bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Study of Confidence Intervals for Proportions in Complex Sample Surveys†
Authors: Franco Carolina , Little Roderick J A , Louis Thomas A , Slud Eric V
Published: August 2018

The most widespread method of computing confidence intervals (CIs) in complex surveys is to add and subtract the margin of error (MOE) from the point estimate, where the MOE is the estimated standard error multiplied by the suitable Gaussian quantile. This Wald-type interval is used by the American Community Survey (ACS), the largest US household sample survey. For inferences on small proportions with moderate sample sizes, this method often results in marked under-coverage and lower CI endpoint less than 0. We assess via simulation the coverage and width, in complex sample surveys, of seven alternatives to the Wald interval for a binomial proportion with sample size replaced by the ‘effective sample size,’ that is, the sample size divided by the design effect. Building on previous work by the present authors, our simulations address the impact of clustering, stratification, different stratum sampling fractions, and stratum-specific proportions. We show that all intervals undercover when there is clustering and design effects are computed from a simple design-based estimator of sampling variance. Coverage can be better calibrated for the alternatives to Wald by improving estimation of the effective sample size through superpopulation modeling. This approach is more effective in our simulations than previously proposed modifications of effective sample size. We recommend intervals of the Wilson or Bayes uniform prior form, with the Jeffreys prior interval not far behind.
Using a social marketing approach to develop Healthy Me, Healthy We: a nutrition and physical activity intervention in early care and education
Authors: Vaughn Amber E , Bartlett Rachel , Luecking Courtney T , Hennink-Kaminski Heidi , Ward Dianne S
Published: August 2018

Although social marketing principles have been successfully employed in school-based interventions to prevent obesity, use in early care and education (ECE) settings has been limited. This paper describes the use of the social marketing approach to develop an ECE-based intervention that encourages an ECE provider–parent partnership to improve the quality of preschool children’s diets and their level of physical activity. A six-step social marketing approach for public health interventions guided the development of this ECE-based intervention. These steps were as follows: (i) initial planning, (ii) formative research, (iii) strategy development, (iv) program development, (v) implementation, and (vi) monitoring and evaluation. During this process, we reviewed current literature, conducted focus groups with ECE providers and parents, developed a detailed conceptual model and content map, created and tested the campaign concept, and developed final campaign materials along with strategies for its implementation. The final intervention resulting from this process was an 8-month campaign known as Healthy Me, Healthy We. The campaign is delivered by the child care center and includes branded materials for use in the classroom and at home. The final campaign is being evaluated in a cluster-randomized trial. Healthy Me, Healthy We offers an innovative approach to promoting healthy eating and physical activity during early childhood, a key developmental period, that leverages partnership between ECE providers and parents to affect behavior change.
Nonnutritive Sucking at the Mother's Breast Facilitates Oral Feeding Skills in Premature Infants
Authors: John Hima B. , Suraj Charis , Padankatti Sanjeev M. , Sebastian Tunny , Rajapandian Earnest
Published: August 2018

Background

Premature infants have difficulties in transitioning from gavage to breastfeeding. Targeted interventions to support breastfeeding in premature infants in the neonatal intensive care unit are scarce.

Purpose:

This pilot study evaluates the effectiveness of nonnutritive sucking at the mother's breast in premature infants to facilitate breastfeeding performance and exclusive breastfeeding.

Methods:

The study design constituted a single-blinded randomized control trial, with 9 participants randomly allocated into experimental (n = 4) and control (n = 5) groups. The intervention, nonnutritive sucking at the mother's breast thrice a day for 5 minutes, till nutritive breastfeeding was started, was done in addition to standard care, which was nonnutritive sucking on a finger during gavage feeds. The control group received only standard care. Nonnutritive sucking was assessed using “Stages of Nonnutritive Sucking Scale,” and breastfeeding performance was assessed using the “Preterm Infant Breastfeeding Behavior Scale” by a blinded assessor unaware of the infants' allocation.

Results:

Five infants in the control arm and 4 in the intervention arm completed the study. The infants in the intervention group showed faster transition to mature stages of nonnutritive sucking (P = .05) and had longer sucking bursts during breastfeeding (P = .06) than those in the control group. There was no difference in the rates of exclusive breastfeeding at 6 months in the intervention and control groups.

Implications for Practice:

Early initiation of nonnutritive sucking at the mother's breast in very preterm infants is a safe and effective intervention to facilitate maturation of oral feeding and breastfeeding behavior.

Implications for Research:

Nonnutritive sucking at the mother's breast can be explored as an intervention, with a larger sample, to facilitate exclusive breastfeeding and to establish intervention fidelity.
Perspectives of immunotherapy in isocitrate dehydrogenase-mutant gliomas
Authors: Friedrich Mirco , Bunse Lukas , Wick Wolfgang , Platten Michael
Published: August 2018

Purpose of review

The present review introduces recent progress in eliciting the role of mutant isocitrate dehydrogenase (IDH) in gliomas, especially regarding its mode of action as a modulator of antitumor immune response, and provides rationales for targeting mutant IDH in glioma immunotherapy. Both the development of small molecule inhibitors repressing the enzymatic activity of mutant IDH and novel, mechanism-led combination immunotherapies are discussed.

