Κυριακή 26 Μαΐου 2019

Foam and liquid Bleomycin in the Management of Venous Malformations in Head and Neck Region

Publication date: Available online 22 May 2019

Source: Journal of Plastic, Reconstructive & Aesthetic Surgery

Author(s): Hesham A. Helal, Nada A. Mahmoud

Abstract
Background

Many treatment options for venous malformations (VMs) have been documented in the literature but injection sclerotherapy has been considered a current mainstay for their treatment. We conducted this study to determine the efficacy and durability of injection of different forms of bleomycin sclerotherapy in the treatment of VMs in cervico-facial region

Patients and Methods

Thirty patients with clinically diagnosed venous malformations of the head and neck region, confirmed by magnetic resonance imaging, had been injected with bleomycin sclerosing material. They were divided into 2 groups according to the form of bleomycin injected; Group A: foam form was injected and Group B: liquid form was injected. Patients' data, anatomical sites, type and volume of the VM, number of injection sessions and the average dose of injected agents were documented and statistically compared between the 2 groups.

Results

MRI imaging showed a decline of more than 90% from the initial size of the lesions in 66.7% of the cases and considerable decline (60%-90%) in 33.3% of the cases. In group A the number of sessions and the amount of sclerosant material injected were lower than that in group B. The cumulative dose in the equal size lesions was lower in the foam form than in the liquid form.

Conclusion

We recommend using bleomycin in its foam form on a greater number of patients with larger venous malformations and in different sites as in this form the results are more promising than in the liquid form.

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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

CLINICAL THYROIDOLOGY FOR THE PUBLIC A publication of the American Thyroid Association Summaries for the Public from recent articles in Clinical Thyroidology

IODINE DEFICIENCY
Iodine content is low or absent in some US multivitamin and prenatal vitamin brands

CTFP Volume 12 Issue 5


BACKGROUND
Iodine is essential for the production of thyroid hormone and for normal development of the baby during pregnancy. During pregnancy and breastfeeding there is an increased requirement for iodine both because of a need for higher thyroid hormone production and for secretion of iodine into breast milk. Many studies have shown that iodine deficiency has been associated with adverse effects in babies and infants that range from severe mental retardation to mild brain deficits. Therefore, organizations such as the American Thyroid Association and the American Academy of Pediatrics have recommended that women who are planning a pregnancy, are pregnant or are breastfeeding should ingest a daily supplement that contains 150 mcgs of iodine.

In the US, it has been challenging to identify the sources of dietary iodine, because most food packaging does not detail their contents for this element. Dairy products and seafood are two important sources, but the consumption of these two types of foods is highly variable across the US population. Although in many regions of the world, universal salt iodization has been successful in preventing iodine deficiency, iodization of salt has never been mandated in the US. Currently, only 53% of salt sold for use in homes contains iodine and salt used in processed foods typically is not iodized.

Due to the variable intake of iodine content in food sources and different types of diets followed by the US population, there is concern that some groups of people are at risk for iodine deficiency. Specifically, mild iodine deficiency has been recently documented to be present among pregnant US women. The importance of multivitamin supplements as a source of iodine for pregnant and non-pregnant US adults is not well understood. A study reviewing the use of multivitamin supplements in the US and Canada reported that supplement use ranged from 7% to 85%, showing how difficult it is to accurately determine the extent of multivitamin use. In addition, it has been reported that only 60% of the different types of prenatal multivitamin supplements marketed in the US list iodine among the ingredients. It also has been shown that iodine content is the most variable and least accurately labeled nutrient contained in US adult multivitamins.

This study aimed to assess whether multivitamins are a significant source of iodine in nonpregnant and pregnant adults by looking at the iodine content reported in the most frequently purchased US adult and prenatal multivitamin preparations, knowing how many purchases for these supplements were made over the course of one year.




THYROID AND PREGNANCY
Pregnancy and perinatal outcome among hypothyroid mothers





BACKGROUND
Hypothyroidism is common in women of reproductive age. About 1% of women will have known hypothyroidism before getting pregnant and another 0.5% of women will be diagnosed with hypothyroidism during pregnancy. Overt hypothyroidism (low T4 and high TSH) has known adverse effects on pregnancy outcome including a higher risk of miscarriage and lower IQ in offspring. The effect of less severe hypothyroidism (high TSH but normal T4, subclinical hypothyroidism) varies with some studies, but not all, showing increased rates of caesarean section, labor induction and ICU admission of the babies. This study took advantage of national registries in Finland where nearly all women receive free maternity care and deliver at national hospitals and data is collected. The goal of the study was to look at pregnancy complications in a large group of patients and evaluate whether consistent use of thyroid hormone in hypothyroid mothers effected the outcomes.

THE FULL ARTICLE TITLE:
Turunen S et al Pregnancy and perinatal outcome among hypothyroid mothers: a population-based cohort study. Thyroid 2019 29:135–141

SUMMARY OF THE STUDY
The investigators studied all pregnancies with a single baby in Finland from 2004-2013. There were 16,364 mothers with a diagnosis of hypothyroidism and 550,860 mothers who were not hypothyroid. They used the extensive Finnish Medical Birth Registry that collects data on mothers and newborns within 7 days of delivery, the Finnish Malformation Registry to identify congenital malformations and the Prescription Register to track thyroid hormone use. Women were considered to be hypothyroid if they had a diagnosis of hypothyroidism or if they purchased thyroid medication within 3 mo prior to pregnancy or during pregnancy.


HYPERTHYROIDISM
Treatment of hyperthyroidism resulting in hypothyroidism decreases the risk of heart disease related hospitalization and death risk


BACKGROUND
Hyperthyroidism is a state when the thyroid is overactive and there is too much thyroid hormone in the body. The main cause of hyperthyroidism in the United States is Graves' disease. This is an autoimmune disease where the body makes an antibody that attacks and turns on the thyroid. There are 3 major options for treatment of hyperthyroidism: 1) antithyroid drugs, such as methimazole or PTU, that decrease the thyroid hormone production; 2) surgery to remove the overactive thyroid and 3) radioactive iodine that is taken up by the thyroid and destroys the gland. The most common result of surgery and radioactive iodine therapy is hypothyroidism. Hypothyroidism can also develop if the dose of antithyroid drug is too high.

Thyroid hormone has major effects on the heart. Hyperthyroidism can cause major problems and symptoms such as irregular heart rhythms and palpitations. Rarely, these problems can lead to death. Despite treatment, the negative effects related to hyperthyroidism may persist. This study examined the effect of radioactive iodine therapy and surgery on heart disease related problems, hospitalizations and mortality.

THE FULL ARTICLE TITLE:
Essi et al 2018 Cardiovascular morbidity and mortality after treatment of hyperthyroidism with either radioactive iodine or thyroidectomy. Thyroid 28:1111–1120. Epub 2018 Jul 23.

SUMMARY OF THE STUDY
Two groups of patients who had been treated for hyperthyroidism in Finland from 1986 to 2007 were identified from a registry. Patients were treated either with surgery or with radioactive iodine therapy. A control group of Finnish residents was formed by randomly selecting 3 age and sex-matched subjects for each patient from a national population registry. A nationwide database system was used to identify causes of all heart related hospitalizations and death.


HYPOTHYROIDISM
Levothyroxine treatment increases mortality in patients with heart failure


BACKGROUND
Hypothyroidism is a common condition that can affect the entire body and is treated with levothyroxine. It is clear that patients with overt hypothyroidism (high TSH and a low T4) should be treated with levothyroxine. It is less clear if patients with mild hypothyroidism (high TSH, normal T4) benefit from treatment. Finally, patients with thyroid abnormalities due to medical illnesses and not due to problems with the thyroid itself should not be treated.

