Craniofacial Surgery

Comparison of 3 Different Techniques on the Movement of the Implants After Evisceration Purpose: To compare the results of 3 evisceration techniques involving placement of an acrylic implant within the scleral shell without posterior sclerotomy (Group 1), posterior sclerotomy with placement of a porous implant within the intraconal space (Group 2) and posterior sclerotomy with placement of a acrylic implant within the intraconal space (Group 3) with respect to ocular mobility, implant complications and patient satisfaction. Methods: Single-center, retrospective, interventional case series. A chart review of 72 patients undergoing evisceration between February 2013 and January 2018 was carried out. Thirty-five patients met the inclusion criteria having a normal or near normal size eye and at least 6 months follow-up. The horizontal movements of the implant and the artificial eye was measured by using a ruler. Data analyses were conducted using the Mann-Whitney U test for 2 independent samples. Results: Neither infection nor prolapse of the implant had occurred in any of the patients. The mean implant sizes were 18 mm in Group 1, 20 mm in Group 2 and 20 mm in Group 3. Statistically, a significant difference was assessed between Group 1 and Group 2 in both nasal and temporal movement of the socket; nasal and temporal movement of the prosthesis. Statistically, a significant difference was assessed between Group 1 and Group 3 in both nasal and temporal movement of the socket; nasal and temporal movement of the prosthesis. However, there was no statistically significant difference between Group 2 and Group 3 in neither nasal and temporal movement of the socket nor nasal and temporal movement of the artificial eye. Conclusion: Group 1 showed the significantly better movement of both prosthesis and socket in adduction and abduction than Group 2 and 3. The likely explanation of for this may be that preserving the scleral shell integrity allows more efficient transmission of muscle contraction to the socket and prosthesis. Address correspondence and reprint requests to Dr Selam Yekta Sendul, MD, Sisli Hamidiye Etfal Training and Research Hospital, Department of Ophthalmology, Istanbul., Etfal Street 34280 Sisli, Istanbul, Turkey; E-mail: sysendul@hotmail.com Received 21 February, 2019 Accepted 20 March, 2019 Written consent was obtained from the patients shown in the figures. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All authors declare that they have no competing interests. © 2019 by Mutaz B. Habal, MD.

A Rotational Flap Combined With a Mucosal Advancement Flap for the Lip Reconstruction The lips play an important role in both esthetics and oral functions, so it should be reconstructed in the light of both. The authors present a patient with the upper lateral lip defect after widely excising the basal cell carcinoma. The lip reconstruction was completed with a rotational flap combined with a mucosal advancement flap. By using 2 flaps simultaneously, the defect was covered with sufficient adjacent tissue without severe deformity and tension. At 2-month follow-up, the patient retained good aesthetic results as the scar was on the natural lines of the face. There was no noticeable deformity on the vermilion contour and oral commissure. Oral competence was also good. Address correspondence and reprint requests to Hyungon Choi, MD, PhD, Department of Plastic Surgery, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 143-729, Korea; E-mail: sweetestfairy@hanmail.net Received 7 March, 2019 Accepted 16 April, 2019 © 2019 by Mutaz B. Habal, MD.

The Natural History of Treated and Untreated Zygomatic Arch Fractures The authors present the case of a 32-year-old patient treated for a left, isolated zygomatic fracture following assault. The injury was reduced without fixation via the Keene approach. The same patient presented to the emergency room 16 months later with a right-sided fracture similar to the previous contralateral injury. This fracture was left untreated. Repeated assaults over a 4-year period provide us with a natural history of both injuries, allowing for comparison between the 2 approaches. The authors found that reduction of the arch without fixation led to an outcome without palpable or visible deformity and no impaired mastication. Additionally, considering etiology of injury, such as alcohol or drug use, treatment may provide an important point of intervention to prevent recurrence. Address correspondence and reprint requests to Alexander Homer, Brown University, 69 Brown Street, Mail #3000, Providence, RI 02912; E-mail: alexander_homer1@brown.edu Received 30 January, 2019 Accepted 25 April, 2019 The authors report no conflicts of interest. © 2019 by Mutaz B. Habal, MD.

Strategy of Mandibular Central Arch Reconstruction After Firearm Injury Gunshot wounds can cause extensive destruction of soft tissue and bone, and the maxillofacial region is often affected. The reconstructive treatment is complex due to the difficulty to reestablish the central arch mandibular contour and volume. Moreover, the goal is to avoid postoperative infections and obtain bone graft neovascularization. Therefore, this report shows a clinical case of a patient presenting mandibular deformity with a mandibular central arch discontinuity caused by a firearm injury. The strategy to the reconstructive treatment as performed with a condensed and stabilized particulate autogenous bone graft was essential and effectiveness. After 1 year, it was obtained a satisfactory result to the patient. Address correspondence and reprint requests to Bruno Coelho Mendes, DDS, Jose Bonifacio, 1193, Araçatuba, São Paulo 16015-050, Brazil; E-mail: brunocoelho.mnds@gmail.com Received 10 February, 2019 Accepted 24 April, 2019 The authors report no conflicts of interest. © 2019 by Mutaz B. Habal, MD.

An Extremely Rare Cause of Headache; Osteoma of the Middle Concha Bullosa Osteomas are benign, slow-growing tumors originating from bone tissue. Osteomas of the paranasal region, which are usually asymptomatic, are detected incidentally on tomographies taken for other medical needs. Paranasal sinus osteomas frequently localized in the frontal and ethmoid sinuses are among the infrequent reasons for headaches. In this case report, the authors submit the first case of an osteoma that was localized inside the middle concha bullosa and causing headache. It was successfully excised via an endoscopic endonasal approach without any complications. Address correspondence and reprint requests to Secaattin Gulsen, MD, Department of Otorhinolaryngology, Private HATEM Hospital, Allaben District, Kemal Köker avenue No:41 Şahinbey, Gaziantep, Turkey. Zip code: 27000; E-mail: drsecaattingulsen@gmail.com Received 3 March, 2019 Accepted 22 April, 2019 The authors report no conflicts of interest © 2019 by Mutaz B. Habal, MD.