Recent findings

Since the discovery of highly frequent IDH mutations in low-grade gliomas and nonsolid malignancies, its tumor cell-intrinsic effects have been intensively investigated. Tumor cells expressing mutant IDH display profound alterations of redox control capacity, phospholipid profile, and ATP supply. Recent findings suggest that IDH mutations – via intricate, yet druggable pathways – cause immunological alterations, highlighting the importance of oncogenic drivers as modulators of antitumor immunity and targets for immunotherapy.

Mutant IDH is not only a disease-defining biomarker and oncogenic driver in glioma, but is also a neoantigen and a regulator of glioma immune evasion. Effective and specific strategies targeting the immunomodulatory properties of mutant IDH may complement current (immuno-)therapeutic strategies and approved antiglioma treatments to improve outcome.
Platelet-Rich Plasma Augments Subcision in Atrophic Acne Scars: A Split-Face Comparative Study
Authors: Deshmukh Nitika S. , Belgaumkar Vasudha A.
Published: August 2018

BACKGROUND

Acne has a prevalence of 90% among adolescents. Facial scarring affects 75% of patients. Autologous platelet-rich plasma (PRP) is a novel treatment option for acne scar management and can be used as an adjuvant to acne scar revision procedures. Owing to its remodeling properties, PRP when used as an adjuvant reduces the total number of sittings.

OBJECTIVE

To compare efficacy of autologous PRP and subcision against subcision alone in acne scars.

METHODOLOGY

It was an experimental analytical study conducted over a period of 2 years. Forty patients successfully completed the trial. It was a split-face study in which the right side of the face was the study side where autologous PRP was injected into each scar after performing subcision. The left side of the face was the control side where only subcision was performed. Digital photographs were taken at every sitting. Analysis was performed using the Wilcoxon signed-rank test and Mann–Whitney tests in SPSS software.

RESULTS

Platelet-rich plasma and subcision showed greater improvement (32.08%) in postacne scars as compared to subcision alone (8.33%). Rolling acne scars responded greatest (39.27%) followed by box-type scars (33.88%).

CONCLUSION

Platelet-rich plasma and subcision act synergistically to improve the appearance of acne scars.
A Pilot Study of the Effectiveness of Lithium Versus Quetiapine Immediate Release Monotherapy in Patients With Bipolar Spectrum Disorders
Authors: Gao Keming , Goto Toyomi , Yuan Chengmei , Brownrigg Brittany , Conroy Carla , Chan Philip K. , Serrano Mary Beth , Ganocy Stephen J. , Fang Fang , Calabrese Joseph R.
Published: August 2018

Objective

The aim of this study was to compare the effectiveness of lithium versus quetiapine immediate release (IR) monotherapy in patients with bipolar I, II, or subthreshold bipolar disorder at any phase.

Methods

Eligible patients were randomized to lithium or quetiapine IR for 16 weeks. The difference in the time to discontinuation from study due to “all causes” between lithium and quetiapine IR groups and changes from baseline to 8 and 16 weeks in depression, mania, anxiety, quality of life (QOL), metabolic profiles, and proinflammatory markers were compared.

Results

Of the 42 patients randomized to lithium (n = 18) and quetiapine IR (n = 24), the median time to discontinuation due to “all causes” was 6 weeks (95% confidence interval, 2–12 weeks) in the lithium group and 8 weeks (95% confidence interval, 6 weeks to not calculable) in the quetiapine IR group. The mean time to discontinuation due to “all causes” was 7.7 ± 1.1 weeks for lithium versus 8.4 ± 0.8 weeks for quetiapine IR (P = 0.54). There was no significant difference between lithium and quetiapine IR in changes in the severity of depression, mania/hypomania, anxiety, and QOL as a whole or only in patients with depressive index episode. The decrease in total cholesterol was significantly larger with lithium than with quetiapine IR (P = 0.05) as a whole, but not only in patients with depression index episode. There was no other significant difference in changes in metabolic panels and inflammatory markers between the 2 groups.

Conclusions

The difference in effectiveness between lithium and quetiapine IR monotherapy in a real-world bipolar population was minimal. Large-sample studies are needed to support or refute this finding.
Antipsychotic Use and the Risk of Initiating Medication for Benign Prostate Hyperplasia in Persons With Alzheimer Disease
Authors: Orsel Kim , Taipale Heidi , Raatikainen Sami , Lampela Pasi , Tolppanen Anna-Maija , Koponen Marjaana , Tanskanen Antti , Tiihonen Jari , Gardarsdottir Helga , Hartikainen Sirpa
Published: August 2018

Background

Antipsychotics (APs) are known to exacerbate symptoms of benign prostate hyperplasia (BPH) and may even cause urinary retention. The anticholinergic effects of APs and their dopamine D2- and α-receptor blockade may lead to voiding dysfunction of BPH patients. The objective of our study was to investigate whether the use of APs is associated with an increased risk of initiating medication for BPH in men with Alzheimer disease (AD).

