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1.  A practical approach to goal-directed echocardiography in the critical care setting 
Critical Care  2014;18(6):681.
Urgent cardiac ultrasound examination in the critical care setting is clinically useful. Application of goal-directed echocardiography in this setting is quite distinct from typical exploratory diagnostic comprehensive echocardiography, because the urgent critical care setting mandates a goal-directed approach. Goal-directed echocardiography most frequently aims to rapidly identify and differentiate the cause(s) of hemodynamic instability and/or the cause(s) of acute respiratory failure. Accordingly, this paper highlights 1) indications, 2) an easily memorized differential diagnostic framework for goal-directed echocardiography, 3) clinical questions that must be asked and answered, 4) practical issues to allow optimal image capture, 5) primary echocardiographic views, 6) key issues addressed in each view, and 7) interpretation of findings within the differential diagnostic framework. The most frequent indications for goal-directed echocardiography include 1) the spectrum of hemodynamic instability, shock, and pulseless electrical activity arrest and 2) acute respiratory failure. The differential diagnostic categories for hemodynamic instability can be remembered using the mnemonic ‘SHOCK’ (for Septic, Hypovolemic, Obstructive, Cardiogenic, and (K) combinations/other kinds of shock). RESP-F (for exacerbation of chronic Respiratory disease, pulmonary Embolism, ST changes associated with cardiac or pericardial disease, Pneumonia, and heart Failure) can be used for acute respiratory failure. The goals of goal-directed echocardiography in the unstable patient are: assessing global ventricular systolic function, identifying marked right ventricular and left ventricular enlargement, assessing intravascular volume, and the presence of a pericardial effusion. In an urgent or emergent setting, it is recommended to go directly to the best view, which is frequently the subcostal or apical view. The five views are the subcostal four-chamber view, subcostal inferior vena cava view, parasternal long axis view, parasternal short axis view, and the apical four chamber view. Always interpret goal-directed echocardiographic findings in the context of clinically available hemodynamic information. When goal-directed echocardiography is insufficient or when additional abnormalities are appreciated, order a comprehensive echocardiogram. Goal-directed echocardiography and comprehensive echocardiography are not to be used in conflict with each other.
doi:10.1186/s13054-014-0681-z
PMCID: PMC4331439  PMID: 25672460
2.  Opioid overdose prevention and naloxone rescue kits: what we know and what we don’t know 
The opioid use and overdose crisis is persistent and dynamic. Opioid overdoses were initially driven in the 1990s and 2000s by the increasing availability and misuse of prescription opioids. More recently, opioid overdoses are increasing at alarming rates due to wider use of heroin, which in some places is mixed with fentanyl or fentanyl derivatives. Naloxone access for opioid overdose rescue is one of the US Department of Health and Human Services’ three priority areas for responding to the opioid crisis. This article summarizes the known benefits of naloxone access and details unanswered questions about overdose education and naloxone rescue kits. Hopefully future research will address these knowledge gaps, improve the effectiveness of opioid overdose education and naloxone distribution programs, and unlock the full promise of naloxone rescue kits.
doi:10.1186/s13722-016-0068-3
PMCID: PMC5219773  PMID: 28061909
Naloxone rescue kits; Overdose prevention; Opioid overdose education
3.  Glenohumeral Joint Kinematics following Clavicular Fracture and Repairs 
PLoS ONE  2017;12(1):e0164549.
Background
The purpose of this biomechanical study was to determine the effect of shortened clavicle malunion on the center of rotation of the glenohumeral (GH) joint, and the capacity of repair to restore baseline kinematics.
Methods
Six shoulders underwent automated abduction (ABD) and abbreviated throwing motion (ATM) using a 7-DoF automated upper extremity testing system in combination with an infrared motion capture system to measure the center of rotation of the GH joint. ATM was defined as pure lateral abduction and late cocking phase to the end of acceleration. Torsos with intact clavicle underwent testing to establish baseline kinematics. Then, the clavicles were subjected to midshaft fracture followed by kinematics testing. The fractured clavicles underwent repairs first by clavicle length restoration with plate fixation, and then by wiring of fragments with a 2-cm overlap to simulate shortened malunion. Kinematic testing was conducted after each repair technique. Center of rotation of the GH joint was plotted across all axes to outline 3D motion trajectory and area under the curve.
