Paediatric Dermatology

Childhood psoriasis: Disease spectrum, comorbidities, and challenges Soumajyoti Sarkar, Sandipan Dhar, Siba P Raychaudhuri Indian Journal of Paediatric Dermatology 2019 20(3):191-198 Psoriasis is a chronic, inflammatory, papulosquamous disorder with a variable clinical spectrum. Although it affects population of all age groups, the significance and negative impact of childhood psoriasis is often neglected worldwide. In nearly one-third of the psoriatic population, psoriasis appears during the childhood. In this article, we have focused on different issues and challenges faced during the management of childhood psoriasis. In addition to the varied clinical spectrum and associated comorbidities, in this article, we have given emphasis on the following real needs for childhood psoriasis: (i) psychological and social effects on the affected children, (ii) impact on their family members, and (iii) early diagnosis and management of psoriasis on children with psoriasis. We have concluded the article with the “concept of total care,” which is a third dimension for the management of psoriasis.

Childhood acanthosis nigricans Anupam Das, Priyankar Misra, Saumya Panda Indian Journal of Paediatric Dermatology 2019 20(3):199-204 Acanthosis nigricans (AN) is a frequently encountered dermatological condition seen commonly in middle aged or elderly, but in the recent times, there has been an increase in the childhood cases, especially in the adolescent age group. AN clinically manifested as dark, velvety, and thickened skin, symmetrically distributed over the neck, axillae, other flexural regions of the body and face. Facial AN, a somewhat recent entity that has been described and significant association with obesity, hyperinsulinemia, and metabolic syndrome, has been established. AN was once considered a rare paraneoplastic dermatosis but is now frequently observed in obese adolescents. Obesity in adolescence is a public health priority because it usually tracks into adulthood, resulting in enormous medical and social costs. This underscores the importance of early identification and intervention. The purpose of this narrative review is to provide a comprehensive overview of AN in childhood, including history, definition, classification, its clinical significance, management challenges, and the direction of future research.

Contact dermatitis in pediatric age group: Indian scenario Yasmeen Jabeen Bhat, Saniya Akhtar, Iffat Hassan Indian Journal of Paediatric Dermatology 2019 20(3):205-211 Contact dermatitis was previously considered to be rare in children except some forms of irritant contact dermatitis which were seen commonly in children. However, nowadays, there are an increasing number of cases of allergic contact dermatitis (ACD) being reported in children due to increased exposure to a variety of allergens at an earlier age. Various predisposing factors which influence the occurrence of contact dermatitis include age, sex, atopy, and presence of any concomitant skin disease. Nickel has been identified as leading cause of ACD in children. Other common allergens reported are cobalt, fragrance mix, rubber, lanolin, thiomersal, neomycin, gold, mercapto mix, balsam of Peru, and colophony. Clinical presentation in children is similar to that in adults with eczema of the hands, feet, wrists, face, forehead, scalp, eyelids, earlobes, neck, axilla, trunk, thighs, and anogenital area being seen. Disseminated lesions can as well be seen. When ACD is suspected, patch testing is the gold standard diagnostic procedure. However, patch testing in children differs from adults as some technical difficulties are encountered in children due to their smaller test area and frequent movements. However, the general opinion stands that children can be patch tested with the same methods and patch test concentrations as adults. For the prevention of recurrence, allergen elimination should be the aim of treatment; however, in many cases, it is not possible to completely eliminate the allergen from the patients environment. Topical steroids and calcineurin inhibitors form the mainstay of treatment in most cases.

Clinical spectrum of dermatological disorders in children referred from pediatrics department Taru Garg, Riaz Ahmed, Srikanta Basu, Ram Chander Indian Journal of Paediatric Dermatology 2019 20(3):212-218 Background: Worldwide, limited studies have been done to study the spectrum of dermatological referrals in children. Aims and Objectives: The aim of this study was to analyze the spectrum of dermatological disorders in children referred from pediatrics department. Materials and Methods: It was a hospital-based observational study. Five hundred twenty-five children of either sex or age ≤18 years, in whom, parents had given written informed consent, and referred to Dermatology from Pediatric medicine department were included in this study. The diagnosis was made based on clinical features supported by necessary investigations. Working hours were considered as routine and emergency. Nelson' severity scoring system was used to classify children as sick. Results: Most of the children were referred during routine hours (85.7%), maximally from inpatient department (46%) followed by outpatient department (37%). Most common diagnosis was viral infections (21.2%), closely followed by eczematous disorders (17.6%) and disorders due to arthropods (17.1%). Majority of patients were not sick (83.61%). Pediatricians did not suggest any diagnosis in 70.85% of referrals followed by doubtful diagnosis in 26.85% and definitive diagnosis in 2.28% of patients. Conclusion: Majority of referrals were done during routine hours in nonsick patients. As many common easily treatable dermatoses were observed in all the referrals reiterating the fact that these referrals should be sought as early as possible to prevent unnecessary delays in the diagnosis and patient management. Furthermore, a robust dermatological training should be provided to undergraduates and interns to better equip the nondermatologists to diagnose common dermatological disorders.

Dermoscopy of congenital dermatoses in pediatric age group: An observational study Prachi Chetankumar Gajjar, Hita Hemant Mehta, Mehul Gosai Indian Journal of Paediatric Dermatology 2019 20(3):219-226 Objective: To study dermoscopic (DS) patterns of various congenital dermatologic conditions affecting pediatric age group. Background: DS helps to fill gap between histopathology and gross examination, especially in children as they are noncooperative for invasive procedure. It also helps in early detection of malignant change. Methodology: One hundred and forty-nine children with congenital dermatoses were enrolled in a study conducted from August 2017 to January 2018 in dermatology outpatient department (OPD). After proper history and examination, DS images were captured using DermLite DL IV and stored for analysis. Results: One hundred and forty-nine DS images of 22 congenital dermatoses were studied including 80 males and 69 females. Homogenous pattern (80%) was the most common pattern observed in melanocytic nevi (26). Mongolian spots (25) had greenish hue (100%) on DS. Hemangioma (13) and port wine stains (5) showed cherry red vacuoles and red dots against a pink background, respectively. Criss-cross, rhomboid, and lamellate pattern of scales were observed in DS of congenital ichthyosis (8). We also analyzed DS features of bullous and perforating disorders, syndromes, few rare miscellaneous conditions, and hair disorders. Conclusions: DS is a non-invasive diagnostic tool which enables visualization of deeper structures of the skin which are not seen with naked eyes. Melanocytic nevus, if disorganized, indicates increased risk for melanoma in situ. Pattern of scales on DS helps to classify ichthyosis. Regular brown dots suggest wart-like infection in epidermodysplasia verruciformis. DS of monilethrix and short anagen syndrome helps in differentiating from other hairs shaft disorders. Although time consuming, DS is easy to perform, especially in children and it aids to confirm the diagnosis.

Halo Nevi in children: A separate entity or a sign of vitiligo? N A Bishurul Hafi, Romita Bachaspatimayum, Ronibala Soraisham, N CP Muhammed Indian Journal of Paediatric Dermatology 2019 20(3):227-230 Background: Halo nevi (HN) can present either singly or along with vitiligo. Whether they are different entities, remains debatable. Objectives: The objective of the study is to compare clinicoepidemiologic and laboratory factors associated with HN, HN with vitiligo and vitiligo alone, in children. Methodology: A total of 205 children <18 years who presented to the outpatient department were sampled purposively to three groups: (a) HN without vitiligo, (b) HN with vitiligo, and (c) Vitiligo without HN. Results: There were seven patients in Group A, 11 in Group B, and 187 in Group C. A statistically significant difference was noted between Group B and C in the age of onset (0.004) as well as the age of presentation (0.031). Even though the disease process had started in head-and-neck region in more than half of the patients in each group, HN was present mostly on trunk (90.9%) in Group B and in 28.6% in Group A. No statistically significant difference was noted in associated disorders, personal or family history of autoimmune disorders, koebnerization, leukotrichia, or laboratory tests. Conclusions: Our study, particularly done among pediatric population, has failed to demonstrate much significant differences between HN and vitiligo, except in the age of presentation as well as the age of onset. It further gives proof to substantiate the hypothesis that HN can be a part of clinical spectra of vitiligo.

Evaluation of efficacy and safety of intralesional Measles-Mumps-Rubella virus vaccine for the treatment of common warts in children and adolescents Vikram K Mahajan, Pushpinder Singh Chauhan, Aditi Sharma, Karaninder Singh Mehta, Ritu Rawat, Vikas Sharma Indian Journal of Paediatric Dermatology 2019 20(3):231-235 Background: No single treatment for warts has proven 100% efficacy and most therapeutic modalities remain unsatisfactory. Immunotherapy with Measles-Mumps-Rubella (MMR) vaccine remains underevaluated, especially in children. Objective: To evaluate the efficacy and safety of intralesional MMR vaccine in the treatment of common warts in children. Materials and Methods: Fifty-five (36 boys and 19 girls) children aged 5–18 (mean ± standard deviation 12.8 ± 3.88) years with common warts received 0.25 ml of MMR vaccine injected intralesionally in the largest wart. The dose was repeated at 2-week interval until complete clearance or for a maximum of 5 doses. Thereafter, they were followed up once a month for 24-week study period. The response was evaluated as complete clearance (complete disappearance of the wart(s) including distant ones and appearance of normal skin), partial clearance (≤99% reduction in size and number including distant ones and few residual warts still visible), good response (some reduction in size only including that of distant ones but no decrease in number of warts), or poor response (no change in size and number). Results: Only 46 patients completed the study and 27 (58.7%) of them had complete clearance of warts, 9 (19.6%) showed partial clearance and 10 (21.3%) patients showed no response. In 15 of 27 patients complete clearance was achieved after 5 doses, 7 had complete clearance after 4 doses and 2 patients each showed complete clearance after 2 and 3 doses, respectively. Conclusion: Intralesional MMR vaccine immunotherapy appears promising, effective, and safe treatment for common warts in children with the advantage of single-lesion infiltration, and resolution without scarring or pigmentary changes commonly seen with destructive therapies. However, better designed larger controlled studies are warranted.