Methods

Data from the nationwide MEDALZ (MEDication use and ALZheimer's disease) cohort, including all community-dwelling persons diagnosed with AD in Finland, were utilized. Register-based data included medication dispensing, comorbidities, and hospital discharge diagnoses. Men who initiated APs (n = 4579) were 1:1 matched with men who did not initiate APs (n = 4579), according to time since AD diagnoses and age. The risk of starting BPH medication was investigated with Cox regression.

Results

Among AP users, BPH medication was initiated to 345 persons (7.5%). Antipsychotic use was not associated with risk of initiating BPH medication (comorbidity-adjusted hazard ratio, 0.92; 95% confidence interval, 0.74–1.15) compared with no use of APs. In addition, no risk was found when AP drug substances were analyzed separately.

Conclusions

Use of APs did not increase the risk of initiating medication for BPH in men with AD.
How to Treat Hypertension in Venlafaxine-Medicated Patients—Pharmacokinetic Considerations in Prescribing Amlodipine and Ramipril
Authors: Augustin Marc , Schoretsanitis Georgios , Gründer Gerhard , Haen Ekkehard , Paulzen Michael
Published: August 2018

Background

Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking.

Methods

Two TDM databases consisting of plasma concentrations of VEN and its active metaboliteO-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO(n = 22); a group comedicated with RAMI, VRAMI(n = 20); and a 4:1 control group age matched to the VAMLOgroup receiving VEN without confounding medications, V0(n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests.

Results

Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P= 0.029), whereas the RAMI group showed lower values for ODVEN (P= 0.029). All other parameters showed no significant differences.

Conclusions

Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.
Incidence of Heart Failure and Cardiomyopathy Following Initiation of Medications for Attention-Deficit/Hyperactivity Disorder
Authors: Mosholder Andrew D. , Taylor Lockwood , Mannheim Glenn , Ortendahl Lisa , Woodworth Tiffany S. , Toh Sengwee
Published: August 2018

Purpose/Background

Stimulant abuse is associated with cardiomyopathy, but cardiomyopathy rates with therapeutic use of stimulants for attention-deficit/hyperactivity disorder (ADHD) are poorly characterized. Labels for methylphenidate, amphetamine, and atomoxetine caution against use in patients with cardiovascular disease. We sought to assess the incidence of new-onset heart failure or cardiomyopathy among initiators of these medications.

Methods/Procedures

Using the Sentinel distributed database, we analyzed new-onset heart failure or cardiomyopathy among initiators of selected ADHD medications (amphetamine products including lisdexamfetamine, methylphenidate, and atomoxetine), by duration of use (0–90, 91–180, 181–270, 271–365, 366–730, and 731–1095 days) and age group (<22, 22–44, 45–64, and ≥65 years).

Findings/Results

In our sample of 2,012,948 initiators of ADHD medications, 44.6% were female, and 54.1% were younger than 22 years. Heart failure/cardiomyopathy rates in the age groups younger than 22 and 22 to 44 years old were less than 50 per 10,000 person-years, without clear trends by duration of use. The highest rates occurred soon after treatment initiation in the age group 65 years or older, with 1 case per 10.5 person-years of follow-up, or 950 cases per 10,000 person-years, for days 0–90.

Implications/Conclusions

Heart failure/cardiomyopathy rates were not higher over 3 years of ADHD medication use compared with shorter-term treatment. In older age groups, lower rates later in treatment could reflect depletion of patients predisposed to the outcome if they develop it soon after starting treatment.
How Do Hospitalized Adolescents Feel Safe? A Qualitative Study
Authors: JAMALIMOGHADAM Neda , YEKTATALAB Shahrzad , MOMENNASAB Marzieh , EBADI Abbas , ZARE Najaf
Published: August 2018

Background:

The feeling of safety makes an important contribution to the sense of well-being and quality of care for hospitalized adolescents, who are at a higher risk of feeling unsafe. Feeling unsafe during hospitalization may have a negative impact on recovery. Nurses must be sensitive to the possibility that patients feel unsafe, even in the absence of obvious direct physical threat.

Purpose:

This study explores the experiences of hospitalized adolescents to obtain an understanding of psychological safety.

Methods:

A qualitative study using unstructured interviews was conducted to explore the sense of psychological safety of hospitalized adolescents aged 12–18 years and registered in a general medical or surgical pediatric unit. Purposive sampling was used to recruit new qualified participants until data saturation was reached (N = 16).

Results:

Psychological safety is reflected by the four themes of receiving comprehensive support, protection of human dignity, relaxing environment, and attempts to adapt.

Conclusions:

Hospitalized adolescents stated that healthcare services should provide comprehensive support in a relaxing environment that allows them to retain their human dignity and that elicits feelings of psychological safety.
Emotional Intelligence Relates to NCLEX and Standardized Readiness Test
Authors: Rode Jennifer , Brown Karen
Published: August 2018

Background

Understanding what factors contribute to NCLEX-RN success is critical to nursing programs. Emotional intelligence is one factor that warrants investigation.

Purpose

The purpose of our study was to examine emotional intelligence, measured via the Mayer-Salovey-Caruso Emotional Intelligence Test 2.0, to 2 standardized measures of nursing student performance: the Kaplan Nursing Assessment Test (NAT) and NCLEX-RN success.