Results
Throughout ABD, malunion resulted in increased posterior and superior translation compared to baseline. Plate fixation restored posterior and superior translations at lower abduction angles but resulted in excess anterior and inferior translation at overhead angles. Throughout ATM, all conditions were significantly anterior and superior to baseline. Translation with malunion was situated anterior to the fractured and ORIF conditions at lower angles of external rotation. Plate fixation did not restore baseline anteroposterior or superoinferior translation at any angle measured.
Conclusions
This study illustrates the complex interplay of the clavicle and the GH joint. While abnormal clavicle alignment alters shoulder motion, restoration of clavicle length does not necessarily restore GH kinematics to baseline. Rehabilitation of the injured shoulder must address the osseous injury and the dynamic forces of the shoulder girdle.
doi:10.1371/journal.pone.0164549
PMCID: PMC5218560  PMID: 28060814
4.  Towards new sources of resistance to the currant-lettuce aphid (Nasonovia ribisnigri) 
Molecular Breeding  2017;37(1):4.
Domesticated lettuce varieties encompass much morphological variation across a range of crop type groups, with large collections of cultivars and landrace accessions maintained in genebanks. Additional variation not captured during domestication, present in ancestral wild relatives, represents a potentially rich source of alleles that can deliver to sustainable crop production. However, these large collections are difficult and costly to screen for many agronomically important traits. In this paper, we describe the generation of a diversity collection of 96 lettuce and wild species accessions that are amenable to routine phenotypic analysis and their genotypic characterization with a panel of 682 newly developed expressed sequence tag (EST)-linked KASP™ single nucleotide polymorphism (SNP) markers that are anchored to the draft Lactuca sativa genome assembly. To exemplify the utility of these resources, we screened the collection for putative sources of resistance to currant-lettuce aphid (Nasonovia ribisnigri) and carried out association analyses to look for potential SNPs linked to resistance.
Electronic supplementary material
The online version of this article (doi:10.1007/s11032-016-0606-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11032-016-0606-4
PMCID: PMC5209396
Lettuce; Diversity; SNP; Aphid; Association; Resistance
5.  Intensive Patient Education Improves Glycaemic Control in Diabetes Compared to Conventional Education: A Randomised Controlled Trial in a Nigerian Tertiary Care Hospital 
PLoS ONE  2017;12(1):e0168835.
Background
Diabetes is now a global epidemic, but most cases are now in low- and middle-income countries. Diabetes self-management education (DSME) is key to enabling patients to manage their chronic condition and can reduce the occurrence of costly and devastating complications. However, there is limited evidence on the effectiveness of different DSME programmes in resource limited settings.
Methods
We conducted an unblinded, parallel-group, individually-randomised controlled trial at the University of Calabar Teaching Hospital (Nigeria) to evaluate whether an intensive and systematic DSME programme, using structured guidelines, improved glycaemic control compared to the existing ad hoc patient education (clinical practice was unchanged). Eligible patients (≥18 years, HbA1c > 8.5% and physically able to participate) were randomly allocated by permuted block randomisation to participate for six months in either an intensive or conventional education group. The primary outcome was HbA1c (%) at six-months.
Results
We randomised 59 participants to each group and obtained six-month HbA1c outcomes from 53 and 51 participants in the intensive and conventional education groups, respectively. Intensive group participants had a mean six-month HbA1c (%) of 8.4 (95% CI: 8 to 8.9), while participants in the conventional education group had a mean six-month HbA1c (%) of 10.2 (95% CI: 9.8 to 10.7). The difference was statistically (P < 0.0001) and clinically significant, with intensive group participants having HbA1c outcomes on average -1.8 (95% CI: -2.4 to -1.2) percentage points lower than conventional group participants. Results were robust to adjustment for a range of covariates and multiple imputation of missing outcome data.
Conclusions
This study demonstrates the effectiveness of a structured, guideline-based DSME intervention in a LMIC setting versus a pragmatic comparator. The intervention is potentially replicable at other levels of the Nigerian healthcare system and in other LMICs, where nurses/diabetes educators can run the programme.
Trial Registration
Pan African Clinical Trial Registry PACTR20130200047835
doi:10.1371/journal.pone.0168835
PMCID: PMC5207750  PMID: 28045979
6.  Trait to gene analysis reveals that allelic variation in three genes determines seed vigour 
The New Phytologist  2016;212(4):964-976.