A girl with alopecia and skeletal deformities: Satoyoshi syndrome with review of literature Vishalakshi S Pandit, K Udaya Indian Journal of Paediatric Dermatology 2019 20(3):236-239 Satoyoshi syndrome is a rare disease characterized by alopecia, recurrent muscle spasms, diarrhea, and skeletal abnormalities. It is a multisystem disorder of suspected autoimmune etiology. We report a 12-year-old-girl presented with loss of hair from the scalp for 7 years. She had a history of muscle spasms of lower limbs, which used to last for a few minutes; the attacks of spasms were intermittent in nature and involved thigh and calf muscles. She had genu valgum deformity of the right knee and knock-knee gait. Central nervous system examination showed no abnormality. Her laboratory investigations including routine screening and endocrine evaluations were within normal limits, except for microcytic hypochromic anemia. Ultrasonography (USG) abdomen revealed relatively small uterus. X-ray of the right knee showed deformed shape of the epiphysis and dense metaphyseal band of bones. Histopathological examination (HPE) scalp showed noncicatricial alopecia with the absence of functional follicles and dermal lymphocytic infiltration. On the basis of clinical investigations, blood investigations, USG, and radiological findings, diagnosis of SS was made. SS is a sporadic disease with the mean age of onset of the disease being 10 years, but a few adult cases have also been reported. The usual initial symptoms are alopecia and painful muscle spasms. Treatment with oral corticosteroids has shown good response. The case is being presented to create awareness not only among dermatologists but also among pediatricians and orthopedicians about the multisystem involvement and long-term-associated complications and to emphasize the need of early diagnosis and treatment.

Eruptive collagenoma: A rare entity in pediatric age Pratiksha Sonkusale, Sonia Jain, Abhay Deshmukh Indian Journal of Paediatric Dermatology 2019 20(3):240-242 Eruptive collagenoma is a rare acquired connective tissue nevus predominantly composed of collagen, with elusive incidence and etiopathogenesis. Many cases are reported in young adults, but there is a dearth of literature in children. Herein, we report a rare case of eruptive collagenoma in a 5-year-old child who presented with multiple asymptomatic papules, plaques, and nodules over the back and face with no systemic involvement. There was no positive family history or history of consanguineous marriage, and diagnosis was confirmed histopathologically. We report this case due to its rarity in Indian literature in pediatric population with facial involvement.

Rothmund–Thomson syndrome presenting with bullous eruption: A rare case report Akshat Tamta, Jitendra Singh Bist, Gunjan Gupta, Sumeet Pal Saini, Anant Kumar Singh Indian Journal of Paediatric Dermatology 2019 20(3):243-245 Rothmund–Thomson syndrome is a rare, autosomal recessive genodermatosis characterized by an early-onset poikiloderma, skeletal abnormalities, short stature, premature aging, and increased susceptibility to malignancy. We report a case of a 1-year-old male child with bullous lesions and pigmentary changes over the face and extremities. Strict photoprotection and careful surveillance for malignancy forms the mainstay of treatment. The case is being reported due to its rarity and the diagnostic dilemmas associated with it.

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

6948891480

alsfakia@gmail.com

Allergy and Clinical Immunology

Current market trends in anterior ocular inflammatory disease landscape Purpose of review In the US anterior ocular inflammatory disease (AOID) composed of the spectrum of ocular allergies, different forms of infectious conjunctivitis, and dry eye diseases, affects over 40% of the population. This review evaluates the current economic costs for AOID associated pharmacotherapies. Recent findings In recent years, with improved understanding in pathophysiology of the AOID, providing novel targets for pharmacotherapy, have led to considerable improvements in outcomes for patients. Despite these advances, there continues to be a need for interventions that inhibit key inflammatory mediators or pathways in the ophthalmic space. In 2018, AOID drugs market represents ∼40% of the costs for the total ophthalmic drugs: dry eye (43%), antiinfectives (15%), antiallergics (13%), and antiinflammatory agents (29%). With increasing treatment costs, the need for improved, cost-effective modalities persists along with treatment algorithms to derive optimal benefits for patients. Summary There has been a dramatic increase in the economic burden of AOID with the annual expenditure for the prescription drugs approaching close to $11 billion in 2018. With increasing prevalence of ocular disease, further investment is required to provide more effective treatment options and deliver improved public health and economic outcomes. Correspondence to Leonard Bielory, MD, 400 Mountain Avenue, Springfield, New Jersey 07081. E-mail: drlbielory@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Office-based ocular procedures for the allergist Purpose The aim of this study is to suggest principles for ocular procedures to be performed by allergists in their offices in helping their diagnosis of ocular diseases and suggest better interactions between allergists and ophthalmologists. Recent findings Diagnosis of ocular allergy is based on clinical history and signs and symptoms, with the support of in-vivo and in-vitro tests for the identification of the specific allergen. Unfortunately, ocular manifestations are frequently misdiagnosed and not properly managed. Summary A multidisciplinary allergist–ophthalmologist approach may improve early differential diagnosis and the prognosis of patients with allergic disease and conjunctivitis through shared management and earlier etiological treatment. Correspondence to Andrea Leonardi, MD, Department of Neuroscience, Ophthalmology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy. Fax: +39 049 875 5168; e-mail: andrea.leonardi@unipd.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The roles of omega-3 fatty acids and resolvins in allergic conjunctivitis Purpose of review Lipids are one of the most important constituents in our body. Advances of lipidomics are elucidating the new roles of various lipid molecules in allergic diseases. For example, some reports showed anti-inflammatory effects of omega-3 fatty acids (FAs), such as docosahexaenoic acid, eicosapentaenoic acid, and their metabolites, on allergic diseases. Here, we introduce the role of lipid mediators in allergic conjunctivitis mouse model. Recent findings Lipidomics using liquid chromatography–tandem mass spectrometry can profile numerous lipid molecules from small tissue samples such as conjunctival specimens. Lipidomics analysis showed that various inflammatory lipid mediators are produced in the conjunctival tissue of allergic conjunctivitis mouse model. Dietary omega-3 FAs reduced these inflammatory lipid mediators in the conjunctiva and alleviated allergic conjunctivitis symptoms in mouse models. In addition, the roles of specialized proresolving lipid mediators (SPMs) have been reported for allergic inflammation. Summary Lipid mediators have important roles for the pathophysiology of the allergic diseases including allergic conjunctivitis. Omega-3 FAs and SPMs are expected as new treatment tools for allergic conjunctivitis. Correspondence to Akira Matsuda, Laboratory of Ocular Atopic Diseases, Department of Ophthalmology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. Tel: +81 3 5802 1031; fax: +81 3 5802 5889; e-mail: akimatsu@juntendo.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Role of the ocular surface microbiome in allergic disease Purpose of review The purpose of this review is to provide an update regarding new and emerging data on the role of the ocular surface microbiome in allergic disease. Recent findings Recent findings support the role of the microbiome in the pathophysiology of allergic disease of the ocular surface. Summary Understanding the role of the ocular surface microbiome in allergic disease may provide a new target for the development of therapeutic interventions. Correspondence to Kara M. Cavuoto, MD, 900 NW 17th Street, Miami, FL 33136, USA. Tel.: +1 305 326 6324;. fax: +1 305 547 3675; e-mail: kcavuoto@med.miami.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Biologics and anaphylaxis Purpose of review The use of biologicals as therapeutic agents in oncology and other inflammatory diseases has dramatically increased during the last years. Due to their biological nature and inherent immunological activity, they are able to induce important adverse events, such as cytokine release reactions (rapid release of proinflammatory cytokines), serum sickness disease, and immediate or delayed hypersensitivity reactions, including anaphylaxis. The aim of the current article is to review the state of the art of anaphylaxis because of biological agents. Recent findings Different phenotypes, and potential underlying endotypes, have been described in anaphylactic reactions to biologicals. There seems to be a spectrum from type 1 reactions (IgE or non-IgE-mediated) to cytokine release reactions, with some reactions falling in between both. Management should be directed according to such phenotypes. Summary There is ongoing research to further define immediate adverse reactions to biologicals and to find relevant biomarkers to aid in their diagnosis. Such information will serve in defining their immediate and long term management. Correspondence to Victoria Cardona, MD, PhD, Allergy Section, Department of Internal medicine, Hospital Universitari Vall d'Hebron, Ps. Vall d'Hebron 119-129, 08035 Barcelona, Spain. Tel: +34 93 274 6169; e-mail: vcardona@vhebron.net Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Topical tacrolimus for allergic eye diseases Purpose of review The spectrum of allergic eye diseases includes a variety of conditions, each characterized by complex immunopathologies. Antiallergic drugs, such as antihistamines and mast cell stabilizers, are often insufficient without concomitant topical corticosteroid treatment. The chronic course of the more severe allergic eye diseases, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC), limits the treatment with topical corticosteroids to short courses. In addition, topical corticosteroid treatment puts patients at high risk of developing severe ocular complications, particularly during childhood when VKC most frequently occurs. The immunopathology of chronic diseases, such as VKC and AKC, involves predominantly T lymphocytes, and as such, immunomodulators that inhibit T-cell activation seem to be the appropriate treatment for these chronic diseases. In the past years, there is an increased incidence of managing chronic allergic eye diseases with the immunomodulator tacrolimus. The current review presents an update of the recent clinical experience with topical tacrolimus for the management of chronic allergic eye diseases. Recent findings Topical tacrolimus significantly improves the symptoms and signs of the various forms of chronic allergic eye disease. Recent studies also demonstrate the efficacy of low concentrations of topical tacrolimus for VKC. Early medical treatment with topical tacrolimus can also prevent the development of serious ocular complications of VKC, such as shield ulcers or limbal stem cell deficiency. Summary Topical tacrolimus has significantly changed the management approaches in severe and chronic allergic eye diseases and has minimized the need for topical corticosteroids. Correspondence to Abraham Solomon, MD, Cornea & Refractive Surgery Service, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Tel: +972 507874664; e-mail: dr.avi.solomon@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Neurotrophic factors and nerve growth factor in ocular allergy Purpose of review During allergic reaction, nervous and immune systems mutually interact through release of mediators, including neurotrophic factors and nerve growth factor (NGF). These mediators modulate allergic reaction through binding their receptors expressed by immune and structural cells and by stimulating neuropeptide release by nerves. The role of neuropeptides and NGF has been demonstrated in allergic asthma and rhinitis, and, to a lesser extent, in allergic conjunctivitis. The aim of this review are to elucidate the evidence of the role of NGF and neuropeptides in the pathogenesis of allergic conjunctivitis. Recent findings NGF modulates allergic reaction by stimulating release of cytokines, inflammatory mediators and neuropeptides by immune and structural cells and nerve endings at the site of inflammation. Evidence showed that local and systemic NGF levels increase in patients with allergic conjunctivitis, including allergic rhinoconjuncivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis. We recently described an increase of conjunctival p75NTR expression in patients with allergic rhinoconjuncivitis, and an increase of tear levels of NGF after conjunctival provocation test with allergen. Summary NGF modulates ocular allergic reaction. Increasing understanding of the role of neuropeptides in allergic conjunctivitis may pave the way to the development of novel therapeutic approaches and improvement of patients' management. Correspondence to Professor Alessandro Lambiase, Department of Sense Organs, University Sapienza of Rome, Vilae del Policlinico, 155, 00161 Rome, Italy. Tel: +39 064 997 5357; e-mail: alessandro.lambiase@uniroma1.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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

6948891480

alsfakia@gmail.com

Clinical Otolaryngology

The Correlation Analysis of Intralabyrinthine Hemorrhage Magnetic Resonance Imaging with Hearing Loss and Prognosis:A Retrospective Analysis of 207 cases Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

Evolving management strategies in head and neck paragangliomas: A single‐centre experience with 147 patients over a 60‐year period Clinical Otolaryngology, EarlyView.