In terms of heart function, it is well known that overt hypothyroidism has negative effects on the heart function that improve with levothyroxine treatment. However, studies of treating patients with subclinical (mild) hypothyroidism with heart problems have shown controversial results, with some studies suggesting that treating does not provide any benefit to the patient. This is especially true in patients with heart failure. While levothyroxine replacement may improve heart failure, it is possible that in this group it could have harmful effects, especially if the levothyroxine dose is too high. This Danish nationwide study evaluated the long-term effects of levothyroxine therapy in patients with heart failure.

THE FULL ARTICLE TITLE:
Einfeldt MN 2018 Long-term outcome in heart failure patients treated with levothyroxine: an observational nationwide cohort study. J Clin Endocrinol Metab. Epub 2018 Dec 4. PMID: 30517746.

SUMMARY OF THE STUDY
This study used the Danish national registers to identify and collect clinical information for all Danish citizens >18 years of age who were diagnosed with heart failure during a hospital admission between 1997 and 2012. The patients who received levothyroxine treatment were identified from a nationwide database of all claimed prescriptions. The patients were divided in three groups: (1) patients already receiving levothyroxine at the time of the heart failure diagnosis, (2) patients who started levothyroxine treatment after being diagnosed with heart failure and (3) patients with heart failure not treated with levothyroxine The study compared the overall death rate, the heart-specific death rate, the number of heart attacks and the combination of major adverse cardiovascular events (including death, heart attack, and stroke) between these patient groups.



Active surveillance for low risk papillary thyroid cancer can be considered in select patients


BACKGROUND
The number of new thyroid cancer cases has increased over recent years, especially the number of small, low-risk papillary thyroid cancers. It is clear now that treating these small cancers aggressively with surgery results in more potential harm to patients than if the small cancer was simply watched. Because of this, simply watching, known as active surveillance, became a promising alternative to surgery for these low-risk cancers in select patients. Active surveillance involves closely monitoring the thyroid cancer over time, instead of treating it with immediate surgery. Prior studies have shown that active surveillance is safe in papillary thyroid cancers measuring 1 cm or smaller and confined to the thyroid without any lymph node involvement or spread outside of the neck. However, little is known about outcomes of active surveillance for patients with larger cancers measuring 1-2 cm and confined to the thyroid. This study compared outcomes of active surveillance for these patients to this with cancers <1 cm. The authors also examined outcomes of patients who had surgery for these small cancers.

THE FULL ARTICLE TITLE:
Sakai T et al 2019 Active surveillance for T1bN0M0 papillary thyroid carcinoma. Thyroid 29:59–63. Epub 2019 Jan 8. PMID: 30560718.

SUMMARY OF THE STUDY
The study included patients who were followed at the Cancer Institute Hospital in Tokyo, Japan, since 1995. Among 406 patients with papillary thyroid cancer < 1 cm, 360 (89%) underwent active surveillance and 46 (11%) underwent surgery. Among 392 patients with papillary thyroid cancer 1-2 cm, 331 (84%) underwent active surveillance and 61 (16%) underwent surgery.


THYROID CANCER
The TIRADS ultrasound system can decrease unnecessary biopsies of PET-positive thyroid nodules
https://www.thyroid.org/patient-thyroid-information/ct-for-patients/may-2019/vol-12-issue-5-p-13-14/

BACKGROUND
PET scanning is a type of imaging commonly used to locate areas of cancer in the human body. This is done in patients with a diagnosed cancer to see if it has spread to other parts if the body. This works because cancer cells are more active than normal cells and will take up more of the tracer (18F-FDG) and will light up positive on the PET scan. However, not all areas that are PET-positive are cancer. Some thyroid nodules are PET-positive and occasionally, PET scanning will identify unexpected/ previously undetected thyroid nodules. Up to 1/3 of PET-positive thyroid nodules will end up being thyroid cancer. For this reason, most experts recommend biopsy of these nodules, especially when they are >1 cm in diameter, in order to determine whether or not a thyroid cancer is present. Unfortunately, thyroid biopsy results do not always rule out cancer and, in such cases, thyroid surgery is often needed. This means that some surgically removed thyroid nodules will ultimately be found to be benign (noncancerous).

An important area of research is the development of new technologies that might allow doctors to avoid thyroid surgery (and even thyroid biopsy) for patients having PET-positive thyroid nodules, but for whom these nodules are benign. One such technology is thyroid ultrasound, which can identify thyroid nodule features that may predict the presence of thyroid cancer. Several different systems have been developed for predicting, on the basis of ultrasound findings, whether or not a thyroid cancer is present in a thyroid nodule. One of these systems is called TIRADS. The TIRADS system places thyroid nodules into one of four different categories (2 thorough 5), depending on how many ultrasound features suspicious for thyroid cancer are identified. The greater number of suspicious ultrasound features identified, the higher the probability of thyroid cancer and the higher the TIRADS category (with TIRADS category 5 having the highest risk of cancer and category 2 having the lowest risk). It is important to note that, although thyroid cancer risk does increase as the TIRADS category number increases, the TIRADS system is by no means perfect. A TIRADS 5 category, for example, does not mean a 100% probability of thyroid cancer.


ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182
https://www.thyroid.org/patient-thyroid-information/ct-for-patients/may-2019/vol-12-issue-5-p-11-12/

Allergy and Clinical Immunology

Role of T cells in non-immediate drug allergy reactions
Purpose of review Nonimmediate drug hypersensitivity reactions (NI-DHR) constitute the most complex group of drug allergy, with many drugs involved. Both parent drugs and their reactive metabolites can be implicated. Although with some drugs the number of metabolites is limited, with others it is quite extensive and many still remain to be identified. The diagnostic approaches are insufficient for the diagnosis and realistic approaches that reproduce the pathological response are lacking. Recent findings A wider view has now been considered, with the inclusion of several mechanisms that may contribute to drug hypersensitivity reactions (DHR): the classical hapten hypothesis, the danger signal and the pharmacological interaction. Monitoring the acute response provides relevant information about the mechanisms involved, with the identification of a large number of genes that can be over-expressed or under-expressed in the acute phase of the response. Assessment of risk of developing reactions can be verified by HLA associations. Summary Further knowledge of these NI-DHR, including molecular genetics and transcriptomic analysis, has enabled a better understanding and management of these reactions. Correspondence to E. Gómez, Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Brunngasse, 40. 4153. Reinach. BL., Switzerland. Tel: +41 76 321 40 37; e-mail: enriquegomezalcaide@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Treatable traits in chronic rhinosinusitis with nasal polyps
Purpose of review Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory sinonasal disease that deserves a multidisciplinary precision medicine approach. In a precision medicine model, a more pragmatic approach taking in consideration disease features that are potentially treatable should be considered. Recent findings Several treatable traits in CRSwNP can be identified: from disease-related ones, to extra-ENT features, to behavioral and environmental factors. This review article summarizes primarily the recent findings of CRSwNP-related treatable traits and how they can be modified by given treatments. Summary The advent of biological agents acting directly to the endotype underlying CRSwNP pushes the scientific community to integrate clinical, surgical and immunological evaluations for each single patient; this naturally leads to the identification of specific treatable traits that can serve as possible outcomes for any single biological. Correspondence to Enrico Heffler, Personalized Medicine, Asthma and Allergy, Humanitas University, Via Rita Levi Montalcini 4; 20089 - Pieve Emanuele, Milan, Italy. Tel: +39 0282247013; e-mail: heffler.enrico@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cutaneous drug hypersensitivity: developments and controversies
Purpose of review Cutaneous drug hypersensitivity reactions (CDHRs) are a complicated area with multiple clinical manifestations and differential diagnoses, requiring differentiated diagnostic measurements and optimized therapeutic management. Recent findings Disseminated CDHRs to classical drugs can be classified by a simple algorithm, whereas chemotherapeuticals or biopharmaceuticals may show drug-specific and atypical clinical presentations. Controversies in drug hypersensitivity diagnosis exist about the benefit and accuracy of in-vitro tests. Although skin tests are the best means of detecting sensitization to drugs, methods have not been sufficiently standardized. The necessity for skin tests before performing drug provocation test (DPT) and of prolonged DPTs is discussed in selected patients. If a suspicion has been documented, β-lactam allergy should be excluded. The standard allergy diagnosis is done by an allergist. In case of urgent need because of an infection and low risk according to history, faster delabeling pathways have been developed. There is weak evidence that patients with mastocytosis may have a slightly increased risk of developing immediate-type drug hypersensitivity; however, if considerations are taken, drugs do not have to be withheld for this patient group. There is particular need for improved diagnostic measurements in patients with drug-induced severe cutaneous adverse reactions (SCARs), both identifying the offending drug and detecting individuals at risk. Further challenges encompass appropriate treatments during the acute as well as chronic phase of SCARs. Summary Recent literature has contributed to our understanding of clinical manifestations and existing controversies and future needs in this area. Correspondence to Knut Brockow, Department of Dermatology and Allergology Biederstein, School of Medicine, Technical University Munich, Biedersteiner Str. 29, 80802 München, Germany. Tel:+ 0049 89 4140 3182; fax+: 0049 89 4140 3127; e-mail: knut.brockow@tum.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