Summary
Predictable seedling establishment is essential for resource‐efficient and cost‐effective crop production; it is widely accepted as a critically important trait determining yield and profitability. Seed vigour is essential to this, but its genetic basis is not understood.We used natural variation and fine mapping in the crop Brassica oleracea to show that allelic variation at three loci influence the key vigour trait of rapid germination. Functional analysis in both B. oleracea and the model Arabidopsis identified and demonstrated activity of genes at these loci.Two candidate genes were identified at the principal Speed of Germination QTL (SOG1) in B. oleracea. One gene BoLCVIG2 is a homologue of the alternative‐splicing regulator (AtPTB1). The other gene BoLCVIG1 was unknown, but different alleles had different splice forms that were coincident with altered abscisic acid (ABA) sensitivity. We identified a further QTL, Reduced ABscisic Acid 1 (RABA1) that influenced ABA content and provide evidence that this results from the activity of a homologue of the ABA catabolic gene AtCYP707A2 at this locus.Lines containing beneficial alleles of these three genes had greater seed vigour. We propose a mechanism in which both seed ABA content and sensitivity to it determines speed of germination.
doi:10.1111/nph.14102
PMCID: PMC5132119  PMID: 27432253
abscisic acid (ABA); allelic variation; Arabidopsis; Brassica oleracea; germination; QTL analysis; seed vigour
7.  Mortality in HIV-Infected Alcohol and Drug Users in St. Petersburg, Russia 
PLoS ONE  2016;11(11):e0166539.
In Russia, up to half of premature deaths are attributed to hazardous drinking. The respective roles of alcohol and drug use in premature death among people with HIV in Russia have not been described. Criminalization and stigmatization of substance use in Russia may also contribute to mortality. We explored whether alcohol, drug use and risk environment factors are associated with short-term mortality in HIV-infected Russians who use substances. Secondary analyses were conducted using prospective data collected at baseline, 6 and 12-months from HIV-infected people who use substances recruited between 2007–2010 from addiction and HIV care settings in a single urban setting of St. Petersburg, Russia. We used Cox proportional hazards models to explore associations between 30-day alcohol hazardous drinking, injection drug use, polysubstance use and environmental risk exposures (i.e. past incarceration, police involvement, selling sex, and HIV stigma) with mortality. Among 700 participants, 59% were male and the mean age was 30 years. There were 40 deaths after a median follow-up of 12 months (crude mortality rate 5.9 per 100 person-years). In adjusted analyses, 30-day NIAAA hazardous drinking was significantly associated with mortality compared to no drinking [adjusted Hazard Ratio (aHR) 2.60, 95% Confidence Interval (CI): 1.24–5.44] but moderate drinking was not (aHR 0.95, 95% CI: 0.35–2.59). No other factors were significantly associated with mortality. The high rates of short-term mortality and the strong association with hazardous drinking suggest a need to integrate evidence-based alcohol interventions into treatment strategies for HIV-infected Russians.
doi:10.1371/journal.pone.0166539
PMCID: PMC5127495  PMID: 27898683
8.  Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial 
eLife  null;5:e17850.
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18–0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.
DOI: http://dx.doi.org/10.7554/eLife.17850.001
eLife digest
Most attempts to transform exciting findings from laboratories into clinical treatments are unsuccessful. One reason for this may be the failure to consider all of the laboratory work that has been performed before deciding to test a treatment on patients for the first time. In particular, negative findings (that suggest that a potential new treatment is ineffective) may be overlooked.
Stem cells may help to treat life-threatening infections, but this has not been tested in human patients. However, the effectiveness of stem cell treatments has been tested in animals that act as models of human infection.
Before deciding to begin a clinical trial of stem cell therapy for life-threatening infections, Lalu et al. performed an exhaustive search to find all the studies in which stem cells were used to treat animal models of infection. Combining the results of all of these studies using particular analysis techniques revealed that stem cell therapy increased the survival of these animals overall. These positive effects were seen over a range of different experimental conditions (for example, when treating the animals with different doses of stem cells, or giving the doses at different times).
Lalu et al. also identified some limitations with most of the laboratory studies that had tested stem cell therapy for infections. Many of the studies used animal models that may not be the best representations of humans with severe infection. In addition, many of the scientists did not report that they had used methods (such as randomization) that would generate the most confidence in their results. Despite these limitations, there was a lot of consistency in the reported results.
Overall, the results support the decision to proceed to a clinical trial that tests the effectiveness of stem cells for treating human infections. More generally, Lalu et al.’s analysis demonstrates a way of considering all laboratory evidence before deciding to proceed to a first clinical trial in humans. This may help researchers to identify promising therapies to further develop, and also to identify potential failures before they are tested in patients.