Functional relevance of Computational Fluid Dynamics in the field of nasal obstruction: a literature review Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

The Management of Suspected or Confirmed Laryngopharyngeal Reflux Patients with recalcitrant Symptoms: A Contemporary Review Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

Large parapharyngeal tumours: Operative technique and Case Series of 17 patients Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

Responsiveness of acoustic rhinometry to septorhinoplasty by comparison to rhinomanometry and subjective instruments Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

CT and clinical prognostic factors in Bell's palsy: a study of 56 cases Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.

Long‐term quality of life and sensory impact of great auricular nerve preservation in parotid surgery as measured with the Parotidectomy Outcome Inventory‐8 Clinical Otolaryngology, EarlyView.

The intra‐operative use of biological products: A multi‐centre regional patient perspective of a potential consenting conundrum Clinical Otolaryngology, EarlyView.

Post‐laryngectomy adjuvant radiotherapy in patients with pharyngocutaneous fistulae: Treatment regimens, outcomes and complications in 67 patients Clinical Otolaryngology, EarlyView.

Psychometric validity of the 22‐item Sinonasal Outcome Test

A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic‐resistant Pseudomonas aeruginosa; a preliminary report of efficacy

Eustachian tube dysfunction: consensus statement on definition, types, clinical presentation and diagnosis

A systematic review and meta‐analysis of the role of positron emission tomography in the follow up of head and neck squamous cell carcinoma following radiotherapy or chemoradiotherapy

Correlation between subjective and objective evaluation of the nasal airway. A systematic review of the highest level of evidence

Endoscopic versus microscopic trans‐sphenoidal pituitary surgery: a systematic review and meta‐analysis

Balloon Eustachian tuboplasty: a retrospective cohort study

A 2013 updated systematic review & meta‐analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti‐inflammatory agents on the risk of bleeding after tonsillectomy

Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999

Scaffolds and biomaterials for tissue engineering: a review of clinical applications

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

6948891480

alsfakia@gmail.com

Oral and Maxillofacial Surgery

Sialadenitis May Be Associated With an Increased Risk for Osteoradionecrosis: A Nationwide Population-Based Cohort Study Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Yi-Fang Huang, Shih-Ping Liu, Chih-Hsin Muo, Chung-Ta Chang, Chun-Hao Tsai, Donald E. Morisky Purpose The impact of sialadenitis on osteoradionecrosis (ORN) is controversial. The aim of this study was to determine the association between sialadenitis and ORN. Materials and Methods Participants were derived from the Taiwanese Longitudinal Health Insurance Database. From January 1, 2000 to December 31, 2008, cases of sialadenitis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 527.2, 527.3, 527.5 to 527.7, 527.9, and 710.2) and ORN (ICD-9-CM codes 526.89, 526.5, 730.0, and 730.1) were identified. Different treatment modalities, including surgery versus medicine, were used to distinguish the severity of sialadenitis. The primary predictor variable was sialadenitis. The secondary predictor variable was severity of sialadenitis. The primary outcome variable was time to developing ORN. Other study variables were grouped for age, gender, risk factor, and medical treatment. Cox proportional hazard regression was used to investigate the associations between sialadenitis and ORN after adjusting for statistical confounders. Results The sample was composed of 47,385 patients with a mean age of 46.6 years (standard deviation, 19.9 yr) and 37.2% were men. Twenty percent had a diagnosis of sialadenitis and 1.13% had a diagnosis of ORN. Sialadenitis was associated with an increased risk of ORN (hazard ratio [HR] = 1.93; 95% confidence interval [CI], 1.61-2.31; P < .0001). After adjustment for confounders, sialadenitis was associated with ORN (multivariable HR = 1.83; 95% CI, 1.52-2.19; P < .0001). Severity of sialadenitis was associated with an increased risk of ORN; risks for ORN were 1.79 (95% CI, 1.49-2.16; P < .0001) and 3.52 (95% CI, 1.67-7.44; P < .001) in patients with mild and serious sialadenitis, respectively, compared with the no-sialadenitis cohort. For the joint effect of ORN between sialadenitis and malignancy type, patients with sialadenitis had 11.6-fold risk for ORN (95% CI, 5.58-23.9) compared with patients without malignancy. Conclusions Sialadenitis markedly increased the risk to develop ORN. The severity of sialadenitis was positively correlated with the incidence of ORN.

News and Announcements Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s):

Deep Parotid Lymph Node Metastasis Is Associated With Recurrence in High-Grade Mucoepidermoid Carcinoma of the Parotid Gland Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Xue Shang, Qigen Fang, Fei Liu, Junfu Wu, Ruihua Luo, Jinxing Qi Purpose The goal of the present study was to assess the association between intraparotid lymph node (IPN) metastasis and prognosis in high-grade mucoepidermoid carcinoma (MEC) of the parotid gland. Patients and Methods Patients with surgically treated primary high-grade MEC of the parotid gland were retrospectively enrolled. The association between IPN metastasis and clinicopathologic variables was analyzed using χ2 tests, and recurrence-free survival (RFS) rate was calculated by the Kaplan-Meier method; independent prognostic factors were evaluated by the Cox proportional hazards method. Results IPN metastasis was noted in 59 patients (48.4%), including 19 cases in the deep lobe and 47 cases in the superficial lobe of the parotid gland. IPN metastasis was statistically related to tumor stage and node stage regardless of the location of the metastasis in the deep or superficial lobe. Patients with superficial and deep lymph node metastasis had a low 5-year RFS rate of 11%. Cox model analysis reported that the status of IPN metastasis was an independent risk factor for recurrence. Conclusions IPN metastasis substantially decreases the RFS rate, especially when there is lymph node metastasis in the deep lobe of the parotid gland.

Management of Mandibular Osteomyelitis With Segmental Resection, Nerve Preservation, and Immediate Reconstruction Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Jeffrey S. Marschall, Robert L. Flint, George M. Kushner, Brian Alpert Purpose The purpose was to present our experience with management of mandibular osteomyelitis with segmental resection, nerve preservation, and immediate reconstruction with nonvascularized bone grafts. Patients and Methods We completed a retrospective analysis of 18 cases overseen by a single practitioner at a university medical center from June 2011 to July 2018. All patients had osteomyelitis and were treated with segmental mandibular resection, inferior alveolar nerve (IAN) preservation, and immediate reconstruction with autogenous bone graft from the tibia. Data obtained from medical records included the chief complaint at initial presentation, resection size, and IAN neurosensory recovery at 6 months, as well as descriptive statistics of the patient cohort. The university institutional review board granted this study exempt status. Results The patient cohort had a mean age of 50.9 years, ranging from 29 to 70 years, and included 11 female and 7 male patients. The mean follow-up time was 15 months. The most common chief complaint at initial presentation was pathologic fracture (39%), followed closely by abscess (33%). The average mandibular resection size of all patients was 8.1 cm (standard deviation [SD], 3.3 cm). The resection size measured 7.1 cm (SD, 2.6 cm) in patients with successful bone grafts (n = 15) and 13.1 cm (SD, 2.0 cm, P = .0016) in those with graft failure (n = 3). IAN neurosensory testing showed that 54% of patients had no meaningful recovery at 6 months, 25% had partial recovery, and 21% had full recovery. Finally, osteomyelitis was eliminated in all patients. Conclusions Segmental mandibular resection is an effective method for eradicating mandibular osteomyelitis. Furthermore, immediate reconstruction via nonvascularized grafts is successful in cases with large defects, with a mean defect size of 7.1 ± 2.6 cm. However, IAN-sparing surgery is not effective for preserving patient IAN function. Taken together, our findings show that mandibular resection with immediate reconstruction is a viable method in the treatment of mandibular osteomyelitis. This method removes infection and shortens the disease course.

Oral Cancer Treatment Through the Ages: Part 2 Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Vahe Petrosyan, Georgina Kane, Phillip Ameerally Purpose Understanding how oral cancer treatment evolved can pave the way for future management. The literature holds an expansive collection of historical findings regarding oral cancer, yet the authors were unable to find a comprehensive review of oral cancer treatment throughout the ages. Materials A thorough literature review was carried out using multiple scientific databases and languages, as well as examination of historical archives. Articles were included for their relevance and their findings were assimilated. Results Part two of this article considers the development of specific surgical concepts relating to head and neck cancer over the previous two centuries, including neck dissection and reconstruction, as well as exploration of non-surgical cancer therapies. Conclusion This paper demonstrates historical landmarks made in oral cancer treatment and the prominent figures who pioneered them, confirming that head and neck cancer surgeons of today have valuable lessons to learn from their previous counterparts.