Anterior Segmental Osteotomy Using Customized Spider-Plates Based on Computer-aided Surgery System Anterior segmental osteotomy (ASO) is considered the treatment modality of choice in patients with the bimaxillary dentoalveolar protrusion. However, this meticulous surgical technique accompanies a number of possible disadvantages. The considerable time required before, during, and after the operation, limited movement of the segment, damage of the mental nerve, loss of tooth vitality, loss of a tooth or teeth, or indeed total loss of the anterior segments are those that affect the result of the surgery. Recently, the authors have devised a computer-aided surgical simulation programme and fabricated the customized osteotomy guides and the spider-shaped plates based on the programme. They were then applied to a 28-year-old patient with the complaint of a bimaxillary dentoalveolar protrusion. This approach helped to overcome several problems related to ASO reported earlier. Address correspondence and reprint requests to Byoung-Eun Yang, DDS, PhD, Department of Oral and Maxillofacial Surgery, Hallym University College of Medicine Sacred Heart Hospital, 11, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do 14066, South Korea; E-mail: face@hallym.or.kr, omsyang@gmail.com Received 25 March, 2019 Accepted 19 April, 2019 The authors received no financial support for the research, authorship, and publication of this article. Informed consent from the patient was obtained after detailed information of the necessary treatment, especially concerning the planned new technique. Furthermore, informed consent was also obtained for publication of the procedure and follow up treatment. The authors report no conflicts of interest. © 2019 by Mutaz B. Habal, MD.

Complication After PDO Threads Lift Thread-lifting is as a minimally invasive procedure with limited scarring, rapid recovery, and fewer complications compared with the standard incisional surgery for facial rejuvenation. Using absorbable thread-like polydioxanone is a relatively simple procedure that is also performed by nonmedical professionals in Korea. Although several acute or delayed complications after using nonabsorbable thread types were also reported, it is uncommon to find cellulitis caused by a delayed complication after thread-lifting. A 41-year-old woman presented to our clinic with inflamed multiple palpable masses. She underwent 3 courses of acupoint embedding therapy at a Korean oriental medical clinic. She was treated with combination antibiotic therapy; however, the inflammation did not subside. Consequently, excisional biopsy was performed under local anesthesia. During the procedure, threads were detected and removed. Dimpling, thread exposure, alopecia, under-correction, asymmetry, and parotid gland injury also can occur as early complications of the procedure. Fortunately, these reactions are predominantly mild to moderate in intensity, and can be corrected by a relatively simple procedure. Chronic inflammatory reactions in the thread-lifting area, as identified in the authors' case, are an infrequent complication. It is recommended to consult with experts in the field for the implementation of this procedure. In addition, experts also need to notify the above side effects and solutions in advance to ensure safe and satisfactory procedures for their patients. Address correspondence and reprint requests to Hwan Jun Choi, MD, PhD, Department of Plastic and Reconstructive Surgery College of Medicine, Soonchunhyang University, Bongmyeong-dong, Dongnam-gu, Cheonan 330-721, Republic of Korea; E-mail: medi619@hanmail.net Received 21 January, 2019 Accepted 19 March, 2019 This study was supported by the Soonchunhyang University Research Fund. The authors report no conflicts of interest. © 2019 by Mutaz B. Habal, MD.

Adding Depth to Cephalometric Analysis: Comparing Two- and Three-Dimensional Angular Cephalometric Measurements Introduction: Lateral cephalometric radiographs (LCR) have been the standard tool used for cephalometric analysis in craniofacial surgery. Over the past decade, a three-dimensional (3D) revolution in cephalometric analysis and surgical planning has been underway. To date, research has not validated whether cephalometric measurements taken from two-dimensional (2D) and 3D data sources are equivalent and interchangeable. The authors sought to compare angular cephalometric measurements taken with 2D and 3D modalities. Methods: Sixty-two head CT scans (36 females, 26 males) with an average age of 63 ± 20 years were studied. Twelve cephalometric angular measurements were taken from 3D reconstructed skulls using the software package Mimics 19.0 (Materialize; Leuven, Belgium). These same facial angles were measured from 2D lateral cephalograms reconstructed from the original CT scans using Dolphin 11.9. Measurements taken with both techniques were compared for agreement using a paired t test. Intra-class correlation coefficient assessment was used to determine inter-rater reliability. Statistical significance was set at P < 0.05. Results: Five of the 12 angular measurements (SNA, SNB, MP-FH, U1-SN, and U1-L1) demonstrated statistically significant differences (P < 0.05) between the 2D and 3D analyses. All of these differences were less than the standard deviations for the respective measure. Conclusion: The differences between angular cephalometric values obtained from 2D LCRs and 3D CT reconstructions are small. This supports the practices of using 2D and 3D cephalometric data interchangeably in most applications. Clinicians must be selective in which measures they employ to maximize accuracy and care must be taken when measuring dental inclination with lateral cephalograms. Address correspondence and reprint requests to S. Alex Rottgers, MD, Assistant Professor of Plastic Reconstructive Surgery, Johns Hopkins All Children's Hospital, Division of Plastic and Reconstructive Surgery, 601 Fifth Street South, Suite 306, St. Petersburg, FL 33701; E-mail: srottge1@jhmi.edu Received 28 November, 2018 Accepted 12 March, 2019 The authors report no conflicts of interest. Supplemental digital contents are 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 Web site (www.jcraniofacialsurgery.com). © 2019 by Mutaz B. Habal, MD.