New phenotypes in hypersensitivity reactions to nonsteroidal anti-inflammatory drugs
Purpose of review Nonsteroidal anti-inflammatory drug (NSAID) is one of the most frequently prescribed medications in the medical field, and hypersensitivity to NSAID is a common adverse drug reaction encountered. However, NSAID hypersensitivity presents a variety of symptoms caused by diverse pharmacological and immunological mechanisms. Recent findings Owing to the heterogeneity of the disease, a new concept for the classification of NSAID hypersensitivity has recently been proposed to diagnose and manage NSAID hypersensitivity for personalized treatment. Acute and delayed reactions were distinguished in this classification, and identification of symptoms and speculation of putative mechanisms help physicians make the right diagnosis. NSAID-exacerbated respiratory disease is a noticeable phenotype of NSAID hypersensitivity that involves upper airway comorbidities (chronic rhinosinusitis with nasal polyps) as well as asthmatic features. The cutaneous phenotypes of NSAID hypersensitivity occur, and cross-reactivity with other types of NSAID should be considered in establishing a proper diagnosis. Hypersensitivity to a single NSAID can present urticaria/angioedema and anaphylaxis, in which an IgE-mediated immune response is suggested to be a prime mechanism. Management of NSAID hypersensitivity reactions includes avoidance, pharmacological treatment following standard guidelines, and aspirin desensitization. Summary The classification, diagnosis, and management of NSAID hypersensitivity should be individually reached by identifying its phenotype. Correspondence to Hae-Sim Park, Department of Allergy and Clinical Immunology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea. Tel: +82 31 219 5150; fax: +82 31 219 5154; e-mail: hspark@ajou.ac.kr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Microbiome and skin biology
Purpose of review The skin is home to a diverse milieu of bacteria, fungi, viruses, bacteriophages, and archaeal communities. The application of culture-independent approaches has revolutionized the characterization of the skin microbiome and have revealed a previously underappreciated phylogenetic and functional granularity of skin-associated microbes in both health and disease states. Recent findings The physiology of a given skin-niche drives the site-specific differences in bacterial phyla composition of healthy skin. Changes in the skin microbiome have consistently been associated with atopic dermatitis. In particular, Staphylococcus aureus overgrowth with concomitant decline in Staphylococcus epidermidis is a general feature associated with atopic dermatitis and is not restricted to eczematous lesions. Changes in fungal species are now also being described. Changes in the composition and metabolic activity of the gut microbiota are associated with skin health. Summary We are now beginning to appreciate the intimate and intricate interactions between microbes and skin health. Multiple studies are currently focused on the manipulation of the skin or gut microbiome to explore their therapeutic potential in the prevention and treatment of skin inflammation. Correspondence to Liam O'Mahony, Office 450, 4th Floor Food Science and Technology Building, University College Cork, Cork, Ireland. Tel.: +353 21 4901316;. e-mail: liam.omahony@ucc.ie Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Recombinant allergens for immunotherapy: state of the art
Purpose of review More than 30 years ago, the first molecular structures of allergens were elucidated and defined recombinant allergens became available. We review the state of the art regarding molecular AIT with the goal to understand why progress in this field has been slow, although there is huge potential for treatment and allergen-specific prevention. Recent findings On the basis of allergen structures, several AIT strategies have been developed and were advanced into clinical evaluation. In clinical AIT trials, promising results were obtained with recombinant and synthetic allergen derivatives inducing allergen-specific IgG antibodies, which interfered with allergen recognition by IgE whereas clinical efficacy could not yet be demonstrated for approaches targeting only allergen-specific T-cell responses. Available data suggest that molecular AIT strategies have many advantages over allergen extract-based AIT. Summary Clinical studies indicate that recombinant allergen-based AIT vaccines, which are superior to existing allergen extract-based AIT can be developed for respiratory, food and venom allergy. Allergen-specific preventive strategies based on recombinant allergen-based vaccine approaches and induction of T-cell tolerance are on the horizon and hold promise that allergy can be prevented. However, progress is limited by lack of resources needed for clinical studies, which are necessary for the development of these innovative strategies. Correspondence to Rudolf Valenta, MD, Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel: +43 140400 51080; e-mail: Rudolf.valenta@meduniwien.ac.at Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Use of biologics in chronic sinusitis with nasal polyps
Purpose of review Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory condition with different endotypes between patients from eastern or western countries. Targeted biologics are currently used to treat CRSwNP, but the outcomes widely vary. This review focuses on the present use of biologics for treating CRSwNP. Recent findings Monoclonal biologics have been used as an innovative therapy for multiple allergic diseases and comorbid allergic conditions. Over the past several decades, numerous biomarkers have been investigated and were found to be closely correlated with CRSwNP, improving the understanding of inflammatory patterns and endotype classifications for CRSwNP and prompting discussion regarding the use of biologics in CRSwNP. Efficacies vary in reports of different research groups, but it has been found that patients with TH-2-driven inflammatory patterns respond better to the use of biologics than those with non-TH-2-driven CRSwNP. These findings suggest the importance and urgency of developing criteria for biologics in CRSwNP. Summary Precisely determining patient criteria, identifying treatment biomarkers based on endotyping for CRSwNP and determinations of contraindications for long-term utilization may be useful for optimizing treatment strategies and improving the therapeutic efficacy of biologics to achieve long-term control starting at early stages. Correspondence to Luo Zhang, MD, PhD, Beijing TongRen Hospital, Capital Medical University, No. 1, DongJiaoMinXiang, DongCheng District, Beijing, China. Tel: +86 13910830399; e-mail: dr.luozhang@139.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Therapeutic approach of anaphylaxis
Purpose of review Anaphylaxis is a recognized cause of death in all ages, which requires prompt recognition and treatment. We here propose to review the current and new pharmacological treatment of anaphylaxis in the view of the new knowledge in the field that can support the quality practice and empower allergists and health professionals with new tools that can be used to treat symptoms and prevent anaphylaxis. Recent findings The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and application of precision medicine. Several biologic therapies and new devices are emerging as potential preventive treatment for anaphylaxis. Summary Adrenaline (epinephrine) is still the first-line treatment for any type of anaphylaxis and is recognized as the only medication documented to prevent hospitalizations, hypoxic sequelae and fatalities. β2-adrenergic agonists and glucagon remains as the second-line treatment of anaphylaxis, meanwhile glucocorticoids and antihistamines should be used only as third-line treatment. Their administration should never delay adrenaline injection in anaphylaxis. More intuitive adrenaline autoinjectors design and features are required as well as a worldwide availability of adrenaline autoinjectors. Biological drugs, such as omalizumab, have been used as therapeutic adjuvants as a preventive treatment of anaphylaxis, but cost-effectiveness should be considered individually. Understanding the specifications of underlying mechanisms can potentially support improvements in the patients' allergological work-up and open the opportunity of developments of potential new drugs, such as biological agents. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among healthcare providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality. Correspondence to Luciana Kase Tanno, MD, PhD, Department of Pulmonology, Division of Allergy, Hôpital Arnaud de Villeneuve, University Hospital of Montpellier, 371, av. du Doyen Gaston Giraud 34295, Montpellier Cedex 5, France. Tel: +33 467336107; fax: +33 467633645; e-mail: luciana.tanno@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Eosinophilic esophagitis during sublingual and oral allergen immunotherapy
Purpose of review The aim of this review is to discuss the current evidence regarding the development of eosinophilic esophagitis (EoE) in individuals undergoing oral and sublingual immunotherapy (SLIT) for both food and environmental allergens. Cumulative incidence of EoE in patients on allergen immunotherapy for peanut, milk, and egg is estimated. Recent findings De novo development of EoE in patients undergoing oral and SLIT has been demonstrated on the scale of case reports and prospective randomized trials. However, few individuals with EoE-like symptoms during immunotherapy undergo endoscopy, and the long-term outcomes of immunotherapy-associated EoE are unknown. Summary Evidence exists to suggest that allergen immunotherapy could place individuals at risk for the development of EoE, the true incidence of which may vary depending on antigen exposure and methods used to define the condition. Correspondence to Jonathan M. Spergel, MD, PhD, Division of Allergy and Immunology, Children's Hospital of Philadelphia, The Wood Building, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA. Tel: +1 215 590 2549; fax: +1 215 590 6849; e-mail: spergel@email.chop.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.



ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Critical Care Medicine

Impact on Patient Outcomes of Pharmacist Participation in Multidisciplinary Critical Care Teams: A Systematic Review and Meta-Analysis
Objectives: The objective of this systematic review and meta-analysis was to assess the effects of including critical care pharmacists in multidisciplinary ICU teams on clinical outcomes including mortality, ICU length of stay, and adverse drug events. Data Sources: PubMed, EMBASE, and references from previous relevant systematic studies. Study Selection: We included randomized controlled trials and nonrandomized studies that reported clinical outcomes such as mortality, ICU length of stay, and adverse drug events in groups with and without critical care pharmacist interventions. Data Extraction: We extracted study details, patient characteristics, and clinical outcomes. Data Synthesis: From the 4,725 articles identified as potentially eligible, 14 were included in the analysis. Intervention of critical care pharmacists as part of the multidisciplinary ICU team care was significantly associated with the reduced likelihood of mortality (odds ratio, 0.78; 95% CI, 0.73–0.83; p < 0.00001) compared with no intervention. The mean difference in ICU length of stay was –1.33 days (95% CI, –1.75 to –0.90 d; p < 0.00001) for mixed ICUs. The reduction of adverse drug event prevalence was also significantly associated with multidisciplinary team care involving pharmacist intervention (odds ratio for preventable and nonpreventable adverse drug events, 0.26; 95% CI, 0.15–0.44; p < 0.00001 and odds ratio, 0.47; 95% CI, 0.28–0.77; p = 0.003, respectively). Conclusions: Including critical care pharmacists in the multidisciplinary ICU team improved patient outcomes including mortality, ICU length of stay in mixed ICUs, and preventable/nonpreventable adverse drug events. Drs. Lee and Ryu contributed equally to this work as co-first authors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by the Korean Hospital Pharmaceutical Education & Research Center (No. KSHPERC-18-01). The authors have disclosed that they have no potential conflicts of interest. For information regarding this article, E-mail: eykimjcb777@cau.ac.kr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Adjusting for Disease Severity Across ICUs in Multicenter Studies
Objectives: To compare methods to adjust for confounding by disease severity during multicenter intervention studies in ICU, when different disease severity measures are collected across centers. Design: In silico simulation study using national registry data. Setting: Twenty mixed ICUs in The Netherlands. Subjects: Fifty-five–thousand six-hundred fifty-five ICU admissions between January 1, 2011, and January 1, 2016. Interventions: None. Measurements and Main Results: To mimic an intervention study with confounding, a fictitious treatment variable was simulated whose effect on the outcome was confounded by Acute Physiology and Chronic Health Evaluation IV predicted mortality (a common measure for disease severity). Diverse, realistic scenarios were investigated where the availability of disease severity measures (i.e., Acute Physiology and Chronic Health Evaluation IV, Acute Physiology and Chronic Health Evaluation II, and Simplified Acute Physiology Score II scores) varied across centers. For each scenario, eight different methods to adjust for confounding were used to obtain an estimate of the (fictitious) treatment effect. These were compared in terms of relative (%) and absolute (odds ratio) bias to a reference scenario where the treatment effect was estimated following correction for the Acute Physiology and Chronic Health Evaluation IV scores from all centers. Complete neglect of differences in disease severity measures across centers resulted in bias ranging from 10.2% to 173.6% across scenarios, and no commonly used methodology—such as two-stage modeling or score standardization—was able to effectively eliminate bias. In scenarios where some of the included centers had (only) Acute Physiology and Chronic Health Evaluation II or Simplified Acute Physiology Score II available (and not Acute Physiology and Chronic Health Evaluation IV), either restriction of the analysis to Acute Physiology and Chronic Health Evaluation IV centers alone or multiple imputation of Acute Physiology and Chronic Health Evaluation IV scores resulted in the least amount of relative bias (0.0% and 5.1% for Acute Physiology and Chronic Health Evaluation II, respectively, and 0.0% and 4.6% for Simplified Acute Physiology Score II, respectively). In scenarios where some centers used Acute Physiology and Chronic Health Evaluation II, regression calibration yielded low relative bias too (relative bias, 12.4%); this was not true if these same centers only had Simplified Acute Physiology Score II available (relative bias, 54.8%). Conclusions: When different disease severity measures are available across centers, the performance of various methods to control for confounding by disease severity may show important differences. When planning multicenter studies, researchers should make contingency plans to limit the use of or properly incorporate different disease measures across centers in the statistical analysis. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Dr. Brakenhoff and Dr. Plantinga contributed equally. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. de Keizer institution received funding from National Intensive Care Evaluation foundation, during the conduct of the study (grants and advisory board member). Dr. Groenwold was supported financially by the Netherlands Organisation for Scientific Research (project 917.16.430). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: N.L.Plantinga@umcutrecht.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Recommendation of New Medical Alarms Based on Audibility, Identifiability, and Detectability in a Randomized, Simulation-Based Study
Objectives: Accurate and timely identification of existing audible medical alarms is not adequate in clinical settings. New alarms that are easily heard, quickly identifiable, and discernable from one another are indicated. The "auditory icons" (brief sounds that serve as metaphors for the events they represent) have been proposed as a replacement to the current international standard. The objective was to identify the best performing icons based on audibility and performance in a simulated clinical environment. Design: Three sets of icon alarms were designed using empirical methods. Subjects participated in a series of clinical simulation experiments that examined the audibility, identification accuracy, and response time of each of these icon alarms. A statistical model that combined the outcomes was used to rank the alarms in overall efficacy. We constructed the "best" and "worst" performing sets based on this ranking and prospectively validated these sets in a subsequent experiment with a new subject sample. Setting: Experiments were conducted in simulated ICU settings at the University of Miami. Subjects: Medical trainees were recruited from a convenience sample of nursing students and anesthesia residents at the institution. Interventions: In Experiment 1 (formative testing), subjects were exposed to one of the three sets of alarms; identical setting and instruments were used throughout. In Experiment 2 (summative testing), subjects were exposed to one of the two sets of alarms, assembled from the best and worst performing alarms from Experiment 1. Measurements and Main Results: For each alarm, we determined the minimum sound level to reach audibility threshold in the presence of background clinical noise, identification accuracy (percentage), and response time (seconds). We enrolled 123 medical trainees and professionals for participation (78 with < 6 yr of training). We identified the best performing icon alarms for each category, which matched or exceeded the other candidate alarms in identification accuracy and response time. Conclusions: We propose a set of eight auditory icon alarms that were selected through formative testing and validated through summative testing for adoption by relevant regulatory bodies and medical device manufacturers. This work was performed at the University of Miami. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http;/journals.lww.com/ccmjournal). Supported, in part, by grant from Association for the Advancement of Medical Instrumentation. Drs. Bennett's, Dudaryk's, Edworthy's, and McNeer's institution received funding from Association for the Advancement of Medical Instrumentation. Dr. Crenshaw disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: mcneer@miami.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