Oral Cancer Treatment Through the Ages: Part 1 Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Georgina Kane, Vahe Petrosyan, Phillip Ameerally Purpose Understanding how oral cancer treatment evolved can pave the way for future management. The literature holds an expansive collection of historical findings regarding oral cancer, yet the authors were unable to find a comprehensive review of oral cancer treatment throughout the ages. Methods A thorough literature review was carried out using multiple scientific databases and languages, as well as examination of historical archives. Articles were included for their relevance and their findings were assimilated. Results Part one of this article reveals a rich history of oral cancer treatment commencing in ancient times, with discussion of Egyptian, Greek and Roman practices, and travelling through the age of discovery to arrive at the dawn of scientific medicine in the 19th century. Conclusion Part one demonstrates how fundamental concepts of oral cancer were discovered, and the significant impact medical innovation had on the success of oral cancer treatment.

Prognostic Impact of Postoperative Complications on Overall Survival in 287 Patients With Oral Cancer: A Retrospective Single-Institution Study Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Chao Zhang, Meng Ying Xi, Jie Zeng, Yong Li, Cong Yu Purpose To investigate the relation between postoperative complications and long-term survival in patients with oral cancer after surgery and to explore the methods that improve survival rate through analyzing risk factors for postoperative complications. Materials and Methods This is a retrospective single-institution study of a cohort of 287 patients with oral cancer who underwent surgery at the Stomatological Hospital of the Chongqing Medical University (Chongqing, China) from January 1, 2007 through December 31, 2012. Results Postoperative complications occurred in 80 patients (27.9%). Patients with pulmonary complications or delirium had worse overall survival than those without these complications, whereas other postoperative complications, such as surgical site infection, postoperative bleeding, salivary fistula, and chylothorax, were not associated with overall survival. American Society of Anesthesiologists (ASA) status and tracheostomy were risk factors for postoperative pulmonary complications according to the Pearson χ2 test or multivariate analysis. Using the Pearson χ2 test, age, comorbidity, and ASA status were risk factors for the incidence of postoperative delirium. However, in multivariate analysis, only comorbidity and ASA status were identified as risk factors. Conclusions Postoperative pulmonary complications and postoperative delirium could be independent predictors of poorer long-term survival in patients with oral cancer. The risk factors for postoperative pulmonary complications and postoperative delirium could help identify patients who are at high risk and help clinicians take some actions to prevent them.

The Feasibility of Using the Posterior Auricular Branch of the Facial Nerve as a Donor for Facial Nerve Reanimation Procedures: A Cadaveric Study Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Shogo Kikuta, Joe Iwanaga, Koichi Watanabe, Jingo Kusukawa, R. Shane Tubbs Purpose Facial nerve paralysis can result in critical complications, including those to the visual, respiratory, and digestive systems. The facial nerve has been reanimated using various nerves, but the posterior auricular nerve (PAN) branching off the facial nerve has not been explored for this purpose. Materials and Methods Ten sides from 6 fresh-frozen adult cadavers were used for dissection of the PAN to explore its potential as a donor for facial nerve reanimation. The facial nerve trunk (FNT) and PAN were consistently and readily identified by deep dissection using the tragal cartilage and tragal pointer as landmarks. The PAN was transected at the point of insertion of its innervated muscles. Its length and diameter were measured, and it was transposed anteriorly to the FNT and its 2 major extracranial divisions. Results The PAN was observed on all sides. Its available length was 27.11 ± 5.02 mm and its mean diameter was 0.85 ± 0.20 mm. In all specimens, the PAN readily reached the FNT and its 2 major divisions without tension. Conclusion No previous study has explored the use of the PAN as a donor for facial nerve reanimation. Based on the present cadaveric study, surgeons might consider it for this purpose.

Three-Dimensional Evaluation of the Postsurgical Stability of Mandibular Setback With the Surgery-First Approach: Comparison Between Patients With Symmetry and Asymmetry Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): LiJun Sun, Kyung-Min Lee Purpose The purpose of the present study was to evaluate the 3-dimensional postsurgical stability of mandibular setback with a surgery-first (SF) orthodontic treatment approach in patients with skeletal Class III malocclusions and facial asymmetry using cone-beam computed tomographic (CBCT) images. Patients and Methods Thirty-six patients who underwent mandibular setback with an SF approach for the correction of mandibular prognathism were enrolled in the present study. Patients were divided into symmetrical (n = 18) and asymmetrical (n = 18) groups according to their degree of menton deviation. CBCT images were acquired before surgery, 1, 6, and 12 months after surgery, and at the end of treatment. After reorienting of CBCT images using automatic volume-based registration, the position of the mandible at each time point was evaluated relative to its post-treatment position. MATLAB (MathWorks, Natick, MA) was used to represent all sequential changes in postoperative mandibular position. The increase in posterior vertical dimension at surgery was measured and then correlated with postsurgical mandibular stability. Results For up to 6 months after surgery, the position of the mandible differed considerably from its post-treatment position. At 12 months after surgery, the position of the mandible no longer differed substantially from its post-treatment position. The asymmetry group exhibited greater outward displacement of the proximal segment. The symmetrical and asymmetrical groups exhibited a positive correlation between postsurgical mandibular instability and the increase in posterior vertical dimension. Conclusion These results indicate that mandibular position stabilizes 12 months after surgery performed with an SF approach. It is necessary to consider mandibular forward movement from the increase in posterior vertical dimension in surgical occlusion during the treatment planning stage. Moreover, clinicians should maintain the surgical position of proximal segments during postsurgical orthodontic treatment at least until 12 months after surgery.

Maintenance of Segmental Maxillary Expansion: The Use of Custom, Virtually Designed, and Manufactured Palatal Appliances Without the Use of an Occlusal Splint Publication date: July 2019 Source: Journal of Oral and Maxillofacial Surgery, Volume 77, Issue 7 Author(s): Mohammed Ismail, John Wessel, Brian Farrell Expansion of the maxilla using a segmental Le Fort I osteotomy is a routine and commonly used procedure in the treatment of dentofacial deformities. Although orthognathic surgery has seen tremendous advancement in technology, including virtual surgical planning and customized hardware, some room for advancement exists in the maintenance of surgical maxillary expansion. Traditionally, this has been accomplished with retention of a maxillary occlusal splint 4 to 8 weeks postoperatively. This article introduces some novel techniques to help maintain this expansion, including the intraoperative transpalatal archwire and custom palatal strap appliance in conjunction with autogenous bone harvest and grafting in lieu of using occlusal-based splints. The aim of these techniques is to improve postoperative patient comfort and surgical outcomes and shorten postoperative orthodontic treatment time.

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

6948891480

alsfakia@gmail.com

Oral and Maxillofacial Surgery

The Anesthetic Management of a Cardiac Transplant Patient Following Extensive Facial Trauma Caused by a Pit Bull Attack A 72-year-old male cardiac transplant patient presented after sustaining facial and extremity trauma caused by a pit bull dog attack. The case was further complicated by duration of the surgery, bleeding, infection risk, intraoperative hypothermia, immunosuppression, and the risk of sepsis. His anesthetic management required careful coordination with his transplant team. We also sought the expertise of the in-house pharmacist to obtain the appropriate administration strategies for the patient's immunosuppressants.

Alternative Payment Models in Oral and Maxillofacial Surgery: A Proposal for Bundled Payments for Total Joint Replacements Current payment models in oral and maxillofacial surgery (OMS) are categorized as 'fee-for-service', in which clinicians are reimbursed for each service they provide. This reimbursement model may incentivize providing a higher volume of services rather than improve the quality of services provided. While this model is lucrative for many oral and maxillofacial surgeons, both public and private insurance reimbursement have made moves in the last decade towards alternative payment models that incentivize 'value' rather than volume1; however, relatively little research exists in OMS concerning value of services provided.

Lifelong learning A higher order of consciousness and a construct for faculty development Learning is an element of human personal and professional development that occurs throughout life in a variety of informal and formal contexts. Meaning making, a process in which people construct meaning of events and experiences that are part of and shape our existence, represents an informal context of learning in that thinking and reflection is all that is required to accomplish this type of learning. Our meaning making equates to informal learning that develops through a lens in which we create meaning of our experiences.

Maxillomandibular Advancement for Obstructive Sleep Apnea Is Associated with Very Long-term Overall Sleep Related Quality of Life Improvement Statement of the problem: Evaluation of the effect of maxillomandibular advancement (MMA) on long term subjective quality of life (QoL) in obstructive sleep apnea (OSA).

Photobiomodulation Alleviates Post-Operative Discomfort After Mandibular Third Molar Surgery Surgical removal of mandibular third molars is associated with some degree of post operative pain, trismus and facial swelling. The purpose of the study was to evaluate the effect of photobiomodulation in reducing these post-operative side effects following surgical removal of mandibular third molars.

Morpho-Functional Effect Of Stem Cells On The Regeneration Of The Facial Nerve In A Rat Model The aim of the present study was to determine the clinical, histological and histomorphometric influence of stem cells on the regeneration of facial nerves in rats submitted to neurotmesis with five-mm defects.

Medulloblastoma with Metastasis to the Jaw in a Child with Nevoid Basal Cell Carcinoma Syndrome: A Case Report Medulloblastoma is the most common childhood malignant brain tumor and is considered a minor criterion in the diagnosis of nevoid basal cell carcinoma syndrome (NBCCS). Metastasis of this primitive neuroectodermal tumor is commonly neuraxial; however, extra-neuraxial metastasis have been documented in the literature. Extra-neuraxial metastasis to the jaws is a rare occurrence with only eight cases previously described in the literature. This case documents a unique case of metastatic medulloblastoma to the mandible in a patient previously diagnosed with NBCCS.

Types of intermaxillary fixation and their interaction with palatine fracture reduction To compare three types of intermaxillary fixation (IMF) and their behavior when they are subjected to tension forces in 3 study models with a palatine fracture feature.

Which Treatment is Effective for Bruxism: Occlusal Splints or Botulinum Toxin? The aim of this study was to compare the efficacy of an occlusal splint and botulinum toxin for the treatment of bruxism.

Do Winter or Pell & Gregory classification systems indicate the apical position of impacted mandibular third molars? This study investigated the relationship of impacted mandibular third molars to the cortical plates and inferior alveolar canal (IAC) using cone-beam computed tomography (CBCT).

