On February 28, 2020, public health officials in the Seattle area were informed of a Covid-19 infection at a long-term care facility. An investigation identified 167 infected persons associated with ...the facility, including residents, health care personnel, and visitors; more than a third of the 101 residents identified died.
Extending the duration of adjuvant endocrine therapy reduces the risk of recurrence in a subset of women with early-stage hormone receptor-positive (HR+) breast cancer. Validated predictive ...biomarkers of endocrine response could significantly improve patient selection for extended therapy. Breast cancer index (BCI) HOXB13/IL17BR ratio (H/I) was evaluated for its ability to predict benefit from extended endocrine therapy in patients previously randomized in the Adjuvant Tamoxifen—To Offer More? (aTTom) trial.
Trans-aTTom is a multi-institutional, prospective–retrospective study in patients with available formalin-fixed paraffin-embedded primary tumor blocks. BCI testing and central determination of estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry were carried out blinded to clinical outcome. Survival endpoints were evaluated using Kaplan–Meier analysis and Cox regression with recurrence-free interval (RFI) as the primary endpoint. Interaction between extended endocrine therapy and BCI (H/I) was assessed using the likelihood ratio test.
Of 583 HR+, N+ patients analyzed, 49% classified as BCI (H/I)-High derived a significant benefit from 10 versus 5 years of tamoxifen treatment hazard ratio (HR): 0.35; 95% confidence interval (CI) 0.15–0.86; 10.2% absolute risk reduction based on RFI, P = 0.027. BCI (H/I)-low patients showed no significant benefit from extended endocrine therapy (HR: 1.07; 95% CI 0.69–1.65; −0.2% absolute risk reduction; P = 0.768). Continuous BCI (H/I) levels predicted the magnitude of benefit from extended tamoxifen, whereas centralized ER and PR did not. Interaction between extended tamoxifen treatment and BCI (H/I) was statistically significant (P = 0.012), adjusting for clinicopathological factors.
BCI by high H/I expression was predictive of endocrine response and identified a subset of HR+, N+ patients with significant benefit from 10 versus 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, establishing level 1B evidence for BCI as a predictive biomarker of benefit from extended endocrine therapy.
ISRCTN17222211; NCT00003678.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The potential impact of efforts in Europe to improve survival from out-of-hospital cardiac arrest is unclear, in part, because estimates of incidence and survival are uncertain. The aim of the ...investigation was to determine a representative European incidence and survival from cardiac arrest in all-rhythms and in ventricular fibrillation treated by the emergency medical services (EMS).
We used Medline to identify peer-reviewed articles published between 1 January 1980 and 30 June 2004 that reported a European community's EMS cardiac arrest experience. Inclusion criteria required the study to include at least 25 cases, report of the total number of all-rhythm and/or ventricular fibrillation arrests, and information about population size and study duration. The incidence was computed by dividing the total number of events by the product of the community's population and the study duration.
Reports from 37 communities met the inclusion criteria. A total of 18,105 all-rhythm EMS-treated cardiac arrests occurred during 48 million person-years of observation, resulting in an overall incidence for all-rhythm arrests of 37.72 per 100,000 person-years. Incidence of ventricular fibrillation arrest was 16.84 per 100,000 person-years. Survival was 10.7% for all-rhythm and 21.2% for ventricular fibrillation cardiac arrest. Applying these results to the European population, approximately, 275,000 persons would experience, all-rhythm cardiac arrest treated by the EMS with 29,000 persons surviving to hospital discharge.
The results provide a framework to assess opportunities and limitations of EMS care with regard to the public health burden of cardiac arrest in Europe.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Drugs that are neither lipophilic nor suitable for encapsulation via remote loading procedures are generally characterized by low entrapment efficiencies and poor retention in ...liposomes. One approach to circumvent this problem consists in covalently linking a lipid to the drug molecule in order to permit its insertion into the vesicle membrane. The nature of the conjugated lipid and linker, as well as the composition of the liposomal bilayer were found to have a profound impact on the pharmacokinetic properties and biodistribution of the encapsulated drugs as well as on their biological activity. This contribution reviews the past and recent developments on liposomal lipid-drug conjugates, and discusses important issues related to their stability and in vivo performance. It also provides an overview of the data that were generated during the clinical assessment of these formulations. The marketing authorization of the immunomodulating compound mifamurtide in several countries as well as the promising results obtained with the lipid prodrug of mitomycin C suggest that carefully designed liposomal formulations of lipid-drug conjugates is a valid strategy to improve a drug’s pharmacokinetic profile and with that its therapeutic index and/or efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Out-of-hospital cardiac arrest (OHCA) remains a leading cause of death and a 2010 meta-analysis concluded that outcomes have not improved over several decades. However, guidelines ...have changed to emphasize CPR quality, minimization of interruptions, and standardized post-resuscitation care. We sought to evaluate whether OHCA outcomes have improved over time among agencies participating in the Resuscitation Outcomes Consortium (ROC) cardiac arrest registry (Epistry) and randomized clinical trials (RCTs). Methods Observational cohort study of 47,148 EMS-treated OHCA cases in Epistry from 139 EMS agencies at 10 ROC sites that participated in at least one RCT between 1/1/2006 and 12/31/2010. We reviewed patient, scene, event characteristics, and outcomes of EMS-treated OHCA over time, including subgroups with initial rhythm of pulseless ventricular tachycardia or ventricular fibrillation (VT/VF). Results Mean response interval, median age and male proportion remained similar over time. Unadjusted survival to discharge increased between 2006 and 2010 for treated OHCA (from 8.2% to 10.4%), as well as for subgroups of VT/VF (21.4% to 29.3%) and bystander witnessed VT/VF (23.5% to 30.3%). Compared with 2006, adjusted survival to discharge was significantly higher in 2010 for treated cases (OR = 1.72; 95% CI 1.53, 1.94), VT/VF cases (OR = 1.69; 95% CI 1.45, 1.98) and bystander witnessed VT/VF cases (OR = 1.65; 95% CI 1.36, 2.00). Tests for trend in each subgroup were significant ( p < 0.001). Conclusions ROC-wide survival increased significantly between 2006 and 2010. Additional research efforts are warranted to identify specific factors associated with this improvement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) ...are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this trial, over 23,000 patients with out-of-hospital cardiac arrest were assigned to standard CPR with a chest compression-to-ventilation ratio of 30:2 or to continuous chest compressions. There ...was no significant between-group difference in survival to hospital discharge.