Risk Factors for Adult Postintubation Tracheal Stenosis Background: To identify risk factors for developing adult postintubation tracheal stenosis (TS) and determine if there were patient characteristics that could serve as prognostic indicators of clinical outcomes in this patient population. Methods: A total of 55 patients with postintubation TS admitted to our institution between February 2009 and March 2017 (TS group) and randomly selected 86 patients admitted to the intensive care unit and intubated over the same period in whom TS was ruled out (control group) were compared. Causal factors of intubation were noted. Patient-, treatment-, and procedure/cuff site-related risk factors of TS were compared. Results: Both groups did not differ from each other by means of age and gender (P = 0.640, and P = 0.724, respectively). Compared to controls, patients with TS had a significantly higher BMI (32.8 ± 7.64 kg/m2 versus 25.9 ± 6.68 kg/m2; p = 0.002) and were more likely to have diabetes (28.4% vs 9.82%; p = 0.0011). Patients who were previously intubated for more than 48 hours (P = 0.016) and patients treated with irradiation (P = 0.028) were significantly more likely to develop TS than control patients. Conclusion: Patients with TS had a significantly higher BMI, and were more likely to have diabetes compared to controls. Patients who were previously intubated for more than 48 hours and patients treated with irradiation were more likely to develop TS than control patients. Address correspondence and reprint requests to Murat Songu, MD, Department of Otorhinolaryngology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey; E-mail: songumurat@yahoo.com Received 16 January, 2019 Accepted 27 February, 2019 The authors report no conflicts of interest. Supplemental digital contents are 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 Web site (www.jcraniofacialsurgery.com). © 2019 by Mutaz B. Habal, MD.

Transnasal Endoscopic Retrieval of a Metallic Intraorbital Intraconal Foreign Body Facilitated by an Intraoperative Magnetic Stick Here, we report the case of an intraorbital intraconal foreign body that was successfully retrieved by a transnasal endoscopic approach facilitated intraoperatively by a magnetic stick. A 36-year-old man was admitted to our unit with a left-sided intraorbital intraconal metallic foreign body. Following 2 failed attempts via a transconjunctiva approach, we finally recovered the foreign body using transnasal endoscopic surgery. During this procedure, a magnetic stick was used to help us locate and successfully remove the foreign body, grapeshot measuring approximately 0.5 cm in diameter. Visual acuity in the injured eye increased from 0.01 preoperatively to 0.04 6 days after surgical intervention. There were no complications. We therefore propose that in selected patients, the endoscopic transnasal approach is an effective, safe and minimally invasive approach for the removal of intraorbital intraconal foreign bodies. The intraoperative use of a magnet can facilitate the successful location and removal of magnetic metallic foreign bodies. Address correspondence and reprint requests to Jianfeng Liu, MD, Department of Otolaryngology, China-Japan Friendship Hospital, Yinghuadong Street, Chaoyang District, Beijing, China 100029; e-mail: mmconfucius@163.com Received 19 February, 2019 Accepted 31 March, 2019 The authors report no conflicts of interest. Supplemental digital contents are 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 Web site (www.jcraniofacialsurgery.com). © 2019 by Mutaz B. Habal, MD.

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

6948891480

alsfakia@gmail.com

Panafrican Medical Journal

RESEARCH Assessment of the current state of knowledge and risk factors of cervical cancer among women in the Buea Health District, Cameroon Ngwayu Claude Nkfusai et al. Cervical cancer is a malignant proliferation of the cells of the uterine cervix and can be treated if diagnosed earlier. It is the second most common gynecological malignancy worldwide and the leading cause of cancer associated mortality among women in Africa and Cameroon. READ MORE Maternal and foetal medical conditions during pregnancy as determinants of intrapartum stillbirth in public health facilities of Addis Ababa: a case-control study Alemayehu Gebremariam Agena et al.  Globally, intrapartum stillbirth accounts for 1 million deaths of babies annually, representing approximately one-third of global stillbirth toll. Intrapartum stillbirth occurs due to causes ranging from maternal medical and obstetric conditions; access to quality obstetric care services during pregnancy; and types, timing and quality of intrapartum care. READ MORE

IMAGES IN CLINICAL MEDICINE Molar pregnancy revealed by voluminous vulvar edema: a case study Mamadou Ibrahima Kampo et al. Molar pregnancy is a benign trophoblastic disease usually discovered in patients with metrorrhagia and early miscarriage. We here report a case of molar pregnancy associated with severe preeclampsia in a 18-year-old primiparous woman presenting with early onset of vulvar swelling occurring in a three-day period. The patient reported metrorrhagias, headaches, vulvar pruritus lasting for a week. READ MORE Herpes Simple Virus proctitis: a diagnostic dilemma between anal disorders Athanasios Syllaios et al. A 72-year-old man was referred to a surgical outpatient department because of severe anal pain, bleeding and itching for the last 5 days. Clinical examination revealed severe efflorescence with painful ulcers around the anus. READ MORE

CASE REPORTS Continuous ambulatory peritoneal dialysis (CAPD) in children: a successful case for a bright future in a developing country Younoussa Keita et al.   Management of chronic kidney disease remains a challenge in developing countries due to the absence of kidney transplant, limited access to extra-renal purification and the low involvement of health policies particularly for children. PD remains a reliable alternative for renal replacement in pediatrics both in acute and chronic situations. The two PD modalities are represented by continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) with their variants. READ MORE A rare case of primary inverted papilloma of the middle ear  Mehdi Hasnaoui et al. Nverted Papilloma (IP) is a benign tumor that develops primarily in the sinonasal tract. Localization in the middle ear, regardless of primary or extension of a sinonasal IP, is exceptional. Only 23 cases of primary inverted papilloma have been reported in the literature. READ MORE

CASE SERIES Epidemiological and clinical features of tuberculosis at the Hôpital de l'Amitié in Bangui Gaspard Tékpa et al. Tuberculosis (TB) is endemic in the Central African Republic (CAR) with an incidence rate of 391 per 100,000 population in 2015. This study aims to analyze current epidemiological and clinical features of TB at the Hôpital de l'Amitié in the Central African Republic. We conducted an analytic retrospective study of patients hospitalized in the Department of Medicine at the Hôpital de l'Amitié from 15 April 2010 to 14 October 2011.   READ MORE Molecular profile of breast cancers in Guinean oncological settings Bangaly Traoré et al. Breast cancer is a major global public health problem. About 1,671,149 cases are diagnosed each year, including 521,907 deaths in worldwide. It represents the leading cause of consultation at the Surgical Oncology Unit (SOU) of Donka National Hospital and represents 26% of all cancers. In Sub Saharan countries, the patients are relatively younger and the stages are aggressive. READ MORE