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

6948891480

alsfakia@gmail.com

Andrology

Validation of targeted microsurgical spermatic cord denervation: comparison of outcomes to traditional complete microsurgical spermatic cord denervation Parviz K Kavoussi Asian Journal of Andrology 2019 21(4):319-323 The aim of this study was to validate the effectiveness of targeted microsurgical spermatic cord denervation (MSCD) of the trifecta nerve complex in comparison to traditional full MSCD with complete skeletonization of the spermatic cord in men with chronic orchialgia. Retrospective chart review was performed by a single fellowship-trained microsurgeon between 2011 and 2016. Patients had follow-ups at 6 weeks, 6 months, and 1 year postoperatively. Thirty-nine men with chronic orchialgia underwent full MSCD between 2011 and 2013. In July 2013, after the publication of an anatomic study with identification of Wallerian degeneration of the trifecta nerve complex in men with chronic orchialgia, the technique was changed to targeted MSCD. From July 2013 to March 2016, 43 men underwent targeted MSCD. When comparing the full MSCD group to the targeted MSCD group, there was no significant difference in resolution of pain (66.7% vs 69.8%, P = 0.88), no difference in partial relief of pain (17.9% vs 23.3%, P = 0.55), and no difference in failure to respond rates (15.4% vs 7.0%, P = 0.22) between the two groups. There was no difference in mean change of visual analog pain scale scores between the two groups (P = 0.27). Targeted MSCD had a shorter operative time (53 min vs 21 min, P = 0.0001). Targeted MSCD offers patients comparable outcomes to traditional full MSCD, with a shorter operative time, a less technically challenging surgery, and potentially less risk to cord structures which should be preserved.

Simplifying the ShangRing technique for circumcision in boys and men: use of the no-flip technique with randomization to removal at 7 days versus spontaneous detachment Mark A Barone, Philip S Li, Richard K Lee, Daniel Ouma, Millicent Oundo, Mukhaye Barasa, Jairus Oketch, Patrick Otiende, Nixon Nyangweso, Mary Maina, Nicholas Kiswi, Betty Chirchir, Marc Goldstein, Quentin D Awori Asian Journal of Andrology 2019 21(4):324-331 To assess safety of the no-flip ShangRing male circumcision technique and to determine clinical course and safety of spontaneous detachment (i.e., allowing the device to fall off), we conducted a case series of no-flip ShangRing circumcision combined with a randomized controlled trial of removal 7 days postcircumcision versus spontaneous detachment at two health facilities in Kenya. The primary outcome was the safety of the no-flip technique based on moderate and severe adverse events (AEs) during the procedure and through 42-day follow-up. A main secondary outcome was clinical course and safety of spontaneous detachment. Two hundred and thirty males 10 years and older underwent no-flip circumcision; 114 randomized to 7-day removal and 116 to spontaneous detachment. All circumcisions were successfully completed. Overall 5.3% (6/114) of participants in the 7-day group and 1.7% (2/116) in the spontaneous group had an AE; with no differences when compared to the 3% AE rate in historical data from African studies using the original flip technique (P = 0.07 and P = 0.79, respectively). Overall 72.4% (84/116) of participants in the spontaneous group wore the ShangRing until it detached. Among the remaining (27.6%; 32/116), the ring was removed, primarily at the participants' request, due to pain or discomfort. There was no difference in AE rates (P = 0.169), visit day declared healed (P = 0.324), or satisfaction (P = 0.371) between randomization groups. The median time to detachment was 14.0 (IQR: 7–21, range: 5–35) days. The no-flip technique and spontaneous detachment are safe, effective, and acceptable to boys and men 10 years and older. Phimosis and penile adhesions do not limit successful ShangRing circumcision with the no-flip technique.

Inhibin B: are modified ranges needed for orchiectomised testicular cancer patients? Alessandra Petrozzi, Francesco Pallotti, Marianna Pelloni, Antonella Anzuini, Antonio Francesco Radicioni, Andrea Lenzi, Donatella Paoli, Francesco Lombardo Asian Journal of Andrology 2019 21(4):332-336 Inhibin B is a gonadal hormone that downregulates the pituitary production of follicle-stimulating hormone (FSH). In recent years, inhibin B has proved to be an excellent marker of spermatogenesis and even a predictive factor for the recovery of fertility in patients undergoing orchiectomy and antineoplastic treatments. We propose to study inhibin B levels in orchiectomised testicular cancer patients, in order to identify a minimum value representative of normal semen quality. This retrospective study evaluates hormonal and semen parameters of 290 normozoospermic patients attending the Laboratory of Seminology - Sperm Bank “Loredana Gandini” (Rome, Italy) for cryopreservation of seminal fluid following a diagnosis of testicular cancer (TC group) and 117 healthy, normozoospermic men as a control group (CTR group). The percentile distribution of gonadotropin and inhibin B values in the TC and CTR groups was analyzed. There was a statistically significant difference between the two groups in the levels of all hormones (P ≤ 0.001) and in all semen parameters (P < 0.05). About 20% of TC patients revealed inhibin B levels below the 5th percentile of CTR group, despite normozoospermia, and 31.4% had normal spermatogenesis in the presence of FSH values >95th percentile of CTR group. Orchiectomised patients for testicular cancer presented inhibin B levels lower than healthy patients, despite normozoospermia. Our study revealed the poor sensitivity of the current inhibin B reference range when applied to monorchidic patients, suggesting the need to establish more representative ranges to enable more appropriate counseling in relation to the patient's new endocrine condition.

Protein kinase A inhibition induces EPAC-dependent acrosomal exocytosis in human sperm Diana Itzhakov, Yeshayahu Nitzan, Haim Breitbart Asian Journal of Andrology 2019 21(4):337-344 To interact with the egg, the spermatozoon must undergo several biochemical and motility modifications in the female reproductive tract, collectively called capacitation. Only capacitated sperm can undergo acrosomal exocytosis, near or on the egg, a process that allows the sperm to penetrate and fertilize the egg. In the present study, we investigated the involvement of cyclic adenosine monophosphate (cAMP)-dependent processes on acrosomal exocytosis. Inhibition of protein kinase A (PKA) at the end of capacitation induced acrosomal exocytosis. This process is cAMP-dependent; however, the addition of relatively high concentration of the membrane-permeable 8-bromo-cAMP (8Br-cAMP, 0.1 mmol l−1) analog induced significant inhibition of the acrosomal exocytosis. The induction of acrosomal exocytosis by PKA inhibition was significantly inhibited by an exchange protein directly activated by cAMP (EPAC) ESI09 inhibitor. The EPAC selective substrate activated AE at relatively low concentrations (0.02–0.1 μmol l−1), whereas higher concentrations (>5 μmol l−1) were inhibitory to the AE induced by PKA inhibition. Inhibition of PKA revealed about 50% increase in intracellular cAMP levels, conditions under which EPAC can be activated to induce the AE. Induction of AE by activating the actin severing-protein, gelsolin, which causes F-actin dispersion, was inhibited by the EPAC inhibitor. The AE induced by PKA inhibition was mediated by phospholipase C activity but not by the Ca2+-channel, CatSper. Thus, inhibition of PKA at the end of the capacitation process induced EPAC/phospholipase C-dependent acrosomal exocytosis. EPAC mediates F-actin depolymerization and/or activation of effectors downstream to F-actin breakdown that lead to acrosomal exocytosis.

Strawberry Notch 1 (SBNO1) promotes proliferation of spermatogonial stem cells via the noncanonical Wnt pathway in mice Cong Shen, Jun Yu, Xi Zhang, Chen-Chen Liu, Yue-Shuai Guo, Jia-Wei Zhu, Ke Zhang, Yi Yu, Ting-Ting Gao, Shen-Min Yang, Hong Li, Bo Zheng, Xiao-Yan Huang Asian Journal of Andrology 2019 21(4):345-350 While it is known that spermatogonial stem cells (SSCs) initiate the production of male germ cells, the mechanisms of SSC self-renewal, proliferation, and differentiation remain poorly understood. We have previously identified Strawberry Notch 1 (SBNO1), a vertebrate strawberry notch family protein, in the proteome profile for mouse SSC maturation and differentiation, revealing SBNO1 is associated with neonatal testicular development. To explore further the location and function of SBNO1 in the testes, we performed Sbno1 gene knockdown in mice to study the effects of SBNO1 on neonatal testicular and SSC development. Our results revealed that SBNO1 is required for neonatal testicular and SSC development in mice. Particularly, in vitro Sbno1 gene knockdown with morpholino oligonucleotides caused a reduction of SSCs and inactivation of the noncanonical Wnt pathway, through Jun N-terminal kinases. Our study suggests SBNO1 maintains SSCs by promoting the noncanonical Wnt pathway.

MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing Li Zhang, Yi Liu, Xian-Guo Chen, Yong Zhang, Jing Chen, Zong-Yao Hao, Song Fan, Li-Gang Zhang, He-Xi Du, Chao-Zhao Liang Asian Journal of Andrology 2019 21(4):351-359 MicroRNAs (miRNAs) are considered to be involved in the pathogenic initiation and progression of chronic nonbacterial prostatitis (CNP); however, the comprehensive expression profile of dysregulated miRNAs, relevant signaling pathways, and core machineries in CNP have not been fully elucidated. In the current research, CNP rat models were established through the intraprostatic injection of carrageenan into the prostate. Then, next-generation sequencing was performed to explore the miRNA expression profile in CNP. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) bioinformatical analyses were conducted to reveal the enriched biological processes, molecular functions, and cellular components and signaling pathways. As a result, 1224, 1039, and 1029 known miRNAs were annotated in prostate tissues from the blank control (BC), normal saline injection (NS), and carrageenan injection (CAR) groups (n = 3 for each group), respectively. Among them, 84 miRNAs (CAR vs BC) and 70 miRNAs (CAR vs NS) with significantly different expression levels were identified. Compared with previously reported miRNAs with altered expression in various inflammatory diseases, the majority of deregulated miRNAs in CNP, such as miR-146b-5p, miR-155-5p, miR-150-5p, and miR-139-5p, showed similar expression patterns. Moreover, bioinformatics analyses have enriched mitogen-activated protein kinase (MAPK), cyclic adenosine monophosphate (cAMP), endocytosis, mammalian target of rapamycin (mTOR), and forkhead box O (FoxO) signaling pathways. These pathways were all involved in immune response, which indicates the critical regulatory role of the immune system in CNP initiation and progression. Our investigation has presented a global view of the differentially expressed miRNAs and potential regulatory networks containing their target genes, which may be helpful for identifying the novel mechanisms of miRNAs in immune regulation and effective target-specific theragnosis for CNP.

