Purpose
To determine whether early goal-directed therapy (EGDT) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department (ED) with septic ...shock.
Methods
Using a search strategy of PubMed, EmBase and CENTRAL, we selected all relevant randomised clinical trials published from January 2000 to January 2015. We translated non-English papers and contacted authors as necessary. Our primary analysis generated a pooled odds ratio (OR) from a fixed-effect model. Sensitivity analyses explored the effect of including non-ED studies, adjusting for study quality, and conducting a random-effects model. Secondary outcomes included organ support and hospital and ICU length of stay.
Results
From 2395 initially eligible abstracts, five randomised clinical trials (
n
= 4735 patients) met all criteria and generally scored high for quality except for lack of blinding. There was no effect on the primary mortality outcome (EGDT: 23.2 % 495/2134 versus control: 22.4 % 582/2601; pooled OR 1.01 95 % CI 0.88–1.16,
P
= 0.9, with heterogeneity
I
2
= 57 %;
P
= 0.055). The pooled estimate of 90-day mortality from the three recent multicentre studies (
n
= 4063) also showed no difference pooled OR 0.99 (95 % CI 0.86–1.15),
P
= 0.93 with no heterogeneity (
I
2
= 0.0 %;
P
= 0.97). EGDT increased vasopressor use (OR 1.25 95 % CI 1.10–1.41;
P
< 0.001) and ICU admission OR 2.19 (95 % CI 1.82–2.65);
P
< 0.001. Including six non-ED randomised trials increased heterogeneity (
I
2
= 71 %;
P
< 0.001) but did not change overall results pooled OR 0.94 (95 % CI 0.82 to 1.07);
P
= 0.33.
Conclusion
EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU resources.
Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result ...from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.
The human temporoparietal junction (TPJ) is a topic of intense research. Imaging studies have identified TPJ activation in association with many higher-order functions such as theory-of-mind, ...episodic memory, and attention, causing debate about the distribution of different processes. One major challenge is the lack of consensus about the anatomical location and extent of the TPJ. Here, we address this problem using data-driven analysis to test the hypothesis that the bilateral TPJ can be parcellated into subregions. We applied independent component analysis (ICA) to task-free fMRI data within a local region around the bilateral TPJ, iterating the ICA at multiple model orders and in several datasets. The localized analysis allowed finer separation of processes and the use of multiple dimensionalities provided qualitative information about lateralization. We identified four subdivisions that were bilaterally symmetrical and one that was right biased. To test whether the independent components (ICs) reflected true subdivisions, we performed functional connectivity analysis using the IC coordinates as seeds. This confirmed that the subdivisions belonged to distinct networks. The right-biased IC was connected with a network often associated with attentional processing. One bilateral subdivision was connected to sensorimotor regions and another was connected to auditory regions. One subdivision that presented as distinct left- and right-biased ICs was connected to frontoparietal regions. Another subdivision that also had left- and right-biased ICs was connected to social or default mode networks. Our results show that the TPJ in both hemispheres hosts multiple neural processes with connectivity patterns consistent with well developed specialization and lateralization.
Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more ...than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.
The empowerment of women in the livestock sector is fundamental to achieve gender equality. It also is instrumental for increased household productivity and improved household health and nutrition. ...Diverse strategies exist to empower women, yet these strategies are difficult to prioritize without a reliable and adapted means to measure women’s empowerment. One quantitative measure is the Women’s Empowerment in Agriculture Index (WEAI). Despite its reliability in certain agricultural contexts, the WEAI requires adaptation in settings where livestock farming is the dominant form of livelihood. Using the WEAI as a starting point, a multidisciplinary team of researchers developed the Women’s Empowerment in Livestock Index (WELI), a new index to assess the empowerment of women in the livestock sector. This paper presents the WELI and the dimensions of empowerment it includes: (1) decisions about agricultural production; (2) decisions related to nutrition; (3) access to and control over resources; (4) control and use of income; (5) access to and control of opportunities; and (6) workload and control over own time. The paper illustrates the use of the WELI by introducing pilot findings from dairy smallholders in four districts of northern Tanzania. The paper addresses considerations for the appropriate use and adaptation of the WELI to balance the needs for context specificity and crosscultural comparisons; it also discusses its limitations. The paper recommends participatory and qualitative methods that are complementary to the WELI to provide context-specific insights on the processes of women’s empowerment in the livestock sector.
The neuroprotective function of the blood–brain barrier (BBB) presents a major challenge for drug delivery to the central nervous system (CNS). Critical to this function, BBB membrane transporters ...include the ATP‐binding cassette (ABC) transporters, which limit drug penetration across the BBB, and the less‐well‐studied solute carrier (SLC) transporters. In this work, expression profiling of 359 SLC transporters, comparative expression analysis with kidney and liver, and immunoassays in brain microvessels (BMVs) identified previously unknown transporters at the human BBB.
Clinical Pharmacology & Therapeutics (2013); 94 6, 636–639. doi:10.1038/clpt.2013.175
Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle ...factors and subsequent all-cause, cancer-specific and non-cancer related survival.
In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid).
After a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31–3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20–7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21–7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC.
Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality.
•Diabetes and co-morbidity were associated with higher EC-specific mortality.•Diabetes and obesity have a negative impact on non-cancer related mortality.•Understanding the impact of these factors can help inform women and clinicians.