A 360° Rotational Positioning Protocol of Organ Donors May Increase Lungs Available for Transplantation
Objectives: To evaluate the improvement in lung donation and immediate lung function after the implementation of a 360° rotational positioning protocol within an organ procurement organization in the Midwest. Design: Retrospective observational study. Setting: The Midwest Transplant Network from 2005 to 2017. Rotational positioning of donors began in 2008. Subjects: Potential deceased lung donors. Interventions: A 360° rotational protocol. Presence of immediate lung function in recipients, change in PaO2:FIO2 ratio during donor management, initial and final PaO2:FIO2 ratio, and proportion of lungs donated were measured. Outcomes were compared between rotated and nonrotated donors. Measurements and Main Results: A total of 693 donors were analyzed. The proportion of lung donations increased by 10%. The difference between initial PaO2:FIO2 ratio and final PaO2:FIO2 ratio was significantly different between rotated and nonrotated donors (36 ± 116 vs 104 ± 148; p < 0.001). Lungs transplanted from rotated donors had better immediate function than those from nonrotated donors (99.5% vs 68%; p < 0.001). Conclusions: There was a statistically significant increase in lung donations after implementing rotational positioning of deceased donors. Rotational positioning significantly increased the average difference in PaO2:FIO2 ratios. There was also superior lung function in the rotated group. The authors recommend that organ procurement organizations consider adopting a rotational positioning protocol for donors to increase the lungs available for transplantation. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). University of Missouri Kansas City and Midwest Transplant Network are sponsoring institutions. Dr. Whitt received funding from Midwest Transplant Network. Dr. Wilkins disclosed that he is the administrative Medical Director for, and is also a member of, Midwest Transplant Network. The remaining authors have disclosed that they do not have any potential conflicts of interest For information regarding this article, E-mail: mendezmar@umkc.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Clinician Perception of a Machine Learning–Based Early Warning System Designed to Predict Severe Sepsis and Septic Shock
Objective: To assess clinician perceptions of a machine learning–based early warning system to predict severe sepsis and septic shock (Early Warning System 2.0). Design: Prospective observational study. Setting: Tertiary teaching hospital in Philadelphia, PA. Patients: Non-ICU admissions November–December 2016. Interventions: During a 6-week study period conducted 5 months after Early Warning System 2.0 alert implementation, nurses and providers were surveyed twice about their perceptions of the alert's helpfulness and impact on care, first within 6 hours of the alert, and again 48 hours after the alert. Measurements and Main Results: For the 362 alerts triggered, 180 nurses (50% response rate) and 107 providers (30% response rate) completed the first survey. Of these, 43 nurses (24% response rate) and 44 providers (41% response rate) completed the second survey. Few (24% nurses, 13% providers) identified new clinical findings after responding to the alert. Perceptions of the presence of sepsis at the time of alert were discrepant between nurses (13%) and providers (40%). The majority of clinicians reported no change in perception of the patient's risk for sepsis (55% nurses, 62% providers). A third of nurses (30%) but few providers (9%) reported the alert changed management. Almost half of nurses (42%) but less than a fifth of providers (16%) found the alert helpful at 6 hours. Conclusions: In general, clinical perceptions of Early Warning System 2.0 were poor. Nurses and providers differed in their perceptions of sepsis and alert benefits. These findings highlight the challenges of achieving acceptance of predictive and machine learning–based sepsis alerts. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Ginestra, Dr. Schweickert, Ms. Meadows, Mr. Lynch, and Ms. Pavan helped with data collection; Dr. Ginestra helped with analysis and interpretation of the data, and drafting of the article; and all authors helped with conception and design, and critical revision of the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http;/journals.lww.com/ccmjournal). Dr. Umscheid's contribution to this project was supported, in part, by the National Center for Research Resources (grant no: UL1RR024134), which is now at the National Center for Advancing Translational Sciences (grant no: UL1TR000003). Presented as a poster at the 2017 Society of Hospital Medicine Annual Meeting, Las Vegas, NV. Dr. Schweickert has received funding from the American College of Physicians and Arjo. Dr. Umscheid's institution has received funding from the National Institutes of Health, Food and Drug Administration, and Agency for Healthcare Research and Quality Evidence-based Practice Center contracts, and he has received funding from the Patient-Centered Outcomes Research Institute Advisory Panel and Northwell Health (grand rounds honoraria). The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Craig A. Umscheid, MD, MS, Office of Clinical Excellence, University of Chicago Medicine, American School Building, 850 E. 58th Street, Suite 123, Office 128, MC 1135, Chicago, IL 60637. E-mail: craigumscheid@medicine.bsd.uchicago.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Calorie Intake During Status Epilepticus and Outcome: A 5-Year Cohort Study
Objectives: Recommendations regarding nutrition during status epilepticus are lacking, and it is unclear whether restriction of calorie intake would result in beneficial effects or potential harm. We thus aimed to investigate associations between daily calorie intake and outcome in adult status epilepticus patients deriving from a 5-year cohort with a systematic and prospective collection of nutritional data. Design: Retrospective observational study. Setting: Medical ICUs at a tertiary academic medical care center. Patients: Consecutive patients with status epilepticus treated at the ICUs from 2012 to 2016 were included. Interventions: None. Measurements and Main Results: All patients with status epilepticus were monitored regarding nutrition support provided according to the guidelines. Relative risks of no return to baseline were estimated by Poisson regression with robust error variance and adjusted for potential confounders. Of 203 patients, 86 (42%) had return to baseline. Metabolic characteristics of patients with and without return to baseline did not differ. Patients without return to baseline received more calories and proteins per status epilepticus day, and increasing nutritional support was associated with ventilator-associated pneumonia (relative risk, 1.19; 95% CI, 1.09–1.28). Multivariable regression analysis revealed significant increases in relative risks for no return to baseline with every percent of days with nutrition (relative risk, 1.35; 95% CI, 1.05–1.74), with every 100 kcal (relative risk, 1.01; 95% CI, 1.002–1.01), and gram of protein intake (relative risk, 1.01; 95% CI, 1.001–1.01) per status epilepticus day, independent of potential confounders (including fatal etiology, duration and severity of status epilepticus, Charlson comorbidity index, and treatment with anesthetics). Conclusions: Our results indicate that increased calorie intake during status epilepticus is independently associated with unfavorable outcome. These findings require further validation and investigations into potential mediators, such as induction of ketogenesis, immunomodulating effects, and/or reduction of ICU-associated complications, such as infections. Drs. Rybitschka and Sutter planned the work, acquired and interpreted the data, and wrote the manuscript. Dr. Semmlack, Mr. Kaplan, Dr. De Marchis, Dr. Rüegg, and Dr. Marsch interpreted the data, revised the manuscript, and substantially contributed to the inaugural