In an analysis including nearly 50,000 patients with sepsis treated at 149 New York hospitals, more rapid delivery of a 3-hour sepsis-care bundle (a protocol recommending blood cultures, ...broad-spectrum antibiotics, and lactate measurement within 3 hours) was associated with lower mortality.
More than 1.5 million cases of sepsis occur in the United States annually, and many patients with sepsis present to the emergency department.
1
International clinical practice guidelines and the Centers for Medicare and Medicaid Services (CMS) recommend the prompt identification of sepsis and treatment with broad-spectrum antibiotic agents and intravenous fluids.
2
,
3
These recommendations are supported by preclinical and observational studies suggesting that early treatment with antibiotics and intravenous fluids could reduce the number of avoidable deaths.
4
,
5
Yet, considerable controversy exists about how rapidly sepsis must be treated.
6
Some clinicians question the potential benefit of rapid treatment, citing the . . .
In this trial involving patients with relapsing–remitting multiple sclerosis, BG-12 (dimethyl fumarate) reduced the annualized relapse rate and number of MRI lesions but not disability progression. ...BG-12 was associated with flushing, diarrhea, and decreased lymphocyte counts.
Multiple sclerosis is a chronic demyelinating and neurodegenerative disease of the central nervous system, which is commonly treated with parenteral agents (interferon beta and glatiramer acetate). Oxidative stress and proinflammatory stimuli are important pathologic factors in multiple sclerosis.
1
–
3
Experimental data suggest that BG-12, an oral formulation of dimethyl fumarate, has antiinflammatory and cytoprotective properties that are mediated through activation of the nuclear factor (erythroid-derived 2)–like 2 transcriptional pathway, among others.
3
–
6
Here, we report the results of the Comparator and an Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (CONFIRM) trial, a randomized, multicenter, double-blind, 2-year study evaluating the efficacy and . . .
Summary Background The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has ...prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. Methods Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. Findings 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25·4%, 95% CI 18·7–32·1%, p<0·0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43·5%, 37·9–49·1%, p<0·0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29·5%, 24·7–34·3%, p<0·0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. Interpretation Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies. Funding Biogen Idec.
This placebo-controlled, randomized trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab (an α
4
integrin antagonist) in all the primary and secondary outcome ...measures. After two years, the probability of sustained progression of disability was 17 percent with natalizumab and 29 percent with placebo. Fatigue and allergic reaction were more common among patients receiving natalizumab.
This trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab in all the primary and secondary outcome measures. In this trial, natalizumab in combination with interferon was more effective than interferon alone. Progressive multifocal leukoencephalopathy developed in two patients. In this systematic evaluation for PML in patients who received natalizumab in clinical trials, no additional cases were identified.
Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions.
1
The interaction of α
4
β
1
integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation.
2
–
6
Furthermore, the interaction of α . . .
•The differences in DLPFC activation in depressed individuals vs. healthy controls during recognition of emotional and neutral facial expressions was examined using functional near-infrared ...spectroscopy.•Depressed individuals, compared to healthy controls, were slower and less accurate in recognizing neutral, but not happy or fearful, facial emotional expressions.•Depressed individuals, but not healthy controls, rely on functioning of the right DLPFC during recognition of neutral and happy facial expressions.•Depressed individuals who had lower activation in the right DLPFC during recognition of neutral facial expression also had lower recognition accuracy for neutral facial expressions compared to depressed individuals who had greater right DLPFC activation.
Depressed individuals often perceive neutral facial expressions as emotional. Neurobiological underpinnings of this effect remain unclear. We investigated the differences in prefrontal cortical (PFC) activation in depressed individuals vs. healthy controls (HC) during recognition of emotional and neutral facial expressions using functional near infrared spectroscopy (fNIRS).
In Experiment 1, 33 depressed individuals and 20 HC performed the Emotion Intensity Rating task in which they rated intensity of facial emotional expressions. In Experiment 2, a different set of participants (18 depressed individuals and 16 HC) performed the same task while their PFC activation was measured using fNIRS.
Both experiments showed that depressed individuals were slower and less accurate in recognizing neutral, but not happy or fearful, facial emotional expressions. Experiment 2 revealed that lower accuracy for neutral facial emotional expressions was associated with lower right PFC activation in depressed individuals, but not HC. In addition, depressed individuals, compared to HC, had lower right PFC activation during recognition of happy facial expressions.