A novel rat model of seminal vesiculitis Peng Zhang, Xiao-Long Wang, Zhong-Hua Yang, Xin-Jun Su, Xing-Huan Wang Asian Journal of Andrology 2019 21(4):360-364 We aimed to establish a novel rat model of seminal vesiculitis that would provide an effective approach to investigate the pathogenesis of this disease in the future. Eight male rats received the same operation, during which the root of one of the two seminal vesicles was partly ligatured with sutures and the other vesicle was left intact. The samples of seminal vesicles were harvested on the 8th day following the operation. Hematoxylin and eosin and Masson's trichrome stains were used to observe the histopathology and the presence of fibrous tissue in seminal vesicles, respectively. Immunoblotting and immunohistochemistry were applied to determine the tumor necrosis factor-alpha and cyclooxygenase-2 levels in seminal vesicle tissues. Real-time fluorescence quantitative polymerase chain reaction was performed to measure the gene expression levels of proinflammatory cytokines. H2O2levelsin the seminal plasma from the seminal vesicle were also measured. Hematoxylin and eosin staining suggested that there was inflammatory cell infiltration into the seminal vesicles treated by partial root ligation. The tumor necrosis factor-alpha and cyclooxygenase-2 proteins were significantly upregulated in the treated seminal vesicles. The tumor necrosis factor-alpha, cyclooxygenase, interleukin 6, and inducible nitric oxide synthase mRNA expression levels were also upregulated in the treated seminal vesicles. The H2O2 levels in the seminal plasma from seminal vesicles with partial root ligation were significantly elevated compared with those from vesicle left intact. In conclusion, partially ligating the root of the seminal vesicle via sutures in rats is an effective method to establish a seminal vesiculitis rat model.

Regulation of blood-testis barrier dynamics by the mTORC1/rpS6 signaling complex: An in vitro study Lin-Xi Li, Si-Wen Wu, Ming Yan, Qing-Quan Lian, Ren-Shan Ge, C Yan Cheng Asian Journal of Andrology 2019 21(4):365-375 During spermatogenesis, developing germ cells that lack the cellular ultrastructures of filopodia and lamellipodia generally found in migrating cells, such as macrophages and fibroblasts, rely on Sertoli cells to support their transport across the seminiferous epithelium. These include the transport of preleptotene spermatocytes across the blood-testis barrier (BTB), but also the transport of germ cells, in particular developing haploid spermatids, across the seminiferous epithelium, that is to and away from the tubule lumen, depending on the stages of the epithelial cycle. On the other hand, cell junctions at the Sertoli cell–cell and Sertoli–germ cell interface also undergo rapid remodeling, involving disassembly and reassembly of cell junctions, which, in turn, are supported by actin- and microtubule-based cytoskeletal remodeling. Interestingly, the underlying mechanism(s) and the involving biomolecule(s) that regulate or support cytoskeletal remodeling remain largely unknown. Herein, we used an in vitro model of primary Sertoli cell cultures that mimicked the Sertoli BTB in vivo overexpressed with the ribosomal protein S6 (rpS6, the downstream signaling protein of mammalian target of rapamycin complex 1 [mTORC1]) cloned into the mammalian expression vector pCI-neo, namely, quadruple phosphomimetic and constitutively active mutant of rpS6 (pCI-neo/p-rpS6-MT) versus pCI-neo/rpS6-WT (wild-type) and empty vector (pCI-neo/Ctrl) for studies. These findings provide compelling evidence that the mTORC1/rpS6 signal pathway exerted its effects to promote Sertoli cell BTB remodeling. This was mediated through changes in the organization of actin- and microtubule-based cytoskeletons, involving changes in the distribution and/or spatial expression of actin- and microtubule-regulatory proteins.

The relationship between human papillomavirus and penile cancer over the past decade: a systematic review and meta-analysis Yong-Bo Yu, Yong-Hua Wang, Xue-Cheng Yang, Yang Zhao, Mei-Lan Wang, Ye Liang, Hai-Tao Niu Asian Journal of Andrology 2019 21(4):375-380 Human papillomavirus (HPV) infection appears to play an important role in the development of penile cancer (PeCa), but their relationship remains unclear. Therefore, we performed a systematic review and meta-analysis to elucidate their relationship. We systematically searched Embase, PubMed, Cochrane Library, and Web of Science for case-control studies and cross-sectional studies using polymerase chain reaction (PCR) technology on formalin-fixed paraffin-embedded (FFPE) or paraffin-embedded (PE) PeCa tissues to detect HPV (published between January 1, 2007, and December 29, 2017; no language restrictions). Twenty-two studies were identified, and 1664 cases were available for analysis. The combined HPV infectious risk of PeCa is 51.0% (95% confidence interval [CI]: 43.0%–60.0%). The three most common subtypes of HPV were HPV16 (28.5%), HPV18 (2.3%), and HPV6 (2.3%). The virus was relevantly associated with basaloid (85.5%, 95% CI: 77.2%–93.8%) and warty (50.0%, 95% CI: 35.2%–64.8%) carcinomas. The invasiveness of PeCa was not associated with HPV (χ[2] = 0.181, df = 1, P < 0.671). HPV infection in PeCa tended to be moderately differentiated (54.4%, 95% CI: 47.7%–61.1%). This study found that almost half of PeCa patients are associated with HPV. The most commonly associated genotype is HPV16, but several other genotypes were also detected. In addition to types 6 and 11, other single low-risk HPV infections have been found to contribute to PeCa to a lesser degree. HPV-positive tumors tend to exhibit warty and/or basaloid features, corresponding to a moderate histological grade. The role of HPV in PeCa should be revisited to provide evidence for the development of PeCa in the presence of HPV infection.

Tubularized urethral reconstruction using a prevascularized capsular tissue prelaminated with buccal mucosa graft in a rabbit model Hai-Lin Guo, Zhi-Ming Jia, Lin Wang, Xing-Qi Bao, Yi-Chen Huang, Jun-Mei Zhou, Hua Xie, Xiu-Jun Yang, Fang Chen Asian Journal of Andrology 2019 21(4):381-386 Tubularized graft urethroplasty fails largely because of inadequate graft take. Prefabrication of buccal mucosa lined flap has theoretical indications for constructing neourethra with an independent blood supply. The efficacy of using a tissue expander capsule as an induced vascular bed to prefabricate an axial vascularized buccal mucosa-lined flap for tubularized urethral reconstruction in a rabbit model was tested. The experiments were performed in three stages. First, silicone tissue expanders were inserted into the groin to induce vascularized capsule pouch formation. Next, buccal mucosa grafts were transplanted to the newly formed capsular tissue supplied by the axial vessel for buccal mucosa-lined flap prefabrication. Then, circumferential urethral defects were created and repaired by buccal mucosa graft (Group 1), capsule flap (Group 2) and prefabricated capsule buccal mucosa composite flap (Group 3). With retrograde urethrography, no rabbits in Group 1 maintained a wide urethral caliber. In Group 2, the discontinued epithelial layer regenerated at 1 month, and the constructed neourethra narrowed even though the lumen surface formed intact urothelial cells at 3 months. In Group 3, buccal mucosa formed the lining in the neourethra and kept a wide urethral caliber for 3 months. The capsule may serve as an induced vascular bed for buccal mucosa-lined flap prefabrication. The prefabricated buccal mucosa-lined flap may serve as a neourethra flap for circumferential urethral replacement.

