Is World Trade Center exposure on and after September 11, 2001, associated with long-term cardiovascular disease risk in Fire Department of the City of New York firefighters?In this cohort study of 9796 firefighters, age-adjusted incident rates of cardiovascular disease were higher for firefighters with greater World Trade Center exposure. Both acute World Trade Center as well as repeated exposure during 6 or more months at the World Trade Center site appeared to be associated with long-term elevated cardiovascular disease risk.These findings suggest the continued need for long-term monitoring of the health of survivors of disasters. Published studies examining the association between World Trade Center (WTC) exposure on and after September 11, 2001, and longer-term cardiovascular disease (CVD) outcomes have reported mixed findings.To assess whether WTC exposure was associated with elevated CVD risk in Fire Department of the City of New York (FDNY) firefighters.In this cohort study, the association between WTC exposure and the risk of CVD was assessed between September 11, 2001, and December 31, 2017, in FDNY male firefighters. Multivariable Cox regression analyses were used to estimate CVD risk in association with 2 measures of WTC exposure: arrival time to the WTC site and duration of work at the WTC site. Data analyses were conducted from May 1, 2018, to March 8, 2019.The primary CVD outcome included myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death. The secondary outcome  included all primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either use of angina medication or cardiac catheterization without intervention; cardiomyopathy; and other CVD .There were 489 primary outcome events among 9796 male firefighters . Age-adjusted incident rates of CVD were higher for firefighters with greater WTC exposure. The multivariable adjusted hazard ratio (HR) for the primary CVD outcome was 1.44  for the earliest arrival group compared with those who arrived later. Similarly, those who worked at the WTC site for 6 or more months vs those who worked less time at the site were more likely to have a CVD event . Well-established CVD risk factors, including hypertension , hypercholesterolemia , diabetes , and smoking , were significantly associated with CVD in the multivariable models. Analyses with the all-CVD outcome were similar.The findings of the study suggest a significant association between greater WTC exposure and long-term CVD risk. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters. This cohort study examines the long-term risk for the development of cardiovascular disease in firefighters who responded to the World Trade Center disaster on September 11, 2001, and worked at the site thereafter. Thousands of Fire Department of the City of New York (FDNY) firefighters were exposed on 9/11 and for up to 10 months thereafter. Studies of the FDNY cohort have repeatedly shown that WTC exposure was directly associated with the proximate and long-term risk of obstructive airways disease, sinus disease, and other conditions, including posttraumatic stress disorder (PTSD); these associations have persisted for years after 9/11.8 Decades of research have identified major modifiable risk factors for CVD, including hypertension, high cholesterol levels, insulin resistance, and cigarette smoking.8 Environmental exposures have more recently emerged as factors of concern.10 Studies associating CVD with environmental particulate matter have relied on residence or employment as markers of long-term exposure to air pollution or traffic exhaust, consistent with a chronic disease model.11 Other studies have noted an increase in CVD events on the same day as elevated air pollution measurements, suggesting a pulmonary or inflammatory response from an acute exposure.15 Similarly, among residents of neighborhoods exposed to WTC dust, CVD-related hospital admissions increased soon after 9/11.18Cardiovascular disease (CVD) has long been the greatest source of mortality and morbidity in the United States.19 while others reported no associations.22 This longitudinal cohort study examined long-term CVD events in a well-defined cohort of FDNY firefighters, established before 9/11, who responded to the WTC disaster and worked at the site over subsequent months. In particular, we assessed whether acute and postacute exposure to the WTC site was associated with elevated long-term CVD risk.Studies examining associations of WTC exposure with longer-term CVD outcomes have reported inconsistent findings. In one study, WTC exposure was found to be associated with an elevated risk of CVD events,STROBE) reporting guideline. The study was approved by the Albert