Participants completed a survey containing five clinical vignettes describing patients with nontraumatic intracerebral hemorrhage. For each patient, numerical estimates of survival and functional independence were explicitly provided, based on the validated outcome risk stratification scale (intracerebral hemorrhage score) and the Prediction of Functional Outcome in Patients with Primary Intracerebral Hemorrhage score.
MEASUREMENTS AND MAIN RESULTS:Participants were asked to make their own prognostic estimates, as well as to describe their preferred goals of care for each hypothetical patient. Respondent demographics were collected, and numeracy was assessed using a modified Lipkus 11-item scale. Poor numeracy was common (42 of 96 total subjects) in this relatively highly educated population. Most prognostic estimates (55%) made by surrogates were discordant with the provided estimates. High numeracy correlated with better concordance (odds ratio, 23.9 5.57–97.64; p < 0.001), independent of several factors, including level of education and religion. Numeracy also affected goals-of-care decisions made by surrogates.
CONCLUSIONS:Poor numeracy is common among surrogate decision makers in an intensive care setting and poses a barrier to communication between surrogates and clinicians regarding prognosis and goals of care.
Human mature IL-33 is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 activity. Its precursor form, full-length interleukin-33 (FLIL33), is an ...intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33. By overexpressing various FLIL33 protein segments and variants in primary human lung fibroblasts and HEK293T cells, we show that FLIL33, but not mature interleukin-33, physically interacts with IPO5 and that this interaction localizes to a cluster of charged amino acids (positions 46–56) but not to an adjacent segment (positions 61–67) in the FLIL33 N-terminal region. siRNA-mediated IPO5 knockdown in cell culture did not affect nuclear localization of FLIL33. However, the IPO5 knockdown significantly decreased the intracellular levels of overexpressed FLIL33, reversed by treatment with the 20S proteasome inhibitor bortezomib. Furthermore, FLIL33 variants deficient in IPO5 binding remained intranuclear and exhibited decreased levels, which were also restored by the bortezomib treatment. These results indicate that the interaction between FLIL33 and IPO5 is localized to a specific segment of the FLIL33 protein, is not required for nuclear localization of FLIL33, and protects FLIL33 from proteasome-dependent degradation.
Multidisciplinary discussion (MDD) is widely recommended for patients with interstitial lung disease (ILD), but published primary data from MDD has been scarce, and factors influencing MDD other than ...chest computed tomography (CT) and lung histopathology interpretations have not been well-described.
Single institution MDD of 179 patients with ILD.
MDD consensus clinical diagnoses included autoimmune-related ILD, chronic hypersensitivity pneumonitis, smoking-related ILD, idiopathic pulmonary fibrosis, medication-induced ILD, occupation-related ILD, unclassifiable ILD, and a few less common pulmonary disorders. In 168 of 179 patients, one or more environmental exposures or pertinent features of the medical history were identified, including recreational/avocational, residential, and occupational exposures, systemic autoimmune disease, malignancy, medication use, and family history. The MDD process demonstrated the importance of comprehensively assessing these exposures and features, beyond merely noting their presence, for rendering consensus clinical diagnoses. Precise, well-defined chest CT and lung histopathology interpretations were rendered at MDD, including usual interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia, but these interpretations were associated with a variety of MDD consensus clinical diagnoses, demonstrating their nonspecific nature in many instances. In 77 patients in which MDD consensus diagnosis differed from referring diagnosis, assessment of environmental exposures and medical history was found retrospectively to be the most impactful factor.
A comprehensive assessment of environmental exposures and pertinent features of the medical history guided MDD. In addition to rendering consensus clinical diagnoses, MDD presented clinicians with opportunities to initiate environmental remediation, behavior modification, or medication alteration likely to benefit individual patients with ILD.
•Multidisciplinary discussion (MDD) is endorsed for interstitial lung disease (ILD).•Prior published MDD data has focused on chest CT and lung biopsy interpretations.•Our MDD showed the value of assessing environmental exposures and medical history.•MDD may offer opportunities for environmental, behavior, or medication modification.
Chronic repeated exposure to hyperthermia in humans results in heat acclimation (HA), an adaptive process that is attained in humans by repeated exposure to hyperthermia and is characterized by ...improved heat elimination and increased exercise capacity, and acquired thermal tolerance (ATT), a cellular response characterized by increased baseline heat shock protein (HSP) expression and blunting of the acute increase in HSP expression stimulated by re-exposure to thermal stress. Epidemiologie studies in military personnel operating in hot environments and elite athletes suggest that repeated exposure to hyperthermia may also exert long-term health effects. Animal models demonstrate that coincident exposure to mild hyperthermia or prior exposure to severe hyperthermia can profoundly affect the course of experimental infection and injury, but these models do not represent HA. In this study, we demonstrate that CD-1 mice continuously exposed to mild hyperthermia (ambient temperature ~37°C causing ~2°C increase in core temperature) for 5 days and then exposed to a thermal stress (42°C ambient temperature for 40 min) exhibited some of the salient features of human HA, including (1) slower warming during thermal stress and more rapid cooling during recovery and (2) increased activity during thermal stress, as well as some of the features of ATT, including (1) increased baseline expression of HSP72 and HSP90 in lung, heart, spleen, liver, and brain; and (2) blunted incremental increase in HSP72 expression following acute thermal stress. This study suggests that continuous 5-day exposure of CD-1 mice to mild hyperthermia induces a state that resembles the physiologic and cellular responses of human HA. This model may be useful for analyzing the molecular mechanisms of HA and its consequences on host responsiveness to subsequent stresses.
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