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

6948891480

alsfakia@gmail.com

Critical Care Medicine

Quantitative Electroencephalogram Trends Predict Recovery in Hypoxic-Ischemic Encephalopathy Objectives: Electroencephalogram features predict neurologic recovery following cardiac arrest. Recent work has shown that prognostic implications of some key electroencephalogram features change over time. We explore whether time dependence exists for an expanded selection of quantitative electroencephalogram features and whether accounting for this time dependence enables better prognostic predictions. Design: Retrospective. Setting: ICUs at four academic medical centers in the United States. Patients: Comatose patients with acute hypoxic-ischemic encephalopathy. Interventions: None. Measurements and Main Results: We analyzed 12,397 hours of electroencephalogram from 438 subjects. From the electroencephalogram, we extracted 52 features that quantify signal complexity, category, and connectivity. We modeled associations between dichotomized neurologic outcome (good vs poor) and quantitative electroencephalogram features in 12-hour intervals using sequential logistic regression with Elastic Net regularization. We compared a predictive model using time-varying features to a model using time-invariant features and to models based on two prior published approaches. Models were evaluated for their ability to predict binary outcomes using area under the receiver operator curve, model calibration (how closely the predicted probability of good outcomes matches the observed proportion of good outcomes), and sensitivity at several common specificity thresholds of interest. A model using time-dependent features outperformed (area under the receiver operator curve, 0.83 ± 0.08) one trained with time-invariant features (0.79 ± 0.07; p < 0.05) and a random forest approach (0.74 ± 0.13; p < 0.05). The time-sensitive model was also the best-calibrated. Conclusions: The statistical association between quantitative electroencephalogram features and neurologic outcome changed over time, and accounting for these changes improved prognostication performance. Drs. Ghassemi and Amorim contributed equally as co-first authors of this work. The Critical Care Electroencephalogram Monitoring Research Consortium Board consists of: Chair: Brandon M. Westover, MD, PhD; Vice-Chair: Emily Gilmore, MD; Secretary: Aaron Struck, MD; Member-at-Large: Nicholas Gaspard, MD, PhD; Immediate Past Chair: Jong Woo Lee, MD, PhD; and Past Chair: Nicholas S. Abend, MD, MSCE. Drs. Ghassemi, Amorim, Lee, Cash, Brown, Mark, and Westover contributed to conception and design of the study. Drs. Ghassemi, Amorim, and Westover contributed to analysis of data. Drs. Ghassemi, Amorim, and Westover contributed to preparing the figures. Drs. Ghassemi and Amorim, Mr. Al Hanai, Drs. Lee, Herman, Sivaraju, and Gaspard, Mr. Biswal, Mr. Moura Junior, and Dr. Westover contributed to data acquisition. Drs. Ghassemi and Amorim, Mr. Al Hanai, Drs. Lee, Herman, Sivaraju, and Gaspard, Mr. Biswal, Mr. Moura Junior, and Drs. Cash, Brown, Mark, and Westover contributed to drafting the text. 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 grants from National Institutes of Health (NIH) 1R01NS102190, 1R01NS102574, and 1R01NS107291 (to Dr. Westover); R01GM104987 (to Dr. Mark); T32HL007901, T90DA22759, and T32EB001680 (to Dr. Ghassemi); National Institute of Neurological Disorders and Stroke 1K23NS090900 (to Dr. Westover); Salerno foundation (M.G.M.); Neurocritical Care Society research training fellowship and American Heart Association postdoctoral fellowship (to Dr. Amorim); and Andrew David Heitman Neuroendovascular Research Fund and the Rappaport Foundation (to Dr. Westover). Preliminary findings of this study were presented at the 14th Annual Neurocritical Care Society Meeting, National Harbor, MD, September 15–18, 2016. Dr. Amorim's institution received funding from the National Institutes of Health (NIH), Neurocritical Care Society, and American Heart Association. Drs. Amorim, Mark, and Westover received support for article research from the NIH. Dr. Lee received funding from SleepMed/DigiTrace, Advance Medical, and United Diagnostics. Drs. Lee's and Mark's institutions received funding from the NIH. Dr. Herman's institution received funding from UCB Pharma, Sage Therapeutics, Neurospace, Epilepsy Therapy Development Project, Acorda Therapeutics, Pfizer, and Philips. Dr. Hirsch's institution received funding from Upsher-Smith and Monteris. He received funding from Adamas; consultation fees for advising from Aquestive, Ceribell, Eisai, and Medtronic; honoraria for speaking from Neuropace; and royalties for authoring chapters for UpToDate-Neurology and from Wiley for coauthoring a book on electroencephalograms in critical care. Dr. Scirica's institution received funding from Merck, Eisai, and Novartis, and he received consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Covance, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, NovoNordisk, Sanofi, and equity in Health [at] Scale. Dr. Brown's institution received funding from Massachusetts General Hospital and Massachusetts Institute of Technology. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mwestover@mgh.harvard.edu; edilbertoamorim@gmail.com. Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Enablers and Barriers to Implementing ICU Follow-Up Clinics and Peer Support Groups Following Critical Illness: The Thrive Collaboratives Objectives: Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. Design: Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. Setting: Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. Subjects: Clinicians from 21 sites. Measurement and Main Results: Ten enablers and nine barriers to implementation of "ICU follow-up clinics" were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of "peer support groups" were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. Conclusions: Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles. This does not necessarily represent the views of the U.S. government or Department of Veterans Affairs. Drs. Haines, McPeake, Boehm, and Sevin 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. All other authors contributed substantially to the study design, data analysis and interpretation, and the writing of the article. 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). Drs. Haines's, McPeake's, Hibbert's, Boehm's, Aparanji's, Bastin's, Drumright's, Holdsworth's, Johnson's, Kloos's, Meyer's, Quasim's, Saft's, Stollings's, and Sevin's institutions received funding from the Society of Critical Care Medicine (SCCM). Dr. Haines, McPeake, Boehm, and Sevin are currently receiving funding from SCCM to undertake this work, although the supporting source had no input into the design, data collection and analysis, although approved the final article for submission for publication. Dr. Boehm's institution received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (1K12HL137943-01) and Vanderbilt Clinical and Translational Science Award. The funding source reviewed and approved the article for submission. Drs. Boehm and Iwashyna received support for article research from the NIH. Dr. Hope's institution received funding from NHLBI K01-HL140279, and he received funding from American Association of Critical Care Nurses. Dr. Khan's institution received funding from the NIH. Dr. Kross's institution received funding from the NIH and the American Lung Association. Dr. Quasim's institution received funding from the Health Foundation. Dr. Saft received funding from Medtronic. Dr. Stollings received funding from Intermountain Health. Dr. Weinhouse received funding from UptoDate. Dr. Hopkins's institution received funding from Intermountain Research and Medical Foundation. Dr. Iwashyna's institution received funding from NIH K12, and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Kimberley.haines@wh.org.au Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Hand Hygiene Compliance in the ICU: A Systematic Review Objectives: To synthesize the literature describing compliance with World Health Organization hand hygiene guidelines in ICUs, to evaluate the quality of extant research, and to examine differences in compliance levels across geographical regions, ICU types, and healthcare worker groups, observation methods, and moments (indications) of hand hygiene. Data Sources: Electronic searches were conducted in August 2018 using Medline, CINAHL, PsycInfo, Embase, and Web of Science. Reference lists of included studies and related review articles were also screened. Study Selection: English-language, peer-reviewed studies measuring hand hygiene compliance by healthcare workers in an ICU setting using direct observation guided by the World Health Organization's "Five Moments for Hand Hygiene," published since 2009, were included. Data Extraction: Information was extracted on study location, research design, type of ICU, healthcare workers, measurement procedures, and compliance levels. Data Synthesis: Sixty-one studies were included. Most were conducted in high-income countries (60.7%) and in adult ICUs (85.2%). Mean hand hygiene compliance was 59.6%. Compliance levels appeared to differ by geographic region (high-income countries 64.5%, low-income countries 9.1%), type of ICU (neonatal 67.0%, pediatric 41.2%, adult 58.2%), and type of healthcare worker (nursing staff 43.4%, physicians 32.6%, other staff 53.8%). Conclusions: Mean hand hygiene compliance appears notably lower than international targets. The data collated may offer useful indicators for those evaluating, and seeking to improve, hand hygiene compliance in ICUs internationally. 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 the Health Research Board. Drs. Lambe and Lydon, Ms. Hehir, Ms. Walsh, and Dr. O'Connor's institutions received funding from Irish Health Research Board. Dr. Lydon also received funding from National Doctors Training and Planning, Health Service Executive, and Trinity College Dublin (for role as adjunct assistant professor). Dr. O'Connor's institution received funding from Health Services Executive, and he received funding from Naval Postgraduate School and National University of Ireland Galway. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kathryn.lambe@nuigalway.ie Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Management of Peripheral Venoarterial Extracorporeal Membrane Oxygenation in Cardiogenic Shock Objectives: Cardiogenic shock is a highly morbid condition in which inadequate end-organ perfusion leads to death if untreated. Peripheral venoarterial extracorporeal membrane oxygenation is increasingly used to restore systemic perfusion despite limited understanding of how to optimally titrate support. This review provides insights into the physiologic basis of extracorporeal membrane oxygenation support and presents an approach to extracorporeal membrane oxygenation management in the cardiogenic shock patient. Data Sources, Study Selection, and Data Extraction: Data were obtained from a PubMed search of the most recent medical literature identified from MeSH terms: extracorporeal membrane oxygenation, cardiogenic shock, percutaneous mechanical circulatory support, and heart failure. Articles included original articles, case reports, and review articles. Data Synthesis: Current evidence detailing the use of extracorporeal membrane oxygenation to support patients in cardiogenic shock is limited to isolated case reports and single institution case series focused on patient outcomes but lacking in detailed approaches to extracorporeal membrane oxygenation management. Unlike medical therapy, in which dosages are either prescribed or carefully titrated to specific variables, extracorporeal membrane oxygenation is a mechanical support therapy requiring ongoing titration but without widely accepted variables to guide treatment. Similar to mechanical ventilation, extracorporeal membrane oxygenation can provide substantial benefit or induce significant harm. The widespread use and present lack of data to guide extracorporeal membrane oxygenation support demands that intensivists adopt a physiologically-based approach to management of the cardiogenic shock patient on extracorporeal membrane oxygenation. Conclusions: Extracorporeal membrane oxygenation is a powerful mechanical circulatory support modality capable of rapidly restoring systemic perfusion yet lacking in defined approaches to management. Adopting a management approach based physiologic principles provides a basis for care. Dr. Keller received support for article research from the National Institutes of Health (1K08HL143342-01). For information regarding this article, E-mail: spkeller@mit.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Causes of Death in Status Epilepticus Objectives: To determine the causes of death in patients with status epilepticus. To analyze the relative contributions of seizure etiology, seizure refractoriness, use of mechanical ventilation, anesthetic drugs for seizure control, and medical complications to in-hospital and 90-day mortality, hospital length of stay, and discharge disposition. Design: Retrospective cohort. Setting: Single-center neuroscience ICU. Participants: Patients with status epilepticus were identified by retrospective search of electronic database from January 1, 2011, to December 31, 2016. Interventions: Review of electronic medical records. Measurements and Main Results: Demographics, clinical characteristics, treatments, and outcomes were collected. Univariable and multivariable logistic regression analysis were used to determine whether the use of anesthetic drugs, mechanical ventilation, Status Epilepticus Severity Score, refractoriness of seizures, etiology of seizures, or medical complications were associated with in-hospital, 90-day mortality or discharge disposition. Among 244 patients with status epilepticus (mean age was 64 yr [interquartile range, 42–76], 55% male, median Status Epilepticus Severity Score 3 [interquartile range, 2–4]), 24 received anesthetic drug infusions for seizure control. In-hospital and 90-day mortality rates were 9.2% and 19.2%, respectively. Death was preceded by withdrawal of life-sustaining treatment in 19 patients (86.3%) and cardiac arrest in three (13.7%). Only Status Epilepticus Severity Score was associated with in-hospital and 90-day mortality, whereas the use of anesthetic drugs for seizure control, mechanical ventilation, medical complications, etiology, and refractoriness of seizures were not. Hospital length of stay was longer in patients with medical complications (p = 0.0091), refractory seizures (p = 0.0077), and in those who required anesthetic drugs for seizure control (p = 0.0035). Patients who had refractory seizures were less likely to be discharged home (odds ratio, 0.295; CI, 0.143–0.608; p = 0.0009). Conclusions: In this cohort, death primarily resulted from the underlying neurologic disease and withdrawal of life-sustaining treatment and not from our treatment choices. Use of anesthetic drugs, medical complications, and mechanical ventilation were not associated with in-hospital and 90-day mortality. 