Methods

A descriptive, cohort design with 2 data collections times points (n = 53) evaluated the contribution of emotional intelligence to NAT and to NCLEX-RN success, while controlling for age.

Results

Emotional intelligence global scores were significantly related to both NAT and NCLEX-RN. Understanding emotions branch was a significant predictor of NAT. Perceiving emotions and understanding emotions branches were both significant predictors of NCLEX-RN.

Conclusions

Results suggest that enhancing nursing curriculum to include training in perceiving and understanding emotions may be beneficial in augmenting student success.
Enterprise Evaluation: A New Opportunity for Public Health Policy
Authors: Sherman Mya , Covert Hannah , Brown Lisanne , Langhinrichsen-Rohling Jennifer , Hansel Tonya , Rehner Timothy , Buckner Ayanna , Lichtveld Maureen
Published: August 2018

Standard evaluation practice in public health remains limited to evaluative measures linked to individual projects, even if multiple interrelated projects are working toward a common impact. Enterprise evaluation seeks to fill this policy gap by focusing on cross-sector coordination and ongoing reflection in evaluation. We provide an overview of the enterprise evaluation framework and its 3 stages: collective creation, individual data collection, and collective analysis. We illustrate the application of enterprise evaluation to the Gulf Region Health Outreach Program, 4 integrated projects that aimed to strengthen health care in Louisiana, Mississippi, Alabama, and the Florida Panhandle after the Deepwater Horizon oil spill. Shared commitment to sustainability and strong leadership were critical to Gulf Region Health Outreach Program's success in enterprise evaluation. Enterprise evaluation provides an important opportunity for funding agencies and public health initiatives to evaluate the impact of interrelated projects in a more holistic and multiscalar manner than traditional siloed approaches to evaluation.
The Impact of Upper Face Botulinum Toxin Injections on Eyebrow Height and Forehead Lines: A Randomized Controlled Trial and an Algorithmic Approach to Forehead Injection
Authors: Jabbour Samer F. , Awaida Cyril J. , ElKhoury Joseph S. , Rayess Youssef A. , Makhoul Rani B. , Kechichian Elio G. , Nasr Marwan W.
Published: August 2018

No previous study has objectively evaluated the effect of different forehead injection patterns on the eyebrow height and forehead lines. The patients were divided into three groups. Botulinum toxin was injected into both the lateral and medial eyebrow depressors in all groups. The frontalis was injected using either a V-pattern (group 1), a middle horizontal pattern (group 2), or a high horizontal pattern (group 3). Objective eyebrow measurements were performed using standardized preinjection and postinjection photographs. Validated photonumeric scales were used to assess the forehead lines. Fifteen patients (30 eyebrows) were included in each group. In all of the groups, 2 weeks after injection, the brow was lower at all the measured positions, with the exception of the lateral brow edge, which was higher in the three injection patterns. No difference was found when comparing group 1 to groups 2 and 3. The middle forehead injection pattern lowered the eyebrow more than the upper forehead injection pattern. The three techniques improved the forehead lines at rest and with contraction. The forehead lines with contraction were more improved in group 1 compared with both groups 2 and 3. Each forehead injection pattern yielded different results on forehead lines and eyebrow position. Upper forehead injections were less effective on forehead lines but prevented eyebrow ptosis.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
The Feasibility Determination of Risky Severe Complications of Arterial Vasculature Regarding the Filler Injection Sites at the Tear Trough
Authors: Jitaree Benrita , Phumyoo Thirawass , Uruwan Sukanya , Sawatwong Worapat , McCormick Liam , Tansatit Tanvaa
Published: August 2018

Background:

The tear trough is a significant sign of periorbital aging and has usually been corrected with filler injection. However, the arterial supply surrounding the tear trough could be inadvertently injured during injection; therefore, this study aimed to evaluate the nearest arterial locations related to the tear trough and investigate the possibility of severe complications following filler injection.

Methods:

Thirty hemifaces of 15 Thai embalmed cadavers were used in this study.

Results:

The artery located closest to both the inferior margin (TT1) and mid-pupil level (TT2) of the tear trough was found to be the palpebral branch of the infraorbital artery. Furthermore, at 0.5 mm along the tear trough from the medial canthus (TT3), the angular artery was identified, which was found to be a branch of the ophthalmic artery. The artery at TT1 and TT2 was located beneath both the zygomaticus major and the orbicularis oculi muscles. The distances from TT1 to the artery were measured as follows: laterally, 2.79 ± 1.08 mm along the x axis; and inferiorly, 2.88 ± 1.57 mm along the y axis. For the TT2, the artery was located inferomedially from the landmark of 4.65 ± 1.83 mm along the x axis and 7.13 ± 3.99 mm along the y axis. However, the distance along the x axis at TT3 was located medially as 4.00 ± 2.37 mm.