LATEST SUPPLEMENT   Sharing Experiences from the Field : Updates from the Nigeria Field Epidemiology and Laboratory Training Program The supplement covers summaries of a surveillance system evaluation, secondary data analyses and several protocol-based studies. The output represents the product of field-based interactions that the residents had in the course of their experiential training in applied epidemiology.This builds up on the first NFELTP supplement published in July 2014 and the progress that the program has made since its inception in 2008.  READ MORE

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

6948891480

alsfakia@gmail.com

Pediatric Critical Care Medicine

A Retrospective Case-Control Study to Identify Predictors of Unplanned Admission to Pediatric Intensive Care Within 24 Hours of Hospitalization Objectives: To identify the clinical findings available at the time of hospitalization from the emergency department that are associated with deterioration within 24 hours. Design: A retrospective case-control study. Setting: A pediatric hospital in Ottawa, ON, Canada. Patients: Children less than 18 years old who were hospitalized via the emergency department between January 1, 2008, and December 31, 2012. Cases (n = 98) had an unplanned admission to the PICU or unexpected death on the hospital ward within 24 hours of hospitalization and controls (n = 196) did not. Interventions: None. Main Results: Ninety-eight children (53% boys; mean age 63.2 mo) required early unplanned admission to the PICU. Multivariable conditional logistic regression resulted in a model with five predictors reaching statistical significance: higher triage acuity score (odds ratio, 4.1; 95% CI, 1.7–10.2), tachypnea in the emergency department (odds ratio, 4.6; 95% CI, 1.8–11.8), tachycardia in the emergency department (odds ratio, 2.6; 95% CI, 1.1–6.5), PICU consultation in the emergency department (odds ratio, 8.0; 95% CI, 1.1–57.7), and admission to a ward not typical for age and/or diagnosis (odds ratio, 4.5; 95% CI, 1.7–11.6). Conclusions: We have identified risk factors that should be included as potential predictor variables in future large, prospective studies to derive and validate a weighted scoring system to identify hospitalized children at high risk of early clinical deterioration. Supported, in part, by an operating grant from the Children's Hospital of Eastern Ontario Research Institute. Dr. Krmpotic disclosed that this study was funded by an operating grant from the Children's Hospital of Eastern Ontario Research Institute. Dr. Toppozini received funding from acting as a Children's Hospital of Eastern Ontario Research Institute research assistant (aided in design of data collection tool, data collection and verification, interpretation, and writing/revising article). Dr. Plint's institution received funding from Children's Hospital of Eastern Ontario Research Institute, and she disclosed that she is supported in part by a University of Ottawa Tier II Clinical Research Chair award. The remaining authors have disclosed that they do not have any potential conflicts of interest. Current affiliation for Dr. Krmpotic: Pediatric Critical Care, IWK Health Centre, 5850/5980 University Ave, Halifax, NS, B3K6R8, Canada. For information regarding this article, E-mail: kristina.krmpotic@iwk.nshealth.ca ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