DOI: http://dx.doi.org/10.7554/eLife.17850.002
doi:10.7554/eLife.17850
PMCID: PMC5153252  PMID: 27870924
stem cells; sepsis; systematic review; preclinical; translation; Mouse; Rat
9.  Influence of disruption of the acromioclavicular and coracoclavicular ligaments on glenohumeral motion: a kinematic evaluation 
Background
Changes to the integrity of the acromioclavicular (AC) joint impact scapulothoracic and clavicular kinematics. AC ligaments provide anterior-posterior stability, while the coracoclavicular (CC) ligaments provide superior-inferior stability and a restraint to scapular internal rotation. The purpose of this cadaveric study was to describe the effect of sequential AC and CC sectioning on glenohumeral (GH) kinematics during abduction (ABD) of the arm. We hypothesized that complete AC ligament insult would result in altered GH translation in the anterior-posterior plane during abduction, while subsequent sectioning of both CC ligaments would result in an increasing inferior shift in GH translation.
Methods
Six cadaveric shoulders were studied to evaluate the impact of sequential sectioning of AC and CC ligaments on GH kinematics throughout an abduction motion in the coronal plane. Following an examination of the baseline, uninjured kinematics, the AC ligaments were then sectioned sequentially: (1) Anterior, (2) Inferior, (3) Posterior, and (4) Superior. Continued sectioning of CC ligamentous structures followed: the (5) trapezoid and then the (6) conoid ligaments. For each group, the GH translation and the area under the curve (AUC) were measured during abduction using an intact cadaveric shoulder. Total translation was calculated for each condition between ABD 30° and ABD 150° using the distance formula, and a univariate analysis was used to compare total translation for each axis during the different conditions.
Results
GH kinematics were not altered following sequential resection of the AC ligaments. Disruption of the trapezoid resulted in significant anterior and lateral displacement of the center of GH rotation. Sectioning the conoid ligament further increased the inferior shift in GH displacement.
Conclusion
A combined injury of the AC and CC ligaments significantly alters GH kinematics during abduction. Type III AC separations, result in a significant change in the shoulder’s motion and may warrant surgical reconstruction to restore normal function.
doi:10.1186/s12891-016-1330-2
PMCID: PMC5112880  PMID: 27855670
Glenohumeral joint; Acromio-clavicular ligaments; Coraco-clavicular ligaments; Kinematics; Type II AC injury; Type III AC injury; Ligament resection
10.  Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial 
Background
Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT).
Methods
Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models.
Results
There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63–0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48–0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69–1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found.
Conclusion
The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up.
Trial registration
ClinicalTrials.gov NCT00066703, registered August 6, 2003.
doi:10.1186/s13058-016-0771-8
PMCID: PMC5101790  PMID: 27825388
Side effects; Aromatase inhibitors; Tamoxifen; Ovarian suppression; Breast cancer; CYP19A1; ESR1
11.  Predictive value and clinical utility of centrally-assessed ER, PgR and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials 
Purpose
The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally-assessed levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 expression in women with HER2-negative disease.
Patients and Methods
Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology.
Results
In this HR+/HER2- population, the median ER, PgR and Ki-67 expression were 95%, 90% and 18% immunostained cells. As most patients had strongly ER positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels though there was a greater 5-year absolute benefit of exemestane+ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67.
Conclusions
Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane+OFS versus tamoxifen+OFS or tamoxifen-alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.
doi:10.1007/s10549-015-3612-z
PMCID: PMC4749471  PMID: 26493064
estrogen receptor; exemestane; Ki-67; ovarian function suppression; progresterone receptor; tamoxifen
12.  Why is it so hard to implement change? A qualitative examination of barriers and facilitators to distribution of naloxone for overdose prevention in a safety net environment 
BMC Research Notes  2016;9:465.
Background
The increase in opioid overdose deaths has become a national public health crisis. Naloxone is an important tool in opioid overdose prevention. Distribution of nasal naloxone has been found to be a feasible, and effective intervention in community settings and may have potential high applicability in the emergency department, which is often the initial point of care for persons at high risk of overdose. One safety net hospital introduced an innovative policy to offer take-home nasal naloxone via a standing order to ensure distribution to patients at risk for overdose. The aims of this study were to examine acceptance and uptake of the policy and assess facilitators and barriers to implementation.
Methods
After obtaining pre-post data on naloxone distribution, we conducted a qualitative study. The PARiHS framework steered development of the qualitative guide. We used theoretical sampling in order to include the range of types of emergency department staff (50 total). The constant comparative method was initially used to code the transcripts and identify themes; the themes that emerged from the coding were then mapped back to the evidence, context and facilitation constructs of the PARiHS framework.