Conclusion:

The high risk of injury to the artery at the tear trough should be considered because of the numerous arteries to this area.
Understanding Fatal Fat Embolism in Gluteal Lipoinjection: A Review of the Medical Records and Autopsy Reports of 16 Patients
Authors: Bayter-Marin Jorge Enrique , Cárdenas-Camarena Lázaro , Aguirre-Serrano Herley , Durán Héctor , Ramos-Gallardo Guillermo , Robles-Cervantes José Antonio
Published: August 2018

Background:

Deaths secondary to gluteal lipoinjection are relatively recent events of major importance. However, little is known in relation to their behavior and clinical evolution. Therefore, an analysis was performed of case records from clinical cases that encountered this problem, correlating the results with the findings during autopsies.

Methods:

An analysis was performed of records from patients who died secondary to gluteal lipoinjection. Patient-specific data, surgical procedure, clinical picture, evolution, and outcome were analyzed. The findings of the autopsies and the involvement of other organs were also analyzed and correlated.

Results:

From 2000 to 2009, 16 files were obtained that fulfilled the indicated requirements. There were no statistically significant differences in the general characteristics of the patients, such as age, body mass index, or volume lipoinjected or liposuctioned. The clinical pictures were similar in all cases, and the autopsy findings showed the presence of microembolism in all cases and macroembolism in the most severe cases.

Conclusions:

The most significant parameter of severity in patients who undergo gluteal lipoinjection is the presence of fat in macroscopic form in the circulation. The volumes of liposuctioned or lipoinjected fat have little influence. Hypoxemia, hypotension, and bradycardia are the characteristic clinical features. Although there is no specific treatment, immediate aggressive vital support to attempt to stabilize the patient is crucial.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, V.
Familial Aggregation of Plastic Surgical Procedures
Authors: Timberlake Andrew T. , Steinbacher Derek M.
Published: August 2018

A growing number of patients seeking plastic surgical procedures in the authors’ practice are first-degree relatives of previous surgical patients. Three possibilities for procedural coalescence within a family unit include (1) similar morphologic and anatomical patterns within relatives; (2) a captive “audience” (family members) appreciates firsthand the surgical result and positive difference, be it functional or aesthetic; or (3) the rapport established between surgeon and patient leads that patient to recommend his or her surgeon to others. The purpose of this study was to identify the authors’ recent cohort of family members undergoing similar or related procedures performed by the same surgeon (D.M.S.), and understand the diagnoses, factors, and rationale for “passing the torch” to other family members to undergo surgery. Survey responses from 17 members of 10 families who sought elective procedures after an index family member indicated that both the result of the first operation and rapport with the surgeon were important factors in their decision to undergo surgery (mean Likert response ± SD, 4.94 ± 0.24). Ninety-four percent of family members (16 of 17) indicated that the result of the original procedure was the most important factor in their decision to undergo subsequent procedures performed by the same surgeon. Eighty-eight percent of family members (15 of 17) seeking subsequent procedures were not considering undergoing surgery before observing the result of the first index procedure. The data demonstrate the importance of achieving an excellent surgical result in earning the trust of patients and establishing strong family referral patterns.
Manipulating the Microcirculation in Sepsis – the Impact of Vasoactive Medications on Microcirculatory Blood Flow: A Systematic Review
Authors: Potter Elizabeth K. , Hodgson Luke , Creagh-Brown Ben , Forni Lui G.
Published: August 2018

Background:

Sepsis is life-threatening organ dysfunction because of a dysregulated host response to infection. Disturbed microvascular blood flow is associated with excess mortality and is a potential future target for interventions. This review addresses the evidence for pharmacological manipulation of the microcirculation in sepsis assessed by techniques that evaluate the sublingual microvasculature.

Methods:

Systematic review using a published protocol. Eligibility criteria were studies of septic patients published from January 2000 to February 2018. Interventions were drugs aimed at improving perfusion. Outcome was improvement in microvascular flow using orthogonal polarization spectral, sidestream dark field, or incident dark field imaging (Grades of Recommendation, Assessment, Development, and Evaluation criteria used).

Results:

Two thousand six hundred and six articles were screened and 22 included. (6 randomized controlled trials, 12 interventional, 3 observational, and 1 pilot, n = 572 participants). Multiple measurement techniques were described, including: automated analyses, subjective, and composite scoring systems. Norepinephrine was not found to improve microvascular flow (low-grade evidence, n = 6 studies); except in chronic hypertension (low, n = 1 study). Addition of arginine vasopressin or terlipressin to norepinephrine maintained flow while decreasing norepinephrine requirements (high, n = 2 studies). Neither dobutamine nor glyceryl trinitrate consistently improved flow (low, n = 6 studies). A single study (n = 40 participants) demonstrated improved flow with levosimendan (high). In a risk of bias assessment 16/16 interventional, pilot and observational studies were found to be high risk.

Conclusions:

There is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow. Furthermore, no study demonstrated outcome benefit of one therapeutic agent over another. Updated consensus guidelines could improve comparable reporting of measurements and reduce bias, to enable meaningful comparisons around the effects of individual pharmacological agents.
Myocardial Redox Hormesis Protects the Heart of Female Mice in Sepsis
Authors: Luptak Ivan , Croteau Dominique , Valentine Catherine , Qin Fuzhong , Siwik Deborah A. , Remick Daniel G. , Colucci Wilson S. , Hobai Ion A.
Published: August 2018

Mice challenged with lipopolysaccharide develop cardiomyopathy in a sex and redox-dependent fashion. Here we extended these studies to the cecal ligation and puncture (CLP) model.