Einstein College of Medicine institutional review board. Participants provided written informed consent; they did not receive financial compensation.We followed up the cohort of FDNY firefighters who reported first arrival at the WTC site in the 2 weeks after 9/11 and were actively employed on 9/11 (N = 10 637). Owing to small numbers and the likely different CVD risk profile, women (n = 25) were excluded, as were those who did not provide consent (n = 803), had prevalent CVD (n = 12), and lacked follow-up information (n = 1); 9796 firefighters were included in the study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  included primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either medication prescribed for angina or cardiac catheterization without intervention; cardiomyopathy; and other CVD . If a participant had more than 1 outcome event, primary events took precedence; among events in the same group, we analyzed the one with the earlier diagnosis date. Two of us (M.D.W. and N.J.) reviewed the detailed physician notes recording the diagnosis to confirm the categorization; disagreement was resolved by one of us (K.L.C.). Cardiovascular disease death information was obtained through linkage to the National Death Index. Some, but not all, of the specific dates of the CVD events were known. Therefore, for consistency, the year of the event was used for all events.Consistent with other studies, we used 2 definitions of CVD outcomes.5: participants who reported their first arrival at the site during the morning of 9/11  were considered the most exposed because they were present during or immediately after the towers collapsed. Those who arrived that afternoon were categorized as arrival group 2. Arrival group 3 included those who first arrived on 9/12, and participants who arrived between days 3 and 14 were denoted as arrival group 4.2 Analyses combined arrival groups 3 and 4 as the reference cohort.Two measures of WTC exposure were assessed based on questionnaire responses because work records were not available. As in previous studies, arrival time, which was our measure of acute exposure, was defined as follows26 We dichotomized the duration variable using the top quartile as the cutoff (working ≥6 months vs <6 months as reference).The second, postacute exposure measure, was based on the number of months in which participants worked at the WTC site, beginning 9/11 and ending July 24, 2002, when the site was officially closed to the FDNY. Values were assigned representing the number of months in which a participant reported working at the site for 1 or more days.26 Beginning December 27, 2005, the FDNY used the PTSD Checklist (PCL-17).28 The earliest measurement from either the PCL-m or the PCL-17 was used; 528 participants (approximately 6%) completed the PCL-17 as their first measure. In the PCL-m, 14 questions were modified to fit the context of 9/11; answer choices were binary (yes or no). To score as having PTSD with the PCL-m, we required symptoms within each of the 3 Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision PTSD symptom groups. We found this modified measure to be similar to the PCL-17.29 When the PCL-17 was used, a score of 44 or higher was considered positive for PTSD.28 Since both the PCL-m and PCL-17 are screening rather than diagnostic tools, our PTSD designation indicates probable PTSD. Race/ethnicity was categorized as non-Hispanic white and other. Body mass index was categorized as normal or underweight , preobesity  obesity class I , obesity class II , and obesity class III . For each variable, the first available measure after 9/11 was considered the baseline value.We combined information from FDNY employee records, medical records, and questionnaires to construct covariates that included baseline values for hypertension, diabetes, hypercholesterolemia, smoking, and PTSD, along with age, race/ethnicity, and body mass index (BMI) . Hypertension was defined as a systolic blood pressure of 140 mm Hg or above or a diastolic blood pressure of 90 mm Hg or above, self-reported hypertension medication use, or physician’s diagnosis of hypertension. Diabetes was defined as a fasting blood glucose level of 126 mg/dL or higher , self-reported diabetes medication use, or physician’s diagnosis of diabetes. Hypercholesterolemia was defined as a total cholesterol level of 200 mg/dL or higher , or self-reported hypercholesterolemia medication use or physician’s diagnosis of high cholesterol level. Cigarette smoking history was categorized as current smoker, former smoker, or never smoker based on self-report. Posttraumatic stress disorder at baseline was defined using 2 measures. Beginning on October 2, 