Prior sepsis studies evaluating antibiotic timing have shown mixed results.
To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within ...6 hours of emergency department registration.
Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors.
The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4-3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval CI, 1.05-1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (95% CI, 0.01-0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1-0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8-3.0%; P = 0.001) for shock.
In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock.
Chemical probes have reached a prominent role in biomedical research, but their impact is governed by experimental design. To gain insight into the use of chemical probes, we conducted a systematic ...review of 662 publications, understood here as primary research articles, employing eight different chemical probes in cell-based research. We summarised (i) concentration(s) at which chemical probes were used in cell-based assays, (ii) inclusion of structurally matched target-inactive control compounds and (iii) orthogonal chemical probes. Here, we show that only 4% of analysed eligible publications used chemical probes within the recommended concentration range and included inactive compounds as well as orthogonal chemical probes. These findings indicate that the best practice with chemical probes is yet to be implemented in biomedical research. To achieve this, we propose 'the rule of two': At least two chemical probes (either orthogonal target-engaging probes, and/or a pair of a chemical probe and matched target-inactive compound) to be employed at recommended concentrations in every study.
Childhood overweight is associated with an increased risk of type 2 diabetes in adulthood. We investigated whether remission of overweight before early adulthood reduces this risk.
We conducted a ...study involving 62,565 Danish men whose weights and heights had been measured at 7 and 13 years of age and in early adulthood (17 to 26 years of age). Overweight was defined in accordance with Centers for Disease Control and Prevention criteria. Data on type 2 diabetes status (at age ≥30 years, 6710 persons) were obtained from a national health registry.
Overweight at 7 years of age (3373 of 62,565 men; 5.4%), 13 years of age (3418 of 62,565; 5.5%), or early adulthood (5108 of 62,565; 8.2%) was positively associated with the risk of type 2 diabetes; associations were stronger at older ages at overweight and at younger ages at diagnosis of type 2 diabetes. Men who had had remission of overweight before the age of 13 years had a risk of having type 2 diabetes diagnosed at 30 to 60 years of age that was similar to that among men who had never been overweight (hazard ratio, 0.96; 95% confidence interval CI, 0.75 to 1.21). As compared with men who had never been overweight, men who had been overweight at 7 and 13 years of age but not during early adulthood had a higher risk of type 2 diabetes (hazard ratio, 1.47; 95% CI, 1.10 to 1.98), but their risk was lower than that among men with persistent overweight (hazard ratio persistently overweight vs. never overweight, 4.14; 95% CI, 3.57 to 4.79). An increase in body-mass index between 7 years of age and early adulthood was associated with an increased risk of type 2 diabetes, even among men whose weight had been normal at 7 years of age.
Childhood overweight at 7 years of age was associated with increased risks of adult type 2 diabetes only if it continued until puberty or later ages. (Funded by the European Union.).
Type II topoisomerase (Top2) poisoning therapy is used to treat a broad range of cancers via induction of double strand breaks (DSBs) in cells undergoing replication and transcription. Preventing the ...repair of DSBs via inhibition of DNA-PK, an inhibitor of non-homologous end-joining (NHEJ), increases cell kill with Top2 poisons and has led to the initiation of several clinical trials. To elucidate the cellular mechanisms leading to synergistic activity of dual DNA-PK/Top2 inhibition we looked at their effects in cycling versus non-cycling cells, in 3D spheroids and in xenograft models. Combined DNA-PK/Top2 inhibition was found to not only increase the cell kill in proliferating cells, the cell population that is typically most vulnerable to Top2 poisoning, but also in non-proliferative but transcriptionally active cells. This effect was observed in both cancer and normal tissue models, killing more cells than high concentrations of etoposide alone. The combination treatment delayed tumor growth in mice compared to Top2 poisoning alone, but also led to increased toxicity. These findings demonstrate sensitization of Top2β-expressing, non-cycling cells to Top2 poisoning by DNA-PK inhibition. Expansion of the target cell population of Top2 poison treatment to include non-proliferating cells via combination with DNA damage repair inhibitors has implications for efficacy and toxicity of these combinations, including for inhibitors of DNA-PK currently in clinical trial.
Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triple‐negative phenotypes ...makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic‐to‐nuclear pathway of the AhR for the possible future treatment of breast cancer.
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population-based cohort study, we examined whether prenatal stress related to maternal bereavement ...during pregnancy was associated with the risk of overweight in offspring during school age.
We followed 65,212 children born in Denmark from 1970-1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval CI 1.08-2.61) at 12 years of age and 1.63 (95% CI 1.00-2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71-6.42 at age 12, and OR 2.31, 95% CI 1.08-4.97 at age 13).
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
Occult breast cancer presenting as axillary metastasis is rare and remains a diagnostic and therapeutic challenge. Evidence to guide clinical management is limited, and locoregional treatment remains ...nonstandardized and highly varied nationally. Historically, occult breast cancer was managed with modified radical mastectomy ± radiotherapy; however, equivalent local control and survival are observed with breast preservation and adjuvant whole breast radiotherapy. Axillary lymph node dissection remains the standard surgical approach to the axilla for occult breast cancer patients. De-escalating axillary surgery in a subset of occult breast cancer patients treated with neoadjuvant chemotherapy with good response to treatment may be appropriate, similar to the management of clinically node-positive patients in a known primary setting. As in other clinically node-positive breast cancer cases, thoughtful integration and tailoring of axillary surgery and regional nodal radiotherapy (for the varying extent of nodal burden) is an area of continued controversy and active investigation.
Childhood obesity adversely affects the structure and function of the cardiovascular system, but the relationship between excessive weight gain during childhood and adult cardiovascular disease (CVD) ...is not fully understood. This review summarizes evidence for associations of change in body mass index (BMI) from childhood onwards with CVD outcomes. We found that excessive gain in BMI from childhood onwards was consistently associated with the presence of CVD risk factors, with increased risks of coronary heart disease, and there were suggestions of associations with stroke, atrial fibrillation and heart failure, but a lack of evidence precludes firm conclusions. These results indicate that the risk of CVD can be traced back to child ages and highlights the importance of primordial prevention of CVD by preventing excessive weight gain in childhood.
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