We compared male and female FVB mice (wild type, WT) and transgenic littermates overexpressing myocardial catalase (CAT). CLP induced 100% mortality within 4 days, with similar mortality rates in male and female WT and CAT mice. 24 h after CLP, isolated (Langendorff) perfused hearts showed depressed contractility in WT male mice, but not in male CAT or female WT and CAT mice. In WT male mice, CLP induced a depression of cardiomyocyte sarcomere shortening (ΔSS) and calcium transients (ΔCai), and the inhibition of the sarcoplasmic reticulum Ca2+ ATPase (SERCA). These deficits were associated with overexpression of NADPH-dependent oxidase (NOX)-1, NOX-2, and cyclooxygenase 2 (COX-2), and were partially prevented in male CAT mice. Female WT mice showed unchanged ΔSS, ΔCai, and SERCA function after CLP. At baseline, female WT mice showed partially depressed ΔSS, ΔCai, and SERCA function, as compared with male WT mice, which were associated with NOX-1 overexpression and were prevented in CAT female mice.

In conclusion, in male WT mice, septic shock induces myocardial NOX-1, NOX-2, and COX-2, and redox-dependent dysregulation of myocardial Ca2+ transporters. Female WT mice are resistant to CLP-induced cardiomyopathy, despite increased NOX-1 and COX-2 expression, suggesting increased antioxidant capacity. Female resistance occurred in association with NOX-1 overexpression and signs of increased oxidative signaling at baseline, indicating the presence of a protective myocardial redox hormesis mechanism.
High Operator and Hospital Volume Are Associated With a Decreased Risk of Death and Stroke After Carotid Revascularization
Authors: Poorthuis Michiel H. F. , Brand Eelco C. , Halliday Alison , Bulbulia Richard , Bots Michiel L. , de Borst Gert J.
Published: August 2018

Objective:

To examine the association between operator or hospital volume and procedural outcomes of carotid revascularization.

Background:

Operator and hospital volume have been proposed as determinants of outcome after carotid endarterectomy (CEA) or carotid artery stenting (CAS). The magnitude and clinical relevance of this relationship are debated.

Methods:

We systematically searched PubMed and EMBASE until August 21, 2017. The primary outcome was procedural (30 days, in-hospital, or perioperative) death or stroke. Obtained or estimated risk estimates were pooled with a generic inverse variance random-effects model.

Results:

We included 87 studies. A decreased risk of death or stroke following CEA was found for high compared to low operator volume with a pooled adjusted odds ratio (OR) of 0.50 (95% confidence interval [CI] 0.28–0.87; 3 cohorts), and a pooled unadjusted relative risk (RR) of 0.59 (95% CI 0.42–0.83; 9 cohorts); for high compared to low hospital volume with a pooled adjusted OR of 0.62 (95% CI 0.42–0.90; 5 cohorts), and a pooled unadjusted RR of 0.68 (95% CI 0.51–0.92; 9 cohorts). A decreased risk of death or stroke after CAS was found for high compared to low operator volume with an adjusted OR of 0.43 (95% CI 0.20–0.95; 1 cohort), and an unadjusted RR of 0.50 (95% CI 0.32–0.79; 1 cohort); for high compared to low hospital volume with an adjusted OR of 0.46 (95% CI 0.26–0.80; 1 cohort), and no significant decreased risk in a pooled unadjusted RR of 0.72 (95% CI 0.49–1.06; 2 cohorts).

Conclusions:

We found a decreased risk of procedural death and stroke after CEA and CAS for high operator and high hospital volume, indicating that aiming for a high volume may help to reduce procedural complications.

Registration:

This systematic review has been registered in the international prospective registry of systematic reviews (PROSPERO): CRD42017051491.
Stem Cell Mobilization Is Lifesaving in a Large Animal Preclinical Model of Acute Liver Failure
Authors: Ahmadi Ali R. , Chicco Maria , Wesson Russell N. , Anders Robert A. , Dor Frank J. M. F. , IJzermans Jan N. M. , Creamer Tyler J. , Williams George M. , Sun Zhaoli , Cameron Andrew M.
Published: August 2018

Introduction:

Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial.

Methods:

Male Yorkshire pigs (14–18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 μg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline.

Results:

All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004).

Conclusions:

Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.
Pure Laparoscopic Donor Hepatectomies
Authors: Samstein Benjamin , Griesemer Adam , Halazun Karim , Kato Tomoaki , Guarrera James V. , Cherqui Daniel , Emond Jean C.
Published: August 2018

Objective:

In order to minimize the impact of donation, fully laparoscopic donor hepatectomy (LDH) is being investigated at a few centers throughout the world. We report here our experience with 51 living donor pure laparoscopic hepatectomies.

Background:

Adoption of minimal access techniques to living donor liver transplantation (LDLT) has been slowed by concerns about donor safety and the quality of the grafts.