Results
Acceptance of the policy was good but uptake was low. Primary themes related to facilitators included: real-world driven intervention with philosophical, clinician and leadership support; basic education and training efforts; availability of resources; and ability to leave the ED with the naloxone kit in hand. Barriers fell into five general categories: protocol and policy; workflow and logistical; patient-related; staff roles and responsibilities; and education and training.
Conclusions
The actual implementation of a new innovation in healthcare delivery is largely driven by factors beyond acceptance. Despite support and resources, implementation was challenging, with low uptake. While the potential of this innovation is unknown, understanding the experience is important to improve uptake in this setting and offer possible solutions for other facilities to address the opioid overdose crisis. Use of the PARiHS framework allowed us to recognize and understand key evidence, contextual and facilitation barriers to the successful implementation of the policy and to identify areas for improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-016-2268-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13104-016-2268-z
PMCID: PMC5070095  PMID: 27756427
Opioid overdose; Overdose prevention; Policy implementation; Emergency department
13.  Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients 
Critical Care  2016;20:315.
Background
Acute kidney injury and hyperchloremia are commonly present in critically ill septic patients. Our study goal was to evaluate the association of hyperchloremia and acute kidney injury in severe sepsis and septic shock patients.
Methods
In this retrospective cohort study in a provincial tertiary care hospital, adult patients with severe sepsis or septic shock and serum chloride measurements were included. Serum chloride was measured on a daily basis for 48 hours. Primary outcome was development of acute kidney injury (AKI) and association of AKI and serum chloride parameters was analyzed.
Results
A total of 240 patients were included in the study, 98 patients (40.8 %) had hyperchloremia. The incidence of acute kidney injury (AKI) was significantly higher in the hyperchloremia group (85.7 % vs 47.9 %; p < 0.001). Maximal chloride concentration in the first 48 hours ([Cl-]max) was significantly associated with AKI. In multivariate analysis, [Cl-]max was independently associated with AKI [adjusted odds ratio (OR) for AKI = 1.28 (1.02–1.62); p = 0.037]. The increase in serum chloride (Δ[Cl-] = [Cl-]max – initial chloride concentration) demonstrated a dose-dependent relationship with severity of AKI. The mean Δ[Cl-] in patients without AKI was 2.1 mmol/L while in the patients with AKI stage 1, 2 and 3 the mean Δ[Cl-] was 5.1, 5.9 and 6.7 mmol/L, respectively. A moderate increase in serum chloride (Δ[Cl-] ≥ 5 mmol/L) was associated with AKI [OR = 5.70 (3.00–10.82); p < 0.001], even in patients without hyperchloremia [OR = 8.25 (3.44–19.78); p < 0.001].
Conclusions
Hyperchloremia is common in severe sepsis and septic shock and independently associated with AKI. A moderate increase in serum chloride (Δ[Cl-] ≥5 mmol/L) is associated with AKI even in patients without hyperchloremia.
doi:10.1186/s13054-016-1499-7
PMCID: PMC5053142  PMID: 27716310
Chloride; Hyperchloremia; Acute kidney injury; Sepsis; Septic shock
14.  Heparin-binding protein is important for vascular leak in sepsis 
Background
Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability.
Methods
Association between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice.
Results
Following adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO2/FiO2) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects.
Conclusions
HBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.
Electronic supplementary material
The online version of this article (doi:10.1186/s40635-016-0104-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40635-016-0104-3
PMCID: PMC5050173  PMID: 27704481
Septic shock; Heparin-binding protein (HBP); Vascular leak; Acute respiratory distress syndrome; Permeability
15.  Prescribe to Prevent: Overdose Prevention and Naloxone Rescue Kits for Prescribers and Pharmacists 
Journal of Addiction Medicine  2016;10(5):300-308.
In March of 2015, the United States Department of Health and Human Services identified 3 priority areas to reduce opioid use disorders and overdose, which are as follows: opioid-prescribing practices; expanded use and distribution of naloxone; and expansion of medication-assisted treatment. In this narrative review of overdose prevention and the role of prescribers and pharmacists in distributing naloxone, we address these priority areas and present a clinical scenario within the review involving a pharmacist, a patient with chronic pain and anxiety, and a primary care physician. We also discuss current laws related to naloxone prescribing and dispensing. This review was adapted from the Prescribe to Prevent online continuing medical education module created for prescribers and pharmacists (http://www.opioidprescribing.com/naloxone_module_1-landing).
doi:10.1097/ADM.0000000000000223
PMCID: PMC5049966  PMID: 27261669
pain; prescription drug abuse; prevention; public health; substance abuse
16.  Genetic Association Studies Identify Unanticipated Gene Pathways Influencing Sepsis Outcome 
EBioMedicine  2016;12:20-21.
doi:10.1016/j.ebiom.2016.09.014
PMCID: PMC5078601  PMID: 27658739
17.  Left ventricular function: time-varying elastance and left ventricular aortic coupling 
Critical Care  2016;20(1):270.