Relatively small sample size
Recognition of neutral facial expressions is impaired in depressed individuals. Greater impairment corresponds to lower right PFC activation during neutral face processing. Recognition of happy facial expressions is comparable for depressed individuals and HC, but the former have significantly lower right PFC activation. Taken together, these findings suggest that the ability of depressed individuals to discriminate neutral and emotional signals in the environment may be affected by aberrant functioning of right PFC.
In 2013, the New York State Department of Health (NYSDOH) began a mandatory state-wide initiative to improve early recognition and treatment of severe sepsis and septic shock.
This study examines ...protocol initiation, 3-hour and 6-hour sepsis bundle completion, and risk-adjusted hospital mortality among adult patients with severe sepsis and septic shock.
Cohort analysis included all patients from all 185 hospitals in New York State reported to the NYSDOH from April 1, 2014, to June 30, 2016. A total of 113,380 cases were submitted to NYSDOH, of which 91,357 hospitalizations from 183 hospitals met study inclusion criteria. NYSDOH required all hospitals to submit and follow evidence-informed protocols (including elements of 3-h and 6-h sepsis bundles: lactate measurement, early blood cultures and antibiotic administration, fluids, and vasopressors) for early identification and treatment of severe sepsis or septic shock.
Compliance with elements of the sepsis bundles and risk-adjusted mortality were studied. Of 91,357 patients, 74,293 (81.3%) had the sepsis protocol initiated. Among these individuals, 3-hour bundle compliance increased from 53.4% to 64.7% during the study period (P < 0.001), whereas among those eligible for the 6-hour bundle (n = 35,307) compliance increased from 23.9% to 30.8% (P < 0.001). Risk-adjusted mortality decreased from 28.8% to 24.4% (P < 0.001) in patients among whom a sepsis protocol was initiated. Greater hospital compliance with 3-hour and 6-hour bundles was associated with shorter length of stay and lower risk and reliability-adjusted mortality.
New York's statewide initiative increased compliance with sepsis-performance measures. Risk-adjusted sepsis mortality decreased during the initiative and was associated with increased hospital-level compliance.
OBJECTIVETo assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.
...METHODSUsing peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed.
RESULTSIn DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.
CONCLUSIONSDMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4 and CD8 T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.
TRIAL REGISTRATION NUMBERSEUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.
Background and purpose
Significant effects on clinical/neuroradiological disease activity have been reported in patients with relapsing–remitting multiple sclerosis treated with delayed‐release ...dimethyl fumarate (DMF) in phase III DEFINE/CONFIRM trials. We conducted a post hoc analysis of integrated data from DEFINE/CONFIRM to evaluate the effect of DMF on achieving no evidence of disease activity (NEDA) in patients with relapsing–remitting multiple sclerosis.
Methods
The analysis included patients randomized to DMF 240 mg twice daily, placebo or glatiramer acetate (CONFIRM only) for ≤2 years. A time‐to‐event method was used to estimate the percentage of patients achieving NEDA. Clinical NEDA (no relapses/no 12‐week confirmed disability progression) was analysed in the intention‐to‐treat (ITT) population. Neuroradiological (no new/newly enlarging T2 hyperintense lesions/no gadolinium‐enhancing lesions) and overall NEDA (clinical and neuroradiological NEDA) were analysed in the magnetic resonance imaging (MRI) cohort.
Results
The ITT and MRI populations comprised 1540 and 692 patients, respectively. The percentage of patients with clinical NEDA (ITT population) and neuroradiological NEDA (MRI cohort) was higher with DMF versus placebo over 2 years clinical NEDA: 38.9% relative reduction; hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.52‐0.72; P < 0.0001; neuroradiological NEDA: 40.0% relative reduction; HR, 0.60; 95% CI, 0.49–0.73; P < 0.0001. The percentage of patients achieving overall NEDA (MRI cohort) was also higher with DMF (26%) versus placebo (12%) over 2 years, with a relative risk reduction of 42.7% (HR, 0.57; 95% CI, 0.48–0.69; P < 0.0001).
Conclusions
A significantly higher percentage of patients treated with DMF achieved NEDA status over 2 years compared with placebo.
Click here to view the accompanying paper in this issue.
Background:
Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 ...DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM.
Objective:
We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE).
Methods:
In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID.
Results:
For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia.
Conclusion:
Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.
PDF