Methods:

Of 344 donor hepatectomies (DHs) for living donor liver transplantation (LDLT) since 1998, 51 pure LDH have been performed since 2009. We report here our experience with 51 living donor pure laparoscopic hepatectomy (LH), based on prospectively collected data. There were 31 left lateral sectionectomy and 20 full lobectomies LH. We matched full lobe LH to open DH prior to introduction of LH.

Results:

LH increased from 21% of all DH in first 5 years of performing LH to 45% of DH in the most recent 3 years. Laparoscopic donors were more likely female, had lower body mass index, smaller total livers, and smaller allografts but longer operating room times. In the total LD experience, total 5 donors were converted to open surgery (10%), 2 donors required transfusion (4%), and there was 2 donor bile leaks (4%). Recipient patient and graft 1-year survival was 98% and 94%.

Conclusions:

Our experience indicates that LDH for LDLT can be safely used with appropriate attention to learning curve and progression from left lateral sectionectomy to right hepatectomy.
Propensity Score–Matched Analysis Comparing Minimally Invasive Ivor Lewis Versus Minimally Invasive Mckeown Esophagectomy
Authors: van Workum Frans , Slaman Annelijn E. , van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Kouwenhoven Ewout A. , van Det Marc J. , van den Wildenberg Frits J. H. , Polat Fatih , Luyer Misha D. P. , Nieuwenhuijzen Grard A. P. , Rosman Camiel
Published: August 2018

Introduction:

Totally minimally invasive esophagectomy (TMIE) is increasingly used in treatment of patients with esophageal carcinoma. However, it is currently unknown if McKeown TMIE or Ivor Lewis TMIE should be preferred for patients in whom both procedures are oncologically feasible.

Methods:

The study was performed in 4 high-volume Dutch esophageal cancer centers between November 2009 and April 2017. Prospectively collected data from consecutive patients with esophageal cancer localized in the distal esophagus or gastroesophageal junction undergoing McKeown TMIE or Ivor Lewis TMIE were included. Patients were propensity score matched for age, body mass index, sex, American Society of Anesthesiologists classification, Charlson Comorbidity Index, tumor type, tumor location, clinical stage, neoadjuvant treatment, and the hospital of surgery. The primary outcome parameter was anastomotic leakage requiring reintervention or reoperation. Secondary outcome parameters were operation characteristics, pathology results, complications, reinterventions, reoperations, length of stay, and mortality.

Results:

Of all 787 included patients, 420 remained after matching. The incidence of anastomotic leakage requiring reintervention or reoperation was 23.3% after McKeown TMIE versus 12.4% after Ivor Lewis TMIE (P = 0.003). Ivor Lewis TMIE was significantly associated with a lower incidence of pulmonary complications (46.7% vs 31.9%), recurrent laryngeal nerve palsy (9.5% vs 0.5%), reoperations (18.6% vs 11.0%), 90-day mortality (7.1% vs 2.9%), shorter median intensive care unit length of stay (2 days vs 1 day) and shorter median hospital length of stay (12 vs 11 days) (all P < 0.05). R0 resection rate was similar between the groups. The median number of examined lymph nodes was 21 after McKeown TMIE and 25 after Ivor Lewis TMIE (P < 0.001).

Conclusions:

Ivor Lewis TMIE is associated with a lower incidence of anastomotic leakage, 90-day mortality and other postoperative morbidity compared to McKeown TMIE in patients in whom both procedures are oncologically feasible.
Gastric Bypass Surgery Reduces De Novo Cases of Type 2 Diabetes to Population Levels
Authors: Backman Olof , Bruze Gustaf , Näslund Ingmar , Ottosson Johan , Marsk Richard , Neovius Martin , Näslund Erik
Published: August 2018

Objective:

The aim of this study was to determine long-term changes in pharmacological treatment of type 2 diabetes after primary Roux-en-Y gastric bypass (RYGB) surgery, in patients with and without pharmacological treatment of diabetes preoperatively.

Summary of Background Data:

Several studies have shown that gastric bypass has good effect on diabetes, at least in the short-term. This study is a nationwide cohort study using Swedish registers, with basically no patients lost to follow-up during up to 7 years after surgery.

Methods:

The effect of RYGB on type 2 diabetes drug treatment was evaluated in this nationwide matched cohort study. Participants were 22,047 adults with BMI ≥30 identified in the nationwide Scandinavian Surgical Obesity Registry, who underwent primary RYGB between 2007 and 2012. For each individual, up to 10 general population comparators were matched on birth year, sex, and place of residence. Prescription data were retrieved from the nationwide Swedish Prescribed Drug Register through September 2015. Incident use of pharmacological treatment was analyzed using Cox regression.

Results:

Sixty-seven percent of patients with pharmacological treatment of type 2 diabetes before surgery were not using diabetes drugs 2 years after surgery and 61% of patients were not pharmacologically treated up to 7 years after surgery. In patients not using diabetes drugs at baseline, there were 189 new cases of pharmacological treatment of type 2 diabetes in the surgery group and 2319 in the matched general population comparators during a median follow-up of 4.6 years (incidence: 21.4 vs 27.9 per 10,000 person-years; adjusted hazard ratio 0.77, 95% confidence interval 0.67–0.89; P < 0.001).