Many aspects of left ventricular function are explained by considering ventricular pressure–volume characteristics. Contractility is best measured by the slope, Emax, of the end-systolic pressure–volume relationship. Ventricular systole is usefully characterized by a time-varying elastance (ΔP/ΔV). An extended area, the pressure–volume area, subtended by the ventricular pressure–volume loop (useful mechanical work) and the ESPVR (energy expended without mechanical work), is linearly related to myocardial oxygen consumption per beat. For energetically efficient systolic ejection ventricular elastance should be, and is, matched to aortic elastance. Without matching, the fraction of energy expended without mechanical work increases and energy is lost during ejection across the aortic valve. Ventricular function curves, derived from ventricular pressure–volume characteristics, interact with venous return curves to regulate cardiac output. Thus, consideration of ventricular pressure–volume relationships highlight features that allow the heart to efficiently respond to any demand for cardiac output and oxygen delivery.
doi:10.1186/s13054-016-1439-6
PMCID: PMC5018161  PMID: 27613430
19.  Sexual violence from police and HIV risk behaviours among HIV-positive women who inject drugs in St. Petersburg, Russia – a mixed methods study 
Journal of the International AIDS Society  2016;19(4Suppl 3):20877.
Introduction
Police violence against people who inject drugs (PWID) is common in Russia and associated with HIV risk behaviours. Sexual violence from police against women who use drugs has been reported anecdotally in Russia. This mixed-methods study aimed to evaluate sexual violence from police against women who inject drugs via quantitative assessment of its prevalence and HIV risk correlates, and through qualitative interviews with police, substance users and their providers in St. Petersburg, Russia.
Methods
Cross-sectional analyses with HIV-positive women who inject drugs (N=228) assessed the associations between sexual violence from police (i.e. having been forced to have sex with a police officer) and the following behaviours: current drug use, needle sharing and injection frequency using multiple regression models. We also conducted in-depth interviews with 23 key informants, including PWID, police, civil society organization workers, and other stakeholders, to explore qualitatively the phenomenon of sexual violence from police in Russia and strategies to address it. We analyzed qualitative data using content analysis.
Results
Approximately one in four women in our quantitative study (24.1%; 95% CI, 18.6%, 29.7%) reported sexual violence perpetrated by police. Affected women reported more transactional sex for drugs or money than those who were not; however, the majority of those reporting sexual violence from police were not involved in these forms of transactional sex. Sexual violence from police was not significantly associated with current drug use or needle sharing but with more frequent drug injections (adjusted incidence rate ratio 1.43, 95% CI 1.04, 1.95). Qualitative data suggested that sexual violence and coercion by police appear to be entrenched as a norm and are perceived insurmountable because of the seemingly absolute power of police. They systematically add to the risk environment of women who use drugs in Russia.
Conclusions
Sexual violence from police was common in this cohort of Russian HIV-positive women who inject drugs. Our analyses found more frequent injection drug use among those affected, suggesting that the phenomenon represents an underappreciated human rights and public health problem. Addressing sexual violence from police against women in Russia will require addressing structural factors, raising social awareness and instituting police trainings that protect vulnerable women from violence and prevent HIV transmission.
doi:10.7448/IAS.19.4.20877
PMCID: PMC4951542  PMID: 27435712
sexual violence; gender-based violence; human rights; police involvement; People living with HIV/AIDS (PLHA); injection drug use; key populations; Russian Federation
20.  Functional, composite polythioether nanoparticles via thiol-alkyne photopolymerization in miniemulsion 
Thiol-yne photopolymerization in miniemulsion is demonstrated as a simple, rapid, and one-pot synthetic approach to polythioether nanoparticles with tuneable particle size and clickable functionality. The strategy is also useful in the synthesis of composite polymer-inorganic nanoparticles.