The Effect of Asphyxia Arrest Duration on a Pediatric End-Tidal CO2-Guided Chest Compression Delivery Model Objectives: To determine the effect of the duration of asphyxial arrest on the survival benefit previously seen with end-tidal CO2-guided chest compression delivery. Design: Preclinical randomized controlled study. Setting: University animal research laboratory. Subjects: Two-week-old swine. Interventions: After either 17 or 23 minutes of asphyxial arrest, animals were randomized to standard cardiopulmonary resuscitation or end-tidal CO2-guided chest compression delivery. Standard cardiopulmonary resuscitation was optimized by marker, monitor, and verbal feedback about compression rate, depth, and release. End-tidal CO2-guided delivery used adjustments to chest compression rate and depth to maximize end-tidal CO2 level without other feedback. Cardiopulmonary resuscitation for both groups proceeded from 10 minutes of basic life support to 10 minutes of advanced life support or return of spontaneous circulation. Measurements and Main Results: After 17 minutes of asphyxial arrest, mean end-tidal CO2 during 10 minutes of cardiopulmonary resuscitation was 18 ± 9 torr in the standard group and 33 ± 15 torr in the end-tidal CO2 group (p = 0.004). The rate of return of spontaneous circulation was three of 14 (21%) in the standard group rate and nine of 14 (64%) in the end-tidal CO2 group (p = 0.05). After a 23-minute asphyxial arrest, neither end-tidal CO2 values (20 vs 26) nor return of spontaneous circulation rate (3/14 vs 1/14) differed between the standard and end-tidal CO2-guided groups. Conclusions: Our previously observed survival benefit of end-tidal CO2-guided chest compression delivery after 20 minutes of asphyxial arrest was confirmed after 17 minutes of asphyxial arrest. The poor survival after 23 minutes of asphyxia shows that the benefit of end-tidal CO2-guided chest compression delivery is limited by severe asphyxia duration. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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/pccmjournal). Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development award R21HD072845, by the National Institute of Neurological Disorders and Stroke awards K08NS080984, R01NS060703, R01NS107417, and R21NS095036, by the National Research Service Award for Clinician Scientists in Pediatric Critical Cardiopulmonary Disease T32HL125239, and by the National Center for Research Resources of the National Institutes of Health Roadmap for Medical Research grant UL1RR025005. Dr. O'Brien's institution received funding from National Institutes of Health (NIH) T32 Institutional Grant (T32HL125239), and she disclosed work for hire. Dr. Lee's institution received funding from the NIH and the American Heart Association, and she received funding from Medtronic (consulting on near-infrared spectroscopy technology in 2016). Dr. Koehler's institution received funding from the NIH. Dr. Hunt received funding from the NIH (grant support as a coinvestigator), Zoll Medical Corporation (consulting on simulation-based medicine education innovation she created called "Rapid Cycle Deliberate Practice" and from medical education technologies that she and her research partners have created that Zoll has a nonexclusive license for two of the devices, although she has not received any royalties), and National Medical Consultants (for performing expert medical reviews). Dr. Shaffner's institution received funding from the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; he received funding from Wolters Kluwer. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed in the research facilities of the Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, Baltimore, MD. For information regarding this article, E-mail: dshaffn1@jhmi.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Etiologies and Clinical Outcomes of Patients With Secondary Hemophagocytic Lymphohistiocytosis at a Tertiary PICU Objectives: To assess the etiologies and outcomes of patients with secondary hemophagocytic lymphohistiocytosis in the PICU. Design: Prospective observational cohort study. Setting: A single PICU at a pediatric tertiary hospital in Hanoi, Vietnam. Patients: Pediatric patients meeting the criteria for secondary hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and Main Results: Between June 2017 and May 2018, 25 consecutive patients with a mean (SD) age of 23.3 months (21.6 mo) were included. Collected variables included etiologies of hemophagocytic lymphohistiocytosis and clinical and laboratory findings at admission. The Pediatric Index of Mortality 2 score at admission was calculated. Outcomes were death and multiple organ dysfunction. The severity of multiple organ dysfunction was assessed by the Pediatric Logistic Organ Dysfunction 2 score. The mean (SD) Pediatric Index of Mortality 2 predicted mortality rate was 5.6% (7.6%). Cytomegalovirus and Epstein-Barr virus coinfections (60%) were the most common suspected etiology of hemophagocytic lymphohistiocytosis. Other etiologies included Epstein-Barr virus sole infections (20%), cytomegalovirus sole infections (16%), and one unknown cause (4%). Multiple organ dysfunction (excluding hematologic failure) was found in 22 patients (88%) with death occurring in 14 patients (56%). The mean (SD) Pediatric Logistic Organ Dysfunction 2 predicted mortality rate among patients with multiple organ dysfunction was 11.9% (11.2%). Despite having lower Pediatric Index of Mortality 2 predicted mortality rates at admission, Epstein-Barr virus-cytomegalovirus coinfection cases with multiple organ dysfunction had slightly greater Pediatric Logistic Organ Dysfunction 2 predicted mortality rates than Epstein-Barr virus sole infection cases with multiple organ dysfunction: 12.2% (10.5%) versus 11.3% (11.0%). However, these rates were lower than cytomegalovirus sole infection cases with multiple organ dysfunction (14.4% [16.3%]). Area under the curve values for Pediatric Index of Mortality 2 and Pediatric Logistic Organ Dysfunction 2 were 0.74 (95% CI, 0.52–0.95) and 0.78 (95% CI, 0.52–1.00), respectively, suggesting that both scales were fair to good at predicting mortality. Conclusions: Viral infections, particularly Epstein-Barr virus-cytomegalovirus coinfections, were a common cause of secondary hemophagocytic lymphohistiocytosis. The implication of these coinfections on the clinical course of hemophagocytic lymphohistiocytosis needs to be delineated. 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/pccmjournal). Ms. Dao received funding and support for article research from Mayo Clinic College of Medicine and Science (Mayo Foundation for Medical Education and Research) (Research Travel Funding). Dr. Galeano received funding from Mayo Clinic Alix School of Medicine (travel grant for research). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: ouellette.yves@mayo.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Antibiotic Prophylaxis for Open Chest Management After Pediatric Cardiac Surgery Objectives: Although open chest management optimizes hemodynamics after cardiac surgery, it increases postoperative infections and leads to increased mortality. Despite the importance of antibiotic prophylaxis during open chest management, no specific recommendations exist. We aimed to compare the occurrence rates of bloodstream infection and surgical site infection between the different prophylactic antibiotic regimens for open chest management after pediatric cardiac surgery. Design: Retrospective, single-center, observational study. Setting: PICU at a tertiary children's hospital. Patients: Consecutive patients less than or equal to 18 years old with open chest management after cardiac surgery followed by delayed sternal closure, between January 2012 and June 2018. Interventions: None. Measurements and Main Results: We compared the composite occurrence rate of postoperative bloodstream infection and surgical site infection within 30 days after cardiac surgery between three prophylactic antibiotic regimens: 1) cefazolin, 2) cefazolin + vancomycin, and 3) vancomycin + meropenem. In 63 pediatric cardiac surgeries with open chest management, 17 bloodstream infections, and 12 surgical site infections were identified postoperatively. The composite occurrence rates of bloodstream infection and surgical site infection were 10 of 15 (67%), 10 of 19 (53%), and nine of 29 (31%) in the cefazolin, cefazolin + vancomycin, and vancomycin + meropenem regimens, respectively (p = 0.07). After adjusting for age, open chest management duration, extracorporeal membrane oxygenation use, and nasal methicillin-resistant Staphylococcus aureus colonization in multivariable analysis, there was no significant difference between the cefazolin and the cefazolin + vancomycin regimens (p = 0.19), while the vancomycin + meropenem regimen had a lower occurrence rate of bloodstream infection and surgical site infection than the cefazolin regimen (odds ratio, 0.0885; 95% CI, 0.0176–0.446; p = 0.003). Conclusions: In this study, a lower occurrence rate of postoperative bloodstream infection and surgical site infection was observed among patients with broad-spectrum antibiotic regimen after pediatric cardiac surgery with open chest management. Further studies, ideally randomized controlled studies investigating the efficacy of broad-spectrum antibiotics and their complications, are warranted before routine implementation of broad-spectrum prophylactic antibiotic regimen. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hatachi@wch.opho.jp ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Noninvasive Determination of Blood Pressure by Heart Sound Analysis Compared With Intra-Arterial Monitoring in Critically Ill Children—A Pilot Study of a Novel Approach Objectives: To develop a novel device to predict systolic and diastolic blood pressure based on measured heart sound signals and evaluate its accuracy in comparison to intra-arterial blood pressure readings. Study Design: Prospective, observational pilot study. Setting: PICU. Patients: Critically ill children (0–18 yr) undergoing continuous blood pressure monitoring via radial artery intra-arterial catheters were enrolled in the study after informed consent. The study included medical, cardiac, and surgical PICU patients. Interventions: Along with intra-arterial blood pressure, patient's heart sounds were recorded simultaneously by a highly sensitive sensor taped to the chest. Additional hardware included a data acquisition unit and laptop computer. Subsequently, advanced signal processing technologies were used to minimize random interfering signals and extract and separate S1 and S2 signals. A computerized model was then developed using artificial neural network systems to estimate blood pressure from the extracted heart sound analysis. Measurements and Main Outcomes: We found a statistically significant correlation for systolic (r = 0.964; R2 = 0.928) and diastolic (r = 0.935; R2 = 0.868) blood pressure readings (n = 491) estimated by the novel heart-sound signal–based method and those recorded by intra-arterial catheters. The mean difference of the individually paired determinations of the blood pressure between the heart-sound–based method and intra-arterial catheters was 0.6 ± 7 mm Hg for systolic blood pressure and –0.06 ± 5 mm Hg for diastolic blood pressure, which was within the recommended range of 5 ± 8 mm Hg for any new blood pressure devices. Conclusions: Our findings provide proof of concept that the heart-sound signal-based method can provide accurate, noninvasive blood pressure monitoring. Drs. Kapur and Chen contributed equally to the article. This work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation (www.michiganbusiness.org). Dr. Kapur's institution received funding from Alexion; a nonprovisional patent (number PCT/US18/17178) titled, "Method and Apparatus for Determining Blood Pressure on Measured Heart Sounds," based on this research was submitted on 02/07/2018 (to Drs. Kapur, Chen, Xu, and Wu listed as co-inventors); and he disclosed off-label product use of the technology reported in the article, which is currently investigational and not approved by the U.S. Food and Drug Administration for any purposes. Drs. Kapur and Chen disclosed that this work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation. Dr. Xu disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gkapur@med.wayne.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Relationship Between Diaphragmatic Electrical Activity and Esophageal Pressure Monitoring in Children Objectives: Mechanical ventilation is an essential life support technology, but it is associated with side effects in case of over or under-assistance. The monitoring of respiratory effort may facilitate titration of the support. The gold standard for respiratory effort measurement is based on esophageal pressure monitoring, a technology not commonly available at bedside. Diaphragmatic electrical activity can be routinely monitored in clinical practice and reflects the output of the respiratory centers. We hypothesized that diaphragmatic electrical activity changes accurately reflect changes in mechanical efforts. The objectives of this study were to characterize the relationship between diaphragmatic electrical activity and esophageal pressure. Design: Prospective crossover study. Setting: Esophageal pressure and diaphragmatic electrical activity were simultaneously recorded using a specific nasogastric tube in three conditions: in pressure support ventilation and in neurally adjusted ventilatory support in a random order, and then after extubation. Patients: Children in the weaning phase of mechanical ventilation. Interventions: The maximal swing in esophageal pressure and esophageal pressure-time product, maximum diaphragmatic electrical activity, and inspiratory diaphragmatic electrical activity integral were calculated from 100 consecutive breaths. Neuroventilatory efficiency was estimated using the ratio of tidal volume/maximum diaphragmatic electrical activity. Measurements and Main Results: Sixteen patients, with a median age of 4 months (interquartile range, 0.5–13 mo), and weight 5.8 kg (interquartile range, 4.1–8 kg) were included. A strong linear correlation between maximum diaphragmatic electrical activity and maximal swing in esophageal pressure (r2 > 0.95), and inspiratory diaphragmatic electrical activity integral and esophageal pressure-time product (r2 > 0.71) was observed in all ventilatory conditions. This correlation was not modified by the type of ventilatory support. Conclusions: On a short-term basis, diaphragmatic electrical activity changes are strongly correlated with esophageal pressure changes. In clinical practice, diaphragmatic electrical activity monitoring may help to inform on changes in respiratory efforts. 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/pccmjournal). Dr. Baudin received funding from Maquet Critical Care (speaking fees and nonfinancial support). Dr. Beck received funding from Maquet Critical Care (she and her husband have made inventions related to neural control of mechanical ventilation that are patented. The patents are assigned to the academic institution[s] where inventions were made. The license for these patents belongs to Maquet Critical Care. Future commercial uses of this technology may provide financial benefit to them through royalties) and Neurovent Research Inc (NVR) (she and her husband own 50% of NVR, which is a research and development company that builds the equipment and catheters for research studies. NVR has a consulting agreement with Maquet Critical Care). Dr. Jouvet's institution received funding from Air Liquide Santé (grant and lecture), and he received salary and grant funding from the Ministry of Health of Quebec, Sainte Justine Hospital, and Public Research Agency of Quebec. Dr. Emeriaud's institution received funding from Fonds de Recherche du Québec—Santé and Maquet Critical Care (currently supporting a feasibility study in neonatal ventilation which Dr. Emeriaud is leading). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sandrine.essouri.hsj@ssss.gouv.qc.ca ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