Conclusions:

Gastric bypass surgery not only induces remission of pharmacological treatment of type 2 diabetes but also protects from new onset of pharmacological diabetes treatment. The effect seems to persist in most, but not all, patients over 7 years of follow-up.
Genomic landscape and chronological reconstruction of driver events in multiple myeloma
Authors: Maura Francesco , Bolli Niccoló , Angelopoulos Nicos , Dawson Kevin J. , Leongamornlert Daniel , Martincorena Inigo , Mitchell Thomas J. , Fullam Anthony , Gonzalez Santiago , Szalat Raphael , Rodriguez-Martin Bernardo , Samur Mehmet Kemal , Glodzik Dominik , Roncador Marco , Fulciniti Mariateresa , Tai Yu Tzu , Minvielle Stephane , Magrangeas Florence , Moreau Philippe , Corradini Paolo , Anderson Kenneth C. , Tubio Jose M. C. , Wedge David C. , Gerstung Moritz , Avet-Loiseau Herve , Munshi Nikhil , Campbell Peter J.
Published: August 2018

Multiple myeloma (MM) has a heterogeneous genome, evolving through both pre-clinical and post-diagnosis phases. Here, using sequences from 67 MM genomes serially collected from 30 patients together with public datasets, we establish a hierarchy of driver lesions. Point mutations, structural variants and copy number aberrations define at least 7 genomic subgroups of MM, each with distinct sets of co-operating driver mutations. Complex structural events are major drivers of MM, including chromothripsis, chromoplexy and a replication-based mechanism of templated insertions: these typically occur early. Hyperdiploidy also occurs early, with individual chromosomes often gained in more than one chronological epoch of MM evolution, showing a preferred order of acquisition. Positively selected point mutations frequently occur in later phases of disease development, as do structural variants involving MYC. Thus, initiating driver events of MM, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of subsequent evolution.
The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens
Authors: Repana Dimitra , Nulsen Joel , Dressler Lisa , Bortolomeazzi Michele , Venkata Santhilata Kuppili , Tourna Aikaterini , Yakovleva Anna , Palmieri Tommaso , Ciccarelli Francesca D.
Published: August 2018

The Network of Cancer Genes (NCG) is a manually curated repository of 2,372 genes whose somatic modifications have a known or predicted cancer driver role. These genes were collected from 275 publications, including two sources of known cancer genes and 273 cancer sequencing screens of 119 cancer types in 31 primary sites from 34,905 cancer donors. This represents a more than 1.5-fold increase in content as compared to the previous version. NCG also annotates properties of cancer genes, such as duplicability, evolutionary origin, RNA and protein expression, miRNA and protein interactions, protein function and essentiality. NCG is accessible athttp://ncg.kcl.ac.uk/.
Large-scale whole-genome sequencing of three diverse Asian populations in Singapore
Authors: Wu Degang , Dou Jinzhuang , Chai Xiaoran , Bellis Claire , Wilm Andreas , Shih Chih Chuan , Soon Wendy Wei Jia , Bertin Nicolas , Khor Chiea Chuen , DeGiorgio Michael , Davila Dominguez Sonia Maria , Tan Patrick , Shabbir Asim , Moh Angela , Tan Eng-King , Foo Jia Nee ,   Tan Tock Seng Hospital Healthy Control Workgroup, Foo Roger S. , Lam Carolyn S.P. , Richards A. Mark , Cheng Ching-Yu , Aung Tin , Wong Tien Yin , Liu Jianjun , Wang Chaolong ,   on behalf of the SG10K Consortium
Published: August 2018

Asian populations are currently underrepresented in human genetics research. Here we present whole-genome sequencing data of 4,810 Singaporeans from three diverse ethnic groups: 2,780 Chinese, 903 Malays, and 1,127 Indians. Despite a medium depth of 13.7×, we achieved essentially perfect (>99.8%) sensitivity and accuracy for detecting common variants and good sensitivity (>89%) for detecting extremely rare variants with <0.1% allele frequency. We found 89.2 million single-nucleotide polymorphisms (SNPs) and 9.1 million small insertions and deletions (INDELs), more than half of which have not been cataloged in dbSNP. In particular, we found 126 common deleterious mutations (MAF>0.01) that were absent in the existing public databases, highlighting the importance of local population reference for genetic diagnosis. We describe fine-scale genetic structure of Singapore populations and their relationship to worldwide populations from the 1000 Genomes Project. In addition to revealing noticeable amounts of admixture among three Singapore populations and a Malay-related novel ancestry component that has not been captured by the 1000 Genomes Project, our analysis also identified some fine-scale features of genetic structure consistent with two waves of prehistoric migration from south China to Southeast Asia. Finally, we demonstrate that our data can substantially improve genotype imputation not only for Singapore populations, but also for populations across Asia and Oceania. These results highlight the genetic diversity in Singapore and the potential impacts of our data as a resource to empower human genetics discovery in a broad geographic region.