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). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: maximilianohawkes@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Association of Elevated Plasma Interleukin 18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome Objective: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. Design: Retrospective analysis of randomized controlled clinical trial. Setting: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. Patients: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. Interventions: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. Measurements and Main Results: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7–3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5–3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. Conclusions: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial. Drs. Rogers, Hunninghake, Matthay, Steingrub, Wheeler, and Baron helped with conception and design. Dr. Guan, Dr. Trtchounian, Ms. Kozikowski, Ms. DeSouza, Ms. Mogan, Dr. Liu, and Dr. Nakahira helped with experimental procedures. Drs. Rogers, Hunninghake, Kaimal, Desai, and Baron helped with analysis and interpretation. Drs. Rogers, Hunninghake, Kaimal, Desai, Liu, Matthay, Steingrub, Yoon, Nakahira, Choi, and Baron helped with manuscript preparation and revision. 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 grants from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01 HL112747, HL111024, HL51856, HL55330, Global Research Laboratory grant number 2016K1A1A2910779, K23 HL125663, NIH/National Center for Advancing Translational Sciences KL2-TR-002385, and NHLBI ARDS Network investigators. Drs. Rogers and Hunninghake, Ms. Kozikowski, Ms. DeSouza, and Drs. Liu, Matthay, Steingrub, Nakahira, Choi, and Baron received support for article research from National Institutes of Health (NIH). Dr. Hunninghake received funding from consulting for Genentech, Boehringer-Ingelheim, the Gerson Lehrman Group, and Mistubishi Chemical for work unrelated to this submission. Ms. Kozikowski's institution received funding from Brigham and Womens Hospital. Ms. DeSouza disclosed work for hire. Dr. Liu's institution received funding from NHLBI, National Institute of Diabetes and Digestive and Kidney Disease, and she received funding from National Policy Forum on Critical Care and Acute Renal Failure, Achaogen (consultant), Durect (consultant), Theravance (consultant), Quark (consultant), Potrero Med (consultant), Amgen (stockholder), and Baxter (presenter at sponsored meeting). Dr. Matthay's institution received funding from Bayer Pharmaceuticals, Department of Defense, GlaxoSmithKline, and he received other support from CSL Behring, Roche-Genentec, Quark Pharmaceuticals, Boerhinger-Ingelheim, Cerus Therapeutics, and NHLBI. Dr. Choi's institution received funding from NIH; he received funding from Teva Pharmaceuticals; and he disclosed that he is a cofounder, stock holder, and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide, and he has a use patent on carbon monoxide. Dr. Baron's institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: ajrogers@stanford.edu; rbaron@partners.org Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child Objectives: Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. Design: Prospective multicenter cohort study. Setting: Three U.K.-based PICUs. Patients: Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). Interventions: Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. Measurements and Main Results: Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = –0.2; p = 0.037). Conclusions: Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Wijeyesekera and Wagner contributed equally. Dr. Wijeyesekera developed and supervised the metabolic profiling strategy, undertook data analysis, and wrote the article. Dr. Wagner developed and supervised the microbial profiling strategy, undertook data analysis, and wrote the article. Dr. De Goffau analyzed the microbial data and co-wrote the article. Ms. Thurston undertook sample processing and data analysis. Drs. Rodrigues Sabino and Zaher, Ms. White, Ms. Ridout, and Dr. Valla undertook sample processing, data collection, and analysis. Dr. Meyer undertook data analysis. Drs. Peters, Branco, Torok, Meyer, and Klein contributed to protocol development, supervised data analysis, and co-wrote the article. Dr. Parkhill developed the microbial profiling protocol, supervised all aspects of the microbial data analysis, and co-wrote the article. Drs. Frost and Holmes developed the metabolic profiling protocol, supervised all aspects of the metabolic data analysis, and co-wrote the article. Dr. Pathan conceived and supervised the study and wrote the article. 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). Aspects of the work were funded by an Imperial College Biomedical Research Centre award (to Drs. Holmes and Pathan), the Evelyn Trust (to Drs. Parkhill and Pathan), a Wellcome Trust Core Informatics Award (to Dr. Parkhill), Great Ormond Street Hospital Children's Charity (to Drs. Peters and Ramnarayan), and a Levi-Montalcini award from the European Society of Intensive Care Medicine (to Dr. Pathan). The research was supported by the National Institute for Health Research Biomedical Research Centres based at Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Great Ormond Street Hospital NHS Foundation Trust, Imperial College Healthcare NHS Trust, and Imperial College London. Dr. Rodrigues Sabino's institution received funding from National Institute for Health Research Imperial Biomedical Research Centre Institute of Translational Medicine and Therapeutics Call for Experimental Medicine Proposals. Dr. Valla received funding from Baxter and Nutricia. Dr. Meyer received funding from academic lectures for Danone, Nestle and Mead Johnson, and from the Mead Johnson Allergy Advisory Board. Dr. Frost's institution received funding from Nestle and Heptares, and he received support for article research from Research Councils UK and Bill & Melinda Gates Foundation. Drs. Frost, Parkhill, and Pathan received support for article research from Wellcome Trust/Charity Open Access Fund. Dr. Parkhill's institution received funding from Wellcome Trust, and he received funding from Next Gen Diagnostics Llc. Dr. Pathan's institution received funding from European Society of Intensive Care Medicine, Evelyn Trust, and Wellcome Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Nazima Pathan, FRCPCH, PhD, Department of Paediatrics, University of Cambridge, Level 8, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. E-mail: np409@cam.ac.uk Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Interprofessional Shared Decision-Making in the ICU: A Systematic Review and Recommendations From an Expert Panel Objectives: There is growing recognition that high-quality care for patients and families in the ICU requires exemplary interprofessional collaboration and communication. One important aspect is how the ICU team makes complex decisions. However, no recommendations have been published on interprofessional shared decision-making. The aim of this project is to use systematic review and normative analysis by experts to examine existing evidence regarding interprofessional shared decision-making, describe its principles and provide ICU clinicians with recommendations regarding its implementation. Data Sources: We conducted a systematic review using MEDLINE, Cumulative Index to Nursing and Allied Health Literature, and Cochrane databases and used normative analyses to formulate recommendations regarding interprofessional shared decision-making. Study Selection: Three authors screened titles and abstracts in duplicate. Data Synthesis: Four papers assessing the effect of interprofessional shared decision-making on quality of care were identified, suggesting that interprofessional shared decision-making is associated with improved processes and outcomes. Five recommendations, largely based on expert opinion, were developed: 1) interprofessional shared decision-making is a collaborative process among clinicians that allows for shared decisions regarding important treatment questions; 2) clinicians should consider engaging in interprofessional shared decision-making to promote the most appropriate and balanced decisions; 3) clinicians and hospitals should implement strategies to foster an ICU climate oriented toward interprofessional shared decision-making; 4) clinicians implementing interprofessional shared decision-making should consider incorporating a structured approach; and 5) further studies are needed to evaluate and improve the quality of interprofessional shared decision-making in ICUs. Conclusions: Clinicians should consider an interprofessional shared decision-making model that allows for the exchange of information, deliberation, and joint attainment of important treatment decisions. Drs. Michalsen, Ganz, White, Jensen, Metaxa, Latour, Truog, and Curtis conceptualized the article. Drs. Michalsen, Long, and Ganz reviewed the literature. All authors drafted and revised the article for important intellectual content as well as final approval for the version submitted. 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. DeKeyser Ganz's institution received funding from the Israel Institute of Health Policy Research, and she received funding from the Israel Higher Education Commission. Dr. Metaxa received funding from European Society of Intensive Care Medicine. Dr. Truog received funding from Covance (Data Safety Monitoring Committee) and Sanofi (Data Safety Monitoring Committees). Dr. Kesecioglu reports receiving honorarium from Xenios A.G. The remaining authors have disclosed that they do not have any potential conflicts of interest. Ethical standards: This research does not involve human participants or animals. For information regarding this article, E-mail: jrc@u.washington.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Outcome Prediction in Postanoxic Coma With Deep Learning Objectives: Visual assessment of the electroencephalogram by experienced clinical neurophysiologists allows reliable outcome prediction of approximately half of all comatose patients after cardiac arrest. Deep neural networks hold promise to achieve similar or even better performance, being more objective and consistent. Design: Prospective cohort study. Setting: Medical ICU of five teaching hospitals in the Netherlands. Patients: Eight-hundred ninety-five consecutive comatose patients after cardiac arrest. Interventions: None. Measurements and Main Results: Continuous electroencephalogram was recorded during the first 3 days after cardiac arrest. Functional outcome at 6 months was classified as good (Cerebral Performance Category 1–2) or poor (Cerebral Performance Category 3–5). We trained a convolutional neural network, with a VGG architecture (introduced by the Oxford Visual Geometry Group), to predict neurologic outcome at 12 and 24 hours after cardiac arrest using electroencephalogram epochs and outcome labels as inputs. Output of the network was the probability of good outcome. Data from two hospitals were used for training and internal validation (n = 661). Eighty percent of these data was used for training and cross-validation, the remaining 20% for independent internal validation. Data from the other three hospitals were used for external validation (n = 234). Prediction of poor outcome was most accurate at 12 hours, with a sensitivity in the external validation set of 58% (95% CI, 51–65%) at false positive rate of 0% (CI, 0–7%). Good outcome could be predicted at 12 hours with a sensitivity of 48% (CI, 45–51%) at a false positive rate of 5% (CI, 0–15%) in the external validation set. Conclusions: Deep learning of electroencephalogram signals outperforms any previously reported outcome predictor of coma after cardiac arrest, including visual electroencephalogram assessment by trained electroencephalogram experts. Our approach offers the potential for objective and real time, bedside insight in the neurologic prognosis of comatose patients after cardiac arrest. 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. van Putten is co-founder of Clinical Science Systems, a supplier of electroencephalogram systems for Medisch Spectrum Twente. The remaining authors have disclosed that they do not have any conflicts of interest. This work was performed in Medisch Spectrum Twente, Rijnstate Hospital, St. Antonius Hospital, University Medical Center Groningen and VieCuri Medical Center, The Netherlands. For information regarding this article, E-mail: m.tjepkema-cloostermans@mst.nl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. Design: Prospective, randomized, controlled study. Setting: Thirty-three hospitals in China. Patients: A total of 710 adults 18–75 years old with severe community-acquired pneumonia. Interventions: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. Measurements and Main Results: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9–21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4–15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). Conclusions: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay. 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. 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 a Tianjin Science and Technology committee grant (14ZXLJSY00230) and National Natural Science Foundation of China (81630001,81490533). Drs. X. Yu and Zhi Liu disclosed work for hire. Dr. B. Zhang disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx. Unique identifier: ChiCTR-TRC-13003534. For information regarding this article, E-mail: bai.chunxue@zs-hospital.sh.cn; shanghongcai@126.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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