International Study of the Epidemiology of Platelet Transfusions in Critically Ill Children With an Underlying Oncologic Diagnosis Objectives: To describe the epidemiology of platelet transfusions in critically ill children with an underlying oncologic diagnosis and to examine effects of prophylactic versus therapeutic transfusions. Design: Subgroup analysis of a prospective, observational study. Setting: Eighty-two PICUs in 16 countries. Patients: All children (3 d to 16 yr old) who received a platelet transfusion during one of the six predefined screening weeks and had received chemotherapy in the previous 6 months or had undergone hematopoietic stem cell transplantation in the last year. Interventions: None. Measurements and Main Results: Of the 548 patients enrolled in the parent study, 237 (43%) had an underlying oncologic diagnosis. In this population, 71% (168/237) of transfusions were given prophylactically, and 59% (139/237) of transfusions were given at a total platelet count greater than 20 × 109/L, higher than the current recommendations. Those with an underlying oncologic diagnosis were significantly older, and received less support including less mechanical ventilation, fewer medications that affect platelet function, and less use of extracorporeal life support than those without an underlying oncologic diagnosis. In this subpopulation, there were no statistically significant differences in median (interquartile range) platelet transfusion thresholds when comparing bleeding or nonbleeding patients (50 × 109/L [10–50 × 109/L] and 30 × 109/L [10–50 × 109/L], respectively [p = 0.166]). The median (interquartile range) interval transfusion increment in children with an underlying oncologic diagnosis was 17 × 109/L (6–52 × 109/L). The presence of an underlying oncologic diagnosis was associated with a poor platelet increment response to platelet transfusion in this cohort (adjusted odds ratio, 0.46; 95% CI, 0.22–0.95; p = 0.035). Conclusions: Children with an underlying oncologic diagnosis receive nearly half of platelet transfusions prescribed by pediatric intensivists. Over half of these transfusions are prescribed at total platelet count greater than current recommendations. Studies must be done to clarify appropriate indications for platelet transfusions in this vulnerable population. The Point Prevalence Study of Platelet Transfusions in Critically Ill Children (P3T) Investigators are listed in the Acknowledgments. Dr. Cushing received funding from Cerus Corporation, Octapharma, and Instrumentation Laboratory. Dr. Steiner's institution received funding from the National Institutes of Health and Boeringer-Ingelheim, and she received funding from Cerus (travel for study design consultation regarding pathogen-inactivated red cells). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: man9026@med.cornell.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Parent Medical Traumatic Stress and Associated Family Outcomes After Pediatric Critical Illness: A Systematic Review Objectives: To critically review, analyze, and synthesize the literature on parent medical traumatic stress from a child's critical illness requiring PICU admission and its association with outcomes of parent mental and physical health, and family functioning. Data Sources: Systematic literature search of Pubmed, Embase, CINAHL, and PsychInfo. Study Selection: Two reviewers identified peer-reviewed published articles with the following criteria: 1) published between January 1, 1980, and August 1, 2018; 2) published in English; 3) study population of parents of children with a PICU admission; and 4) quantitative studies examining factors associated with outcomes of parent mental health, parent physical health, or family functioning. Data Extraction: Literature search yielded 2,476 articles, of which 23 studies met inclusion criteria. Study data extracted included study characteristics, descriptive statistics of parent outcomes after critical illness, and variables associated with parent and family outcomes. Data Synthesis: Studies examined numerous variables associated with parent and family outcomes and used multiple survey measures. These variables were categorized according to their phase in the Integrative Trajectory Model of Pediatric Medical Traumatic Stress, which included peri-trauma, acute medical care, and ongoing care or discharge from care. The majority of objective elements of a child's illness, such as severity of illness and length of hospitalization, did not have a clear relationship with parent and family outcomes. However, familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge were often associated with parent and family outcomes. Conclusions: This systematic literature review suggests that parent and family outcomes after pediatric critical illness are impacted by familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge. Developing parent interventions focused on modifying the parent's subjective experience in the PICU could be an effective approach to improve parent outcomes. 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/pccmjournal). This work was supported by the Department of Pediatrics at Children's Hospital of Michigan and the Department of Pediatrics at the University of Michigan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lyagiela@dmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms Objectives: To describe characteristics of liver transplant patients with severe sepsis in the PICU. Design: Retrospective descriptive analysis. Setting: Tertiary children's hospital PICU. Patients: Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. Interventions: None. Measurements and Main Results: Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1–6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25–39.75 d) and 25 days (9–41 d), whereas 54.5 days (17–131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. Conclusions: We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies. Supported, in part, by grant from National Institutes of Health (NIH) T32-HD40686 (to Dr. Alcamo) and NIH R01-GM108618 (to Dr. Carcillo). Dr. Alcamo's institution received funding from National Institutes of Health (NIH) T32 HD040686. Drs. Alcamo, Carcillo, and Aneja received support for article research from the NIH. Dr. Carcillo's institution received funding from the NIH/National Institute of General Medical Sciences. Dr. Michaels' institution received funding from Pfizer (unrelated study grant), and she received funding as an American Society of Transplantation board member (travel and room for meetings, no honoraria) and from National Institute of Allergy and Infectious Diseases (honoraria and travel and room for Data and Safety Monitoring Board meetings). Dr. Aneja received royalties from UpToDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Alicia.Alcamo@chp.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

