Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal ...that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H
O
) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H
O
production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H
O
secretion compared with normal fibroblasts (FIBs). These results suggest that extracellular H
O
acts as a field effect carcinogen. Indeed, H
O
-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H
O
resulted in the acquisition of an oxidative, CAF-like state. In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H
O
production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways.
The 2007 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) guidelines defined severe community-acquired pneumonia (CAP) and recommended intensive care unit (ICU) admission ...when patients fulfilled three out of nine minor criteria. These criteria have not been validated.
All patients admitted to our hospital from 2004 to 2007 for CAP were reviewed retrospectively. Patients who fulfilled any IDSA/ATS major criteria for severe CAP at the emergency department (ie, the need for mechanical ventilation or vasopressors) were excluded. The predictive characteristics of the IDSA/ATS minor criteria were compared with those of the Pneumonia Severity Index (PSI) and the CURB-65 score for hospital mortality and ICU admission.
1242 patients were studied (mean age 65.7 years, hospital mortality 14.7%). The areas under the receiver operating characteristic curves for the IDSA/ATS minor criteria were 0.88 (95% CI 0.86 to 0.91) and 0.85 (95% CI 0.81 to 0.88) for predicting hospital mortality and ICU admission, respectively. These were greater than the corresponding areas for the PSI and the CURB-65 score (p < 0.05). The sensitivity, specificity, positive and negative predictive values of the minor criteria were 81.4%, 82.9%, 45.2% and 96.3%, respectively, for hospital mortality and 58.3%, 90.6%, 52.9% and 92.3%, respectively, for ICU admission. The minor criteria were more specific than the PSI and more sensitive than the CURB-65 score for both outcomes.
These findings support the use of the IDSA/ATS minor criteria to predict hospital mortality and guide ICU admission in inpatients with CAP who do not require emergency mechanical ventilation or vasopressors.
The primary objective of the present study was to evaluate the effect on hospital mortality of a delay in intensive care unit (ICU) admission for severe community-acquired pneumonia (CAP). The ...secondary objectives were to assess if such delays were associated with treatment variations by the emergency department (ED) and deterioration in the general wards, and to evaluate the prognostic ability of the Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) minor criteria. We retrospectively compared patients who were admitted straight from the ED to the ICU (direct group, n = 54) and those who were first admitted from the ED to the general wards before ICU transfer (delayed group, n = 49), over 2.5 yrs. Even after excluding patients who required mechanical ventilation and/or vasopressors at the ED, delayed ICU admission was an independent predictor of hospital mortality (OR 9.61). The delayed group received fewer fluid boluses in the ED and rapidly deteriorated in the general wards. The presence of ≥3 IDSA/ATS minor criteria was associated with increased mortality in the delayed group. In conclusion, prompt recognition of severe CAP using the IDSA/ATS minor criteria, followed by aggressive management at the ED and direct ICU admission, are all crucial toward improving outcomes.
Summary Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of ...modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval UI 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. Funding Bill & Melinda Gates Foundation.
Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, ...using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.
Culture-negative sepsis is a common but relatively understudied condition. The aim of this study was to compare the characteristics and outcomes of culture-negative versus culture-positive severe ...sepsis.
This was a prospective observational cohort study of 1001 patients who were admitted to the medical intensive care unit (ICU) of a university hospital from 2004 to 2009 with severe sepsis. Patients with documented fungal, viral, and parasitic infections were excluded.
There were 415 culture-negative patients (41.5%) and 586 culture-positive patients (58.5%). Gram-positive bacteria were isolated in 257 patients, and gram-negative bacteria in 390 patients. Culture-negative patients were more often women and had fewer comorbidities, less tachycardia, higher blood pressure, lower procalcitonin levels, lower Acute Physiology and Chronic Health Evaluation II (median 25.0 (interquartile range 19.0 to 32.0) versus 27.0 (21.0 to 33.0), P = 0.001) and Sequential Organ Failure Assessment scores, less cardiovascular, central nervous system, and coagulation failures, and less need for vasoactive agents than culture-positive patients. The lungs were a more common site of infection, while urinary tract, soft tissue and skin infections, infective endocarditis and primary bacteremia were less common in culture-negative than in culture-positive patients. Culture-negative patients had a shorter duration of hospital stay (12 days (7.0 to 21.0) versus 15.0 (7.0 to27.0), P = 0.02) and lower ICU mortality than culture-positive patients. Hospital mortality was lower in the culture-negative group (35.9%) than in the culture-positive group (44.0%, P = 0.01), the culture-positive subgroup, which received early appropriate antibiotics (41.9%, P = 0.11), and the culture-positive subgroup, which did not (55.5%, P < 0.001). After adjusting for covariates, culture positivity was not independently associated with mortality on multivariable analysis.
Significant differences between culture-negative and culture-positive sepsis are identified, with the former group having fewer comorbidities, milder severity of illness, shorter hospitalizations, and lower mortality.
Background. Non-attendance is common in primary care and previous studies have reported that reminders were useful in reducing broken appointments. Objective. To determine the effectiveness of a text ...messaging reminder in improving attendance in primary care. Design. Multicentre three-arm randomized controlled trial. Setting. Seven primary care clinics in Malaysia. Participants. Patients (or their caregivers) who required follow-up at the clinics between 48 hours and 3 months from the recruitment date. Interventions. Two intervention arms consisted of text messaging and mobile phone reminders 24–48 hours prior to scheduled appointments. Control group did not receive any intervention. Outcome measures. Attendance rates and costs of interventions. Results. A total of 993 participants were eligible for analysis. Attendance rates of control, text messaging and mobile phone reminder groups were 48.1, 59.0 and 59.6%, respectively. The attendance rate of the text messaging reminder group was significantly higher compared with that of the control group (odds ratio 1.59, 95% confidence interval 1.17 to 2.17, P = 0.005). There was no statistically significant difference in attendance rates between text messaging and mobile phone reminder groups. The cost of text messaging reminder (RM 0.45 per attendance) was lower than mobile phone reminder (RM 0.82 per attendance). Conclusions. Text messaging reminder system was effective in improving attendance rate in primary care. It was more cost-effective compared with the mobile phone reminder.
Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute ...respiratory failure (C-ARF) has resulted in wide variation in clinical practice.
Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ
) test (p < 0·05 was considered as unstable).
Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment.
Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited.
The study was registered with Clinical trials.gov Identifier: NCT04534569.
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