Graphical abstract
Thiol-yne photopolymerization in miniemulsion is demonstrated as a rapid one-pot synthetic approach to polythioether nanoparticles with tuneable particle size and clickable functionality.
doi:10.1039/c5cc03319e
PMCID: PMC4857709  PMID: 26060848
21.  Adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression: patient-reported outcomes in the TEXT and SOFT randomised trials 
The Lancet. Oncology  2015;16(7):848-858.
Background
Efficacy analysis of the combined IBCSG TEXT and SOFT trials showed a significant disease-free survival benefit for exemestane plus ovarian function suppression (OFS) compared with tamoxifen +OFS. We present patient-reported outcomes from these trials.
Methods
Between 7 November 2003 and 7 April 2011, 4717 premenopausal patients with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unblinded adjuvant treatment with 5 years of exemestane+OFS or tamoxifen+OFS. Chemotherapy use was optional. Randomization was performed via IBCSG’s internet-based system with the use of permuted blocks and was stratified by chemotherapy use and lymph nodes status. Patients completed a quality of life (QoL) form including several global and symptom-specific indicators at baseline, every 6 months for 24 months, then annually during years 3 to 6. Differences in change of QoL from baseline between the two treatments were tested at short-, mid-, and long-term using mixed-models for repeated measures, for each trial with and without chemotherapy and overall. The analysis was intention-to-treat using treatment as randomly assigned. At the time of analysis, the median follow-up was 5·7 years (IQR, 3·7 to 6·9 years), with treatment and follow-up of patients ongoing.
Findings
Patients reported considerable worsening from baseline in key endocrine symptoms. Those on tamoxifen+OFS were more affected by hot flushes and sweats over five years than those on exemestane+OFS, although these symptoms improved. Patients on exemestane+OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused. These differences persisted over time. An increase in bone/joint pain was more pronounced, particularly in the short-term, in patients on exemestane+OFS. Changes of global QoL indicators from baseline were small and similar between treatments over the whole treatment period.
Interpretation
Overall, from a QoL perspective, there is no strong indication to favor either exemestane+OFS or tamoxifen+OFS. The differential effects of the two treatments on endocrine symptoms burden need to be addressed with patients individually.
Funding
TEXT and SOFT receive financial support for trial conduct from Pfizer, the International Breast Cancer Study Group and the US National Cancer Institute. Pfizer and Ipsen provide drug supply. See Acknowledgment for grants and grant numbers.
doi:10.1016/S1470-2045(15)00049-2
PMCID: PMC4562429  PMID: 26092816
adjuvant therapy; aromatase inhibitor; breast cancer; endocrine therapy; exemestane; GnRH agonist; ovarian function suppression; premenopausal; quality of life; sexual functioning; tamoxifen; triptorelin
22.  Improving the quality of care of children in community clinics: an intervention and evaluation in Bangladesh 
Public Health Action  2016;6(2):77-82.
Setting: Community health care providers (CHCPs) in 40 rural community clinics of Comilla district, Bangladesh, were trained using a newly developed case-management job aid based on the World Health Organization Integrated Management of Childhood Illness and a communication guide.
Objectives: To assess 1) the change in knowledge of the CHCPs after training; 2) the absolute quality of care provided by the CHCPs (determined as the proportion of children aged <5 years [under-fives] correctly diagnosed, treated and referred); and 3) the consultation behaviour of the CHCPs.
Design: Change in knowledge was assessed by tests pre-and post-training. The quality of care was determined by reassessments at the clinic exit by a medical officer, without a baseline comparison. Consultation behaviour was assessed through direct observation. The study was performed during 2014–2015.
Results: The mean standard knowledge score of the CH-CPs increased from 19 to 25 (P < 0.001). Of 1490 under-fives examined, 91% were correctly diagnosed, 86% were correctly treated and 99.5% received a correct referral decision. The CHCPs performed well on most of the measures of good communication, although one third did not explain the diagnosis and treatment to patients.
Conclusion: The training was effective in changing knowledge. The CHCPs applied the knowledge gained and provided good quality care. Following these results, the Bangladesh Ministry of Health and Family Welfare has scaled up the training nationwide. The lessons learnt should be useful for other countries.
doi:10.5588/pha.16.0004
PMCID: PMC4913689  PMID: 27358800
primary care; childhood pneumonia; antibiotic reduction
23.  Heroin Use and HIV Disease Progression: Results from a Pilot Study of a Russian Cohort 
AIDS and behavior  2015;19(6):1089-1097.