State of the Unit: Physician Gender Diversity in Pediatric Critical Care Medicine Leadership Gender disparities in leadership are receiving increased attention throughout medicine and medical subspecialties. Little is known about the disparities in Pediatric Critical Care Medicine. In this piece, we explore gender disparities in Pediatric Critical Care Medicine physician leadership. We examine physician leadership in the Accreditation Council for Graduate Medical Education fellowship programs, as well as a limited sample of major Pediatric Critical Care Medicine textbooks and societies. Overall, the gender composition of division directors is not significantly different from that of workforce composition, although regional differences exist. More women than men lead fellowship programs, at a higher ratio compared with workforce composition. However, greater gender disparities are present in editorial leadership in this limited analysis. We conclude by recommending potential paths forward for further study and intervention, such as tracking gender diversity and being cognizant of the unique challenges that women currently experience in professional advancement. 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/pccmjournal). Dr. Riley receives support from the Institute for Healthcare Improvement to develop measurement framework and measures for the 100 Million Healthier Lives Initiative. Dr. Stalets received funding from Fisher & Paykel (hotel and flight accommodations to attend a conference). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Andrea.Maxwell@cchmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

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

6948891480

alsfakia@gmail.com

Human Genetics

Correction to: Therapeutic application of the CRISPR system: current issues and new prospects In Original article publication, the Acknowledgment statement was not included. The acknowledgement of this article is given below:

Estimation of metabolic syndrome heritability in three large populations including full pedigree and genomic information Abstract Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib–household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ( \(h_{\text{SNP}}^{2}\) : 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and \(h_{\text{SNP}}^{2}\) ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.