Standard cardiopulmonary resuscitation (CPR) consists of manual chest compressions to maintain blood flow and positive-pressure ventilation to maintain oxygenation until spontaneous circulation is restored.
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Chest compressions are interrupted frequently by ventilations given as rescue breathing during the treatment of out-of-hospital cardiac arrest.
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These interruptions reduce blood flow and potentially reduce the effectiveness of CPR.
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One strategy to reduce the interruption of compressions is to provide asynchronous positive-pressure ventilation while not pausing for ventilations.
The interruption of chest compressions has been associated with decreased survival in animals with cardiac arrest.
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In nonasphyxial arrest, continuous compressions were as effective as compressions . . .
BACKGROUND:Antiarrhythmic drugs have not proven to significantly improve overall survival after out-of-hospital cardiac arrest from shock-refractory ventricular fibrillation/pulseless ventricular ...tachycardia. How this might be influenced by the route of drug administration is not known.
METHODS:In this prespecified analysis of a randomized, placebo-controlled clinical trial, we compared the differences in survival to hospital discharge in adults with shock-refractory ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest who were randomly assigned by emergency medical services personnel to an antiarrhythmic drug versus placebo in the ALPS trial (Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study), when stratified by the intravenous versus intraosseous route of administration.
RESULTS:Of 3019 randomly assigned patients with a known vascular access site, 2358 received ALPS drugs intravenously and 661 patients by the intraosseous route. Intraosseous and intravenous groups differed in sex, time-to-emergency medical services arrival, and some cardiopulmonary resuscitation characteristics, but were similar in others, including time-to-intravenous/intrasosseous drug receipt. Overall hospital discharge survival was 23%. In comparison with placebo, discharge survival was significantly higher in recipients of intravenous amiodarone (adjusted risk ratio, 1.26 95% CI, 1.06–1.50; adjusted absolute survival difference, 5.5% 95% CI, 1.5–9.5) and intravenous lidocaine (adjusted risk ratio, 1.21 95% CI, 1.02–1.45; adjusted absolute survival difference, 4.7% 95% CI, 0.7–8.8); but not in recipients of intraosseous amiodarone (adjusted risk ratio, 0.94 95% CI, 0.66–1.32) or intraosseous lidocaine (adjusted risk ratio, 1.03 95% CI, 0.74–1.44). Survival to hospital admission also increased significantly when drugs were given intravenously but not intraosseously, and favored improved neurological outcome at discharge. There were no outcome differences between intravenous and intraosseous placebo, indicating that the access route itself did not demarcate patients with poor prognosis. The study was underpowered to assess intravenous/intraosseous drug interactions, which were not statistically significant.
CONCLUSIONS:We found no significant effect modification by drug administration route for amiodarone or lidocaine in comparison with placebo during out-of-hospital cardiac arrest. However, point estimates for the effects of both drugs in comparison with placebo were significantly greater for the intravenous than for the intraosseous route across virtually all outcomes and beneficial only for the intravenous route. Given that the study was underpowered to statistically assess interactions, these findings signal the potential importance of the drug administration route during resuscitation that merits further investigation.
Abstract Background Although epinephrine is essential for successful return of spontaneous circulation (ROSC), the influence of this drug on recovery during the post–cardiac arrest phase is ...debatable. Objectives This study sought to investigate the relationship between pre-hospital use of epinephrine and functional survival among patients with out-of-hospital cardiac arrest (OHCA) who achieved successful ROSC. Methods We included all patients with OHCA who achieved successful ROSC admitted to a cardiac arrest center from January 2000 to August 2012. Use of epinephrine was coded as yes/no and by dose (none, 1 mg, 2 to 5 mg, >5 mg). A favorable discharge outcome was coded using a Cerebral Performance Category 1 or 2. Analyses incorporated multivariable logistic regression, propensity scoring, and matching methods. Results Of the 1,556 eligible patients, 1,134 (73%) received epinephrine; 194 (17%) of these patients had a good outcome versus 255 of 422 patients (63%) in the nontreated group (p < 0.001). This adverse association of epinephrine was observed regardless of length of resuscitation or in-hospital interventions performed. Compared with patients who did not receive epinephrine, the adjusted odds ratio of intact survival was 0.48 (95% confidence interval CI: 0.27 to 0.84) for 1 mg of epinephrine, 0.30 (95% CI: 0.20 to 0.47) for 2 to 5 mg of epinephrine, and 0.23 (95% CI: 0.14 to 0.37) for >5 mg of epinephrine. Delayed administration of epinephrine was associated with worse outcome. Conclusions In this large cohort of patients who achieved ROSC, pre-hospital use of epinephrine was consistently associated with a lower chance of survival, an association that showed a dose effect and persisted despite post-resuscitation interventions. These findings suggest that additional studies to determine if and how epinephrine may provide long-term functional survival benefit are needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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