Opioids have immunosuppressive properties, yet their impact on HIV disease progression remains unclear. Using longitudinal data from HIV-infected antiretroviral therapy-naïve Russian individuals (n=77), we conducted a pilot study to estimate the effect of heroin use on HIV disease progression. Heroin use was categorized based on past 30 day self-report at baseline, 6 months and 12 months as none, intermittent or persistent. We estimated the effect of heroin use on HIV disease progression, measured as change in CD4 count from baseline to 12 months, using multivariable linear regression. Those with intermittent (n=21) and no heroin use (n=39) experienced mean decreases in CD4 count from baseline to 12 months (−103 cells/mm3 and −10 cells/mm3, respectively; adjusted mean difference (AMD) −93, 95% CI: −245, 58). Those with persistent use (n=17) showed a mean increase of 53 cells/mm3 (AMD 63, 95% CI: −95, 220). Future studies exploring the effects of heroin withdrawal on HIV disease progression are warranted.
doi:10.1007/s10461-014-0948-z
PMCID: PMC4440848  PMID: 25413642
heroin; HIV disease progression; HIV; CD4
24.  Protocol for a pragmatic cluster randomised controlled trial for reducing irrational antibiotic prescribing among children with upper respiratory infections in rural China 
BMJ Open  2016;6(5):e010544.
Introduction
Irrational use of antibiotics is a serious issue within China and internationally. In 2012, the Chinese Ministry of Health issued a regulation for antibiotic prescriptions limiting them to <20% of all prescriptions for outpatients, but no operational details have been issued regarding policy implementation. This study aims to test the effectiveness of a multidimensional intervention designed to reduce the use of antibiotics among children (aged 2–14 years old) with acute upper respiratory infections in rural primary care settings in China, through changing doctors' prescribing behaviours and educating parents/caregivers.
Methods and analysis
This is a pragmatic, parallel-group, controlled, cluster-randomised superiority trial, with blinded evaluation of outcomes and data analysis, and un-blinded treatment. From two counties in Guangxi Province, 12 township hospitals will be randomised to the intervention arm and 13 to the control arm. In the control arm, the management of antibiotics prescriptions will continue through usual care via clinical consultations. In the intervention arm, a provider and patient/caregiver focused intervention will be embedded within routine primary care practice. The provider intervention includes operational guidelines, systematic training, peer review of antibiotic prescribing and provision of health education to patient caregivers. We will also provide printed educational materials and educational videos to patients' caregivers. The primary outcome is the proportion of all prescriptions issued by providers for upper respiratory infections in children aged 2–14 years old, which include at least one antibiotic.
Ethics and dissemination
The trial has received ethical approval from the Ethics Committee of Guangxi Provincial Centre for Disease Control and Prevention, China. The results will be disseminated through workshops, policy briefs, peer-reviewed publications, local and international conferences.
Trial registration number
ISRCTN14340536; Pre-results.
doi:10.1136/bmjopen-2015-010544
PMCID: PMC4885273  PMID: 27235297
Antibiotics; Rational use; Clustered randomized control trial; PRIMARY CARE; China
25.  Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor 
PLoS ONE  2016;11(5):e0155030.
Sepsis is the leading cause of death in critically ill patients. While decreased Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) function improves clinical outcomes in murine and human sepsis, the mechanisms involved have not been fully elucidated. We tested the hypothesis that lipopolysaccharide (LPS), the major Gram-negative bacteria endotoxin, is cleared from the circulation by hepatocyte Low Density Lipoprotein Receptors (LDLR)—receptors downregulated by PCSK9. We directly visualized LPS uptake and found that LPS is rapidly taken up by hepatocytes into the cell periphery. Over the course of 4 hours LPS is transported towards the cell center. We next found that clearance of injected LPS from the blood was reduced substantially in Ldlr knockout (Ldlr-/-) mice compared to wild type controls and, simultaneously, hepatic uptake of LPS was also reduced in Ldlr-/- mice. Specifically examining the role of hepatocytes, we further found that primary hepatocytes isolated from Ldlr-/- mice had greatly decreased LPS uptake. In the HepG2 immortalized human hepatocyte cell line, LDLR silencing similarly resulted in decreased LPS uptake. PCSK9 treatment reduces LDLR density on hepatocytes and, therefore, was another independent strategy to test our hypothesis. Incubation with PCSK9 reduced LPS uptake by hepatocytes. Taken together, these findings demonstrate that hepatocytes clear LPS from the circulation via the LDLR and PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatic LDLR.
doi:10.1371/journal.pone.0155030
PMCID: PMC4865154  PMID: 27171436

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