draft. All authors approved the final submitted version. Mr. Kaplan has provided unsponsored grand rounds, published books on EEG, status epilepticus, and epilepsy for which he received honoraria, has consulted for Cadwell, has been on the board of the ABCN, ICCN, and the ACNS. Dr. Semmlack disclosed government work. Mr. Kaplan has provided unsponsored grand rounds; published books on electroencephalography (EEG), status epilepticus, and epilepsy for which he received honoraria; has consulted for Cadwell; and has been on the board of the ABCN, ICCN, and the ACNS. Dr. De Marchis is supported by the Swiss National Science Foundation; Science Funds of the University Hospital Basel and University of Basel; Bangerter-Rhyner Foundation; the Swisslife Jubiläumsstiftung for Medical Research; the Swiss Neurological Society; the Fondazione Dr. Ettore Balli; De Quervain research grant; and the Thermo Fisher GmbH. He received travel honoraria by Bayer and speaker honoraria by Medtronic and BMS/Pfizer. Dr. Rüegg received unconditional research grants from UCB-pharma. He received honoraria from serving on the scientific advisory boards of Desitin, Eisai, GlaxoSmithKline (GSK), and UCB-pharma; travel grants from GSK, Janssen-Cilag, and UCB-pharma; and speaker fees from UCB-pharma and from serving as a consultant for Eisai, GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB-pharma. He does not hold any stocks of any pharmaceutical industries or manufacturers of medical devices. He received funding from Sandoz Switzerland; Novartis Oncology, Switzerland; Desitin GmbH, Switzerland; Editor Swiss EEG-Bulletin, support of UCB Switzerland and EGI USA Portland, currently Philips, Eindhoven, The Netherlands; and the Swiss Society of Clinical Neurophysiology and Swiss Neurological Society. He received funding from UCB-pharma, Novartis, and Swiss National Science Foundation Grants: grant number 320030_169379/1 and coapplicant for grants numbers 33CM30_125115/1 and 33CM30_140338/1; he disclosed that he is the president of the Swiss League against Epilepsy (no payments), Editor of EPILEPTOLOGIE (Journal of the Swiss League against Epilepsy) (no payments), and Editor of the Swiss EEG Bulletin (payments from UCB); he received honoraria from serving on the scientific advisory boards of Desitin, Eisai, GSK, and UCB-pharma; travel grants from GSK, Janssen-Cilag, and UCB-pharma; and speaker fees from UCB-pharma. Dr. Sutter received research grants from the Swiss National Foundation (No 320030_169379), the Research Fund of the University Basel, the Scientific Society Basel, and the Bangerter-Rhyner Foundation. He received personal grants from UCB-pharma and holds stocks from Novartis, Roche, and Johnson & Johnson. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at the University Hospital Basel, Basel, Switzerland. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. For information regarding this article, E-mail: raoul.sutter@usb.ch Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Assessing Competence in Central Venous Catheter Placement by Pediatric Critical Care Fellows: A National Survey Study
Objectives: To describe the current approach to initial training, ongoing skill maintenance, and assessment of competence in central venous catheter placement by pediatric critical care medicine fellows, a subset of trainees in whom this skill is required. Design: Cross-sectional internet-based survey with deliberate sampling. Setting: United States pediatric critical care medicine fellowship programs. Subjects: Pediatric critical care medicine program directors of Accreditation Council for Graduate Medical Education-accredited fellowship programs. Interventions: None. Measurements and Main Results: A working group of the Education in Pediatric Intensive Care Investigators research collaborative conducted a national study to assess the degree of standardization of training and competence assessment of central venous catheter placement across pediatric critical care medicine fellowship programs. After piloting, the survey was sent to all program directors (n = 67) of Accreditation Council for Graduate Medical Education-accredited pediatric critical care medicine programs between July 2017 and September 2017. The response rate was 85% (57/67). Although 98% of programs provide formalized central venous catheter placement training for first-year fellows, only 42% of programs provide ongoing maintenance training as part of fellowship. Over half (55%) of programs use a global assessment tool and 33% use a checklist-based tool when evaluating fellow central venous catheter placement competence under direct supervision. Only two programs (4%) currently use an assessment tool previously published and validated by the Education in Pediatric Intensive Care group. A majority (82%) of responding program directors believe that a standardized approach to assessment of central venous catheter competency across programs is important. Conclusions: Despite national mandates for skill competence by many accrediting bodies, no standardized system currently exists across programs for assessing central venous catheter placement. Most pediatric critical care medicine programs use a global assessment and decisions around the ability of a fellow to place a central venous catheter under indirect supervision are largely based upon subjective assessment of performance. Further investigation is needed to determine if this finding is consistent in other specialties/subspecialties, if utilization of standardized assessment methods can improve program directors' abilities to ensure trainee competence in central venous catheter insertion in the setting of variable training approaches, and if these findings are consistent with other procedures across critical care medicine training programs, adult and pediatric. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Supported, in part, by grant from UL1 TR000445 NCATS/NIH (Research Electronic Data Capture [REDCap]). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: boyerd@email.chop.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Epidemiology of Hospital-Onset Versus Community-Onset Sepsis in U.S. Hospitals and Association With Mortality: A Retrospective Analysis Using Electronic Clinical Data
Objectives: Prior studies have reported that hospital-onset sepsis is associated with higher mortality rates than community-onset sepsis. Most studies, however, have used inconsistent case-finding methods and applied limited risk-adjustment for potential confounders. We used consistent sepsis criteria and detailed electronic clinical data to elucidate the epidemiology and mortality associated with hospital-onset sepsis. Design: Retrospective cohort study. Setting: 136 U.S. hospitals in the Cerner HealthFacts dataset. Patients: Adults hospitalized in 2009–2015. Interventions: None. Measurements and Main Results: We identified sepsis using Centers for Disease Control and Prevention Adult Sepsis Event criteria and estimated the risk of in-hospital death for hospital-onset sepsis versus community-onset sepsis using logistic regression models. In patients admitted without community-onset sepsis, we estimated risk of death associated with hospital-onset sepsis using Cox regression models with sepsis as a time-varying covariate. Models were adjusted for baseline characteristics and severity of illness. Among 2.2 million hospitalizations, there were 95,154 sepsis cases: 83,620 (87.9%) community-onset sepsis and 11,534 (12.1%) hospital-onset sepsis (0.5% of hospitalized cohort). Compared to community-onset sepsis, hospital-onset sepsis patients were younger (median 66 vs 68 yr) but had more comorbidities (median Elixhauser score 14 vs 11), higher Sequential Organ Failure Assessment scores (median 4 vs 3), higher ICU admission rates (61% vs 44%), longer hospital length of stay (median 19 vs 8 d), and higher in-hospital mortality (33% vs 17%) (p < 0.001 for all comparisons). On multivariate analysis, hospital-onset sepsis was associated with higher mortality versus community-onset sepsis (odds ratio, 2.1; 95% CI, 2.0–2.2) and patients admitted without sepsis (hazard ratio, 3.0; 95% CI, 2.9–3.2). Conclusions: Hospital-onset sepsis complicated one in 200 hospitalizations and accounted for one in eight sepsis cases, with one in three patients dying in-hospital. Hospital-onset sepsis preferentially afflicted ill patients but even after risk-adjustment, they were twice as likely to die as community-onset sepsis patients; in patients admitted without sepsis, hospital-onset sepsis tripled the risk of death. Hospital-onset sepsis is an important target for surveillance, prevention, and quality improvement initiatives. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). This work was funded by the Centers for Disease Control and Prevention (U54CK000484), the Agency for Healthcare Research and Quality (K08HS025008 to Dr. Rhee), and intramural funds from the National Institutes of Health Clinical Center and National Institute of Allergy and Infectious Diseases (to Dr. Kadri). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, or the National Institutes of Health. Dr. Rhee received support for article research from the Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention (CDC). Drs. Rhee and Klompas received funding from UptoDate. Dr. Fram's institution received funding from Harvard Pilgrim Health Care Institute; he received funding from Commonwealth Informatics; and he disclosed work for hire. Dr. Kadri received support for article research from the National Institutes of Health, and he disclosed government work. Dr. Klompas' institution received funding from the CDC and Massachusetts Department of Public Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: crhee@bwh.harvard.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Frailty and Associated Outcomes and Resource Utilization Among Older ICU Patients With Suspected Infection
Objectives: Suspected infection and sepsis are common conditions seen among older ICU patients. Frailty has prognostic importance among critically ill patients, but its impact on outcomes and resource utilization in older patients with suspected infection is unknown. We sought to evaluate the association between patient frailty (defined as a Clinical Frailty Scale ≥ 5) and outcomes of critically ill patients with suspected infection. We also evaluated the association between frailty and the quick Sequential Organ Failure Assessment score. Design: Analysis of a prospectively collected registry. Setting: Two hospitals within a single tertiary care level hospital system between 2011 and 2016. Patients: We analyzed 1,510 patients 65 years old or older (at the time of ICU admission) and with suspected infection at the time of ICU admission. Of these, 507 (33.6%) were categorized as "frail" (Clinical Frailty Scale ≥ 5). Interventions: None. Measurements and Main Results: The primary outcome was in-hospital mortality. A total of 558 patients (37.0%) died in-hospital. Frailty was associated with increased risk of in-hospital death (adjusted odds ratio, 1.81 [95% CIs, 1.34–2.49]). Frailty was also associated with higher likelihood of discharge to long-term care (adjusted odds ratio, 2.06 [95% CI, 1.50–2.64]) and higher likelihood of readmission within 30 days (adjusted odds ratio, 1.83 [95% CI, 1.38–2.34]). Frail patients had increased ICU resource utilization and total costs. The combination of frailty and quick Sequential Organ Failure Assessment greater than or equal to 2 further increased the risk of death (adjusted odds ratio, 7.54 [95% CI, 5.82–9.90]). Conclusions: The presence of frailty among older ICU patients with suspected infection is associated with increased mortality, discharge to long-term care, hospital readmission, resource utilization, and costs. This work highlights the importance of clinical frailty in risk stratification of older ICU patients with suspected infection. Drs. Fernando, McIsaac, Perry, Rochwerg, Bagshaw, and Kyeremanteng designed the study. Drs. Fernando, Dave, and Kyeremanteng gathered the data. Drs. Fernando, McIsaac, Perry, Rochwerg, Bagshaw, Thavorn, Seely, Forster, Fiest, Tran, Reardon, Tanuseputro, and Kyeremanteng analyzed the data. All authors wrote the manuscript. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/ccmjournal). Dr. Bagshaw is supported by a Canada Research Chair in Critical Care Nephrology. Dr. Seely holds patents related to multiple organ variability analysis and has shares in Therapeutic Monitoring Systems. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sfernando@qmed.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Impact of Structured Pathways for Postcardiac Arrest Care: A Systematic Review and Meta-Analysis
Objectives: Recent research has demonstrated value in selected therapeutic and prognostic interventions delivered to patients following cardiac arrest. The aim of this work was to determine if the implementation of a structured care pathway, which combines different interventions, could improve outcomes in survivors of cardiac arrest. Data Sources: PubMed and review of citations in retrieved articles. Study Selection: Randomized trials and prospective observational studies conducted in adult cardiac arrest patients, which evaluated the impact on outcome of a structured care pathway, defined as an organized set of interventions designed specifically for postcardiac arrest patients. Data Extraction: Data collected included study characteristics and methodologic quality, populations enrolled, interventions that were part of the cardiac arrest structured care pathway, and outcomes. The principal outcome was favorable functional status defined as a Cerebral Performance Category score of 1–2 at or after hospital discharge. Data Synthesis: The systematic search retrieved 481 articles of which nine (total, 1,994 patients) were selected for systematic review, and six (1,422 patients) met criteria for meta-analysis. Interventions in the care pathways included early coronary angiography with or without percutaneous coronary intervention (eight studies), targeted temperature management (nine studies), and protocolized management in the ICU (seven studies). Neurologic prognostication was not a part of any of the structured pathways. Meta-analysis found significantly higher odds of achieving a favorable functional outcome in patients who were treated in a structured care pathway, when compared with standard care (odds ratio, 2.35; 95% CI, 1.46–3.81). Conclusions: Following cardiac arrest, patients treated in a structured care pathway may have a substantially higher likelihood of favorable functional outcome than those who receive standard care. These findings suggest benefit of a highly organized approach to postcardiac arrest care, in which a cluster of evidence-based interventions are delivered by a specialized interdisciplinary team. Given the overall low certainty of evidence, definitive recommendations will need confirmation in additional high-quality studies. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http:/journals.lww.com/ccmjournal). Dr. Storm has a relationship with C. R. Bard GmbH (Wachhausstrasse, Karlsruhe, Germany) by having received honoraria and taking expert witness and with Zoll GmbH (Emil-Hoffmann-Straße, Köln, Germany) by having received honoraria. Dr. Leithner has received honoraria from Bard Medical and Edwards Lifesciences GmbH (Edisonstraße, Unterschleißheim, Germany) for work in a Critical Event Committee. Dr. Krannich has no conflict of interest related to this publication but independent from this publication and the presented topic, however, Dr. Krannich has a financial relationship to Pfizer GmbH (Linkstraße, Berlin, Germany). Dr. Suarez is the Chair of the Data and Safety Monitoring Board of the Impact of Fever Prevention in brain Injured Patients (INTREPID) Study (ClinicalTrials.gov Identifier: NCT02996266) funded by C. R. Bard (Murray Hill, NJ). Dr. Stevens has disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: rstevens@jhmi.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.



ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Genetics and Genomics

Genetic analysis and preimplantation genetic diagnosis of Chinese Marfan syndrome patients

Publication date: Available online 24 May 2019

Source: Journal of Genetics and Genomics

Author(s): Meng Qin, Xiaohui Zhu, Zhe Zhang, Xuemin Li, Zhiqiang Yan, Yuqian Wang, Shuo Guan, Yihua He, Wenxin Zhang, Liying Yan, Jie Qiao, Xu Zhi



mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs

Publication date: Available online 18 May 2019

Source: Journal of Genetics and Genomics

Author(s): Xiaochen Gai, Bufu Tang, Fangming Liu, Yuting Wu, Fang Wang, Yanling Jing, Fuqiang Huang, Di Jin, Ling Wang, Hongbing Zhang

Abstract

Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.



Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development

Publication date: Available online 18 May 2019

Source: Journal of Genetics and Genomics

Author(s): Wenjing Zhao, Jieqiong Tan, Tengfei Zhu, Jianjun Ou, Ying Li, Lu Shen, Huidan Wu, Lin Han, Yanling Liu, Xiangbin Jia, Ting Bai, Honghui Li, Xiaoyan Ke, Jingping Zhao, Xiaobing Zou, Zhengmao Hu, Hui Guo, Kun Xia

Abstract

Excess de novo likely gene-disruptive and missense variants within dozens of genes have been identified in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, many rare inherited missense variants of these high-risk genes have not been thoroughly evaluated. Here, we analyzed the rare missense variant burden of POGZ in a large cohort of ASD patients from the Autism Clinical and Genetic Resources in China (ACGC) and further dissected the functional effect of disease-associated missense variants on neuronal development. Our results showed a significant burden of rare missense variants in ASD patients compared to the control population (P = 4.6×10-5, OR = 3.96), and missense variants in ASD patients showed more severe predicted functional outcomes than those in controls. Furthermore, by leveraging published large-scale sequencing data of neurodevelopmental disorders (NDDs) and sporadic case reports, we identified 8 de novo missense variants of POGZ in NDD patients. Functional analysis revealed that two inherited, but not de novo, missense variants influenced the cellular localization of POGZ and failed to rescue the defects in neurite and dendritic spine development caused by Pogz knockdown. Significantly, L1CAM, an autism candidate gene, is differentially expressed in POGZ knockout cell lines. Reduced expression of L1cam was able to partially rescue the neurite length defects. Our study showed the important roles of rare inherited missense variants of POGZ in ASD risk and neuronal development and identified the potential downstream targets of POGZ, which are important for further molecular mechanism studies.



Ciliopathy-associated proteins are involved in vesicle distribution in sensory cilia

Publication date: Available online 15 May 2019

Source: Journal of Genetics and Genomics

Author(s): Ming Li, Wanzhong He, Wei Li, Guangshuo Ou



HDAC6 regulates lipid droplet turnover in response to nutrient deprivation via p62-mediated selective autophagy

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Yan Yan, Hao Wang, Chuanxian Wei, Yuanhang Xiang, Xuehong Liang, Chung-Weng Phang, Renjie Jiao

Abstract

Autophagy has been evolved as one of the adaptive cellular processes in response to stresses such as nutrient deprivation. Various cellular cargos such as damaged organelles and protein aggregates can be selectively degraded through autophagy. Recently, the lipid storage organelle, lipid droplet (LD), has been reported to be the cargo of starvation-induced autophagy. However, it remains largely unknown how the autophagy machinery recognizes the LDs and whether it can selectively degrade LDs. In this study, we show that Drosophila histone deacetylase 6 (dHDAC6), a key regulator of selective autophagy, is required for the LD turnover in the hepatocyte-like oenocytes in response to starvation. HDAC6 regulates LD turnover via p62/SQSTM1 (sequestosome 1)-mediated aggresome formation, suggesting that the selective autophagy machinery is required for LD recognition and degradation. Furthermore, our results show that the loss of dHDAC6 causes steatosis in response to starvation. Our findings suggest that there is a potential link between selective autophagy and susceptible predisposition to lipid metabolism associated diseases in stress conditions.



Understanding the importance of autophagy in human diseases using Drosophila

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Arindam Bhattacharjee, Áron Szabó, Tamás Csizmadia, Hajnalka Laczkó-Dobos, Gábor Juhász

Abstract

Autophagy is a lysosome-dependent intracellular degradation pathway that has been implicated in the pathogenesis of various human diseases, either positively or negatively impacting disease outcomes depending on the specific context. The majority of medical conditions including cancer, neurodegenerative diseases, infections and immune system disorders and inflammatory bowel disease could probably benefit from therapeutic modulation of the autophagy machinery. Drosophila represents an excellent model animal to study disease mechanisms thanks to its sophisticated genetic toolkit, and the conservation of human disease genes and autophagic processes. Here, we provide an overview of the various autophagy pathways observed both in flies and human cells (macroautophagy, microautophagy and chaperone-mediated autophagy), and discuss Drosophila models of the above-mentioned diseases where fly research has already helped to understand how defects in autophagy genes and pathways contribute to the relevant pathomechanisms.



Understanding human diseases using Drosophila

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Jun-Yuan Ji, Chun Han, Wu-Min Deng



Perspectives on gene expression regulation techniques in Drosophila

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Rong-Gang Xu, Xia Wang, Da Shen, Jin Sun, Huan-Huan Qiao, Fang Wang, Lu-Ping Liu, Jian-Quan Ni

Abstract

Gene expression regulation, including loss-of-function and gain-of-function assays, is a powerful method to study developmental and disease mechanisms. Drosophila melanogaster is an ideal model system particularly well-equipped with many genetic tools. In this review, we describe and discuss the gene expression regulation techniques recently developed and their applications, including the CRISPR/Cas9-triggered heritable mutation system, CRISPR/dCas9-based transcriptional activation (CRISPRa) system, and CRISPR/dCas9-based transcriptional repression (CRISPRi) system, as well as the next-generation transgenic RNAi system. The main purpose of this review is to provide the fly research community with an updated summary of newly developed gene expression regulation techniques and help the community to select appropriate methods and optimize the research strategy.



Lipid storage regulator CdsA is essential for Drosophila metamorphosis

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Yuan Liu, Yuan Ji, Xia Li, Guanghou Shui, Xun Huang



Human mitochondrial DNA diseases and Drosophila models

Publication date: 20 April 2019

Source: Journal of Genetics and Genomics, Volume 46, Issue 4

Author(s): Zhe Chen, Fan Zhang, Hong Xu

Abstract

Mutations that disrupt the mitochondrial genome cause a number of human diseases whose phenotypic presentation varies widely among tissues and individuals. This variability owes in part to the unconventional genetics of mitochondrial DNA (mtDNA), which includes polyploidy, maternal inheritance and dependence on nuclear-encoded factors. The recent development of genetic tools for manipulating mitochondrial genome in Drosophila melanogaster renders this powerful model organism an attractive alternative to mammalian systems for understanding mtDNA-related diseases. In this review, we summarize mtDNA genetics and human mtDNA-related diseases. We highlight existing Drosophila models of mtDNA mutations and discuss their potential use in advancing our knowledge of mitochondrial biology and in modeling human mitochondrial disorders. We also discuss the potential and present challenges of gene therapy for the future treatment of mtDNA diseases.





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