Autophagy in aging and longevity Abstract Our understanding of the process of autophagy and its role in health and diseases has grown remarkably in the last two decades. Early work established autophagy as a general bulk recycling process which involves the sequestration and transport of intracellular material to the lysosome for degradation. Currently, autophagy is viewed as a nexus of metabolic and proteostatic signalling that can determine key physiological decisions from cell fate to organismal lifespan. Here, we review the latest literature on the role of autophagy and lysosomes in stress response and longevity. We highlight the connections between autophagy and metabolic processes, the network associated with its regulation, and the links between autophagic dysfunction, neurodegenerative diseases, and aging.

Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway Abstract Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identification of genetic predictors by genome exome sequencing and their influence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could influence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most significant associations in 81 other cases. The analysis of exome sequencing identified one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identified five gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMTand GLI3 with NTD risk in the 81 cases. We found a significant hemimethylation of CFAP46 that may influence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identified new candidate genes and rare variants that highlight an interacting influence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.

Insights into the loss of the Y chromosome with age in control individuals and in patients with age-related macular degeneration using genotyping microarray data Abstract The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.

Epidemiology, genetic epidemiology and Mendelian randomisation: more need than ever to attend to detail Abstract In the current era, with increasing availability of results from genetic association studies, finding genetic instruments for inferring causality in observational epidemiology has become apparently simple. Mendelian randomisation (MR) analyses are hence growing in popularity and, in particular, methods that can incorporate multiple instruments are being rapidly developed for these applications. Such analyses have enormous potential, but they all rely on strong, different, and inherently untestable assumptions. These have to be clearly stated and carefully justified for every application in order to avoid conclusions that cannot be replicated. In this article, we review the instrumental variable assumptions and discuss the popular linear additive structural model. We advocate the use of tests for the null hypothesis of 'no causal effect' and calculation of the bounds for a causal effect, whenever possible, as these do not rely on parametric modelling assumptions. We clarify the difference between a randomised trial and an MR study and we comment on the importance of validating instruments, especially when considering them for joint use in an analysis. We urge researchers to stand by their convictions, if satisfied that the relevant assumptions hold, and to interpret their results causally since that is the only reason for performing an MR analysis in the first place.

Therapeutic application of the CRISPR system: current issues and new prospects Abstract Since its discovery, the Clustered Regularly Interspaced Short Palindromic Repeat (the CRISPR) system has been increasingly applied to therapeutic genome editing. Employment of several viral and non-viral vectors has enabled efficient delivery of the CRISPR system to target cells or tissues. In addition, the CRISPR system is able to modulate the target gene's expression in various ways, such as mutagenesis, gene integration, epigenome regulation, chromosomal rearrangement, base editing and mRNA editing. However, there are still limitations hindering an ideal application of the system: inefficient delivery, dysregulation of the delivered gene, the immune response against the CRISPR system, the off-target effects or the unintended on-target mutations. In addition, there are recent discoveries that have not been yet applied to CRISPR-mediated therapeutic genome editing. Here, we review the overall principles related to the therapeutic application of the CRISPR system, along with new strategies for the further application and prospects to overcome the limitations.

Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution Abstract Sequences encoding Olduvai (DUF1220) protein domains show the largest human-specific increase in copy number of any coding region in the genome and have been linked to human brain evolution. Most human-specific copies of Olduvai (119/165) are encoded by three NBPF genes that are adjacent to three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis. Here, employing genomic, phylogenetic, and transcriptomic evidence, we show that these NOTCH2NL/NBPF gene pairs evolved jointly, as two-gene units, very recently in human evolution, and are likely co-regulated. Remarkably, while three NOTCH2NL paralogs were added, adjacent Olduvai sequences hyper-amplified, adding 119 human-specific copies. The data suggest that human-specific Olduvai domains and adjacent NOTCH2NL genes may function in a coordinated, complementary fashion to promote neurogenesis and human brain expansion in a dosage-related manner.

Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy Abstract Cytochrome c oxidase 20 (COX20)/FAM36A encodes a conserved protein that is important for the assembly of COX, complex IV of the mitochondrial respiratory chain. A homozygous mutation (p.Thr52Pro) in COX20 gene has been previously described to cause muscle hypotonia and ataxia. In this study, we describe two patients from a non-consanguineous family exhibiting autosomal recessive sensory-dominant axonal neuropathy and static encephalopathy. The whole-exome sequencing analysis revealed that both patients harbored compound heterozygous mutations (p.Lys14Arg and p.Trp74Cys) of COX20 gene. The pathogenicity of the variants was further supported by morphological alternations of mitochondria observed in sural nerve and decreased COX20 protein level of peripheral blood leucocytes derived from the patients. In conclusion, COX20 might be considered as a candidate gene for the complex inherited disease. This observation broadens the clinical and genetic spectrum of COX20-related disease. However, due to the limitation of a single-family study, additional cases and studies are definitely needed to further confirm the association.

An update on the genetics of ocular coloboma Abstract Ocular coloboma is an uncommon, but often severe, sight-threatening condition that can be identified from birth. This congenital anomaly is thought to be caused by maldevelopment of optic fissure closure during early eye morphogenesis. It has been causally linked to both inherited (genetic) and environmental influences. In particular, as a consequence of work to identify genetic causes of coloboma, new molecular pathways that control optic fissure closure have now been identified. Many more regulatory mechanisms still await better understanding to inform on the development of potential therapies for patients with this malformation. This review provides an update of known coloboma genes, the pathways they influence and how best to manage the condition. In the age of precision medicine, determining the underlying genetic cause in any given patient is of high importance.

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

6948891480

alsfakia@gmail.com