Abstract
Background
Physician decision-making skills training is a priority to improve adoption of the cerebral palsy (CP) clinical guideline and, through this, lower the age of CP diagnosis. ...Clinical guideline implementation aims to improve physician practice, but evaluating meaningful change is complex. Limitations in the validity evidence of evaluation instruments impact the evidence base. Validity frameworks, such as Kane’s, enable a targeted process to gather evidence for instrument scores, congruent to context and purpose. Yet, application of argument-based methodology to implementation validation is rare. Key-features examination methodology has established validity evidence supporting its use to measure decision-making skills, with potential to predict performance. We aimed to apply Kane’s framework to evaluate a pilot key-features examination on physician decision-making in early CP diagnosis.
Methods
Following Kane’s framework, we evaluated evidence across inferences of scoring, generalisation, extrapolation and implications in a study design describing the development and pilot of a CP diagnosis key-features examination for practising physicians. If found to be valid, we proposed to use the key-feature scores as an outcome measure of decision-making post education intervention to expedite CP diagnosis and to correlate with real-world performance data to predict physician practice.
Results
Supporting evidence for acceptance of scoring inferences was achieved through examination development with an expert group (
n
= 10) and pilot results (
n
= 10): (1) high internal consistency (0.82); (2) acceptable mean item-discrimination (0.34); and (3) acceptable reliability of examination scorers (95.2% congruence). Decreased physician acceptance of examination time (70%) was identified as a threat and prioritised in case reduction processes. Partial acceptance of generalisation, extrapolation and implications inferences were defensible with: (1) accumulated development evidence following established key-features methodology; (2) high pilot acceptance for authenticity (90%); and (3) plausibility of assumptions of score correlation with population register data.
Conclusions
Kane’s approach is beneficial for prioritising sources of validity evidence alongside the iterative development of a key-features examination in the CP field. The validity argument supports scoring assumptions and use of scores as an outcome measure of physician decision-making for CP guideline education implementation interventions. Scoring evidence provides the foundation to direct future studies exploring association of key-feature scores with real-world performance.
Critical illness leading to prolonged length of stay (LOS) in an intensive care unit (ICU) is associated with significant mortality and resource utilization. This study assessed the independent ...effect of ICU LOS on in-hospital and long-term mortality after hospital discharge.
Clinical and mortality data of 22 298 patients, aged 16 yr and older, admitted to ICU between 1987 and 2002 were included in this linked-data cohort study. Cox's regression with restricted cubic spline function was used to model the effect of LOS on in-hospital and long-term mortality after adjusting for age, gender, acute physiology score (APS), maximum number of organ failures, era of admission, elective admission, Charlson's co-morbidity index, and diagnosis. The variability each predictor explained was calculated by the percentage of the χ2 statistic contribution to the total χ2 statistic.
Most hospital deaths occurred within the first few days of ICU admission. Increasing LOS in ICU was not associated with an increased risk of in-hospital mortality after adjusting for other covariates, but was associated with an increased risk of long-term mortality after hospital discharge. The variability on the long-term mortality effect associated with ICU LOS (2.3%) appeared to reach a plateau after the first 10 days in ICU and was not as important as age (35.8%), co-morbidities (18.6%), diagnosis (10.9%), and APS (3.6%).
LOS in ICU was not an independent risk factor for in-hospital mortality, but it had a small effect on long-term mortality after hospital discharge after adjustment for other risk factors.
Context:
Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global safety surveillance study of long-term treatment of acromegaly with pegvisomant.
Objective:
The objective of the study was ...to monitor long-term safety and treatment outcomes.
Design:
ACROSTUDY is open to all patients with acromegaly who are treated with pegvisomant. We report an interim analysis of data captured from 1288 subjects enrolled before a database freeze of December 31, 2009.
Setting:
This was a global noninterventional surveillance study.
Main Outcome Measure(s):
Long-term monitoring of safety, including central magnetic resonance imaging (MRI) reading and treatment outcomes, was measured.
Results:
Subjects (n = 1288) were treated with pegvisomant for a mean of 3.7 yr and followed up in ACROSTUDY for a mean of 2.1 yr. A total of 1147 adverse events (AE) were recorded in 477 subjects (37%), among which 192 AE in 124 subjects (9.6%) were considered to be related to pegvisomant. Serious AE were recorded in 159 subjects (12.3%), whereas pegvisomant-related Serious AE were recorded in 26 subjects (2%). No deaths (15 subjects; 1.2%) were attributed to pegvisomant use. The incidence of increase in pituitary tumor size in the subset with confirmed MRI increases on central reading represented 3.2% of the overall cohort with at least two available MRI (n = 936). Injection-site reactions were reported in 28 cases (2.2%). In 30 patients (2.5%), an elevated aspartate aminotransferase or alanine aminotransferase of more than 3 times the upper level of normality was reported. There were no reports of liver failure. After 5 yr of pegvisomant treatment, 63.2% of subjects had normal IGF-I levels at a mean dose of 18 mg/d.
Conclusions:
Data entered and evaluated in ACROSTUDY indicate that pegvisomant is an effective and safe medical treatment in patients with acromegaly. The reported low incidence of pituitary tumor size increase, liver enzyme elevations, and lipodystrophy at the injection site are reassuring.
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