2001, the FDNY-modified PTSD Checklist (PCL-m) was administered.2 test for categorical variables and analysis of variance for age. Age-adjusted incidence rates per 1000 person-years were calculated for the primary CVD outcome and all CVD and reported by exposure categories.Baseline characteristics were compared across arrival groups and duration groups using the χP value for linear trend was assessed to test whether the association between the 3 arrival time groups and CVD was linear. First-order interactions of covariates with the exposure variables were assessed. In addition, we fit models that included both exposure variables in the same model. Schoenfeld residuals were examined to assess violation of the proportional hazards assumptions.30 Multivariable models were constructed for both the primary outcome and all CVD.Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models. Because age is a risk factor for CVD, we used age as the time scale in the models. Follow-up began at age on 9/11 and ended at the youngest of age at event (if applicable), age at end of study , age at last FDNY health examination, or age at death. Models were first adjusted for race/ethnicity alone, and then for race/ethnicity, BMI, hypertension, hypercholesterolemia, diabetes, smoking, and PTSD. A We conducted a sensitivity analysis by substituting the first PCL-17 measurement for the baseline PCL-m measurement and repeated the primary analyses. Accordingly, we began follow-up at the age on January 1, 2006, and used covariate values from the first available measure after January 1, 2006. Participants who were censored before January 1, 2006, in the primary analysis were similarly excluded from this sensitivity analysis.P values for HRs were derived from Wald statistics; a 2-tailed α level of .05 was used to denote statistical significance. Data analyses were conducted from May 1, 2018, to March 8, 2019, using SAS software, version 9.4 (SAS Institute Inc).P < .001), race/ethnicity ; P < .001), current smoker , and probable PTSD . Duration of work between group 1 vs 2 was significantly associated with age , race/ethnicity , and probable PTSD .The study population included 9796 male firefighters; most were never smokers (7210 of 9796 [73.6%]) and non-Hispanic white (9225 of 9796 [94.2%]). The In more than 16 years of follow-up, there were 489 primary outcome events. The distribution of events over time for the primary outcome and for all CVD is shown in P = .02), and the fully adjusted HR of primary CVD was 1.44 . The HRs for arrival group 2 vs arrival groups 3 and 4 were not significantly elevated. The P value for linear trend for the HRs of the 3 arrival group categories was P = .009 for fully adjusted models.Schoenfeld residuals suggested that the Cox models met proportional hazards assumptions. P = .01), hypercholesterolemia , diabetes , smoking , and class I obesity , were associated with the primary CVD outcome in the arrival group multivariable analysis. These same risk factors were also associated with the primary CVD outcome in the duration group multivariable analysis. Neither BMI nor PTSD was significantly associated with the primary CVD outcome. No significant interactions of arrival group with other covariates were observed. For all-CVD variables, HRs for arrival groups 1 and 2 were modestly smaller than for the primary CVD outcome, but in the same direction. The P value for linear trend across the 3 arrival group categories for all CVD was P = .02 for the fully adjusted model. Hypertension, hypercholesterolemia, diabetes, smoking, and elevated BMI  showed significant associations with this outcome, while PTSD did not. Adjusted HRs for arrival groups were of similar magnitude to HRs for hypertension.Well-established CVD risk factors, including hypertension  for minimally adjusted models and 1.30  for fully adjusted models. Results for the other covariates were similar to those in models using arrival group as the exposure. No significant interactions of duration with other covariates were observed. For all CVD, these HRs were 1.30  for minimally adjusted models and 1.31  for fully adjusted models.The fully adjusted Cox models using duration as the exposure measure and the primary CVD outcome are displayed in P = .27, arrival group model) and 1.24 . The main associations between both acute and postacute work exposure variables with CVD were similar to those of the primary analyses.In sensitivity analyses examining the CVD association with PTSD using PCL-17 scores only, the magnitude of the association was greater, although PTSD remained nonsignificant. For the primary CVD outcome, the HRs for PTSD were 1.19  and postacute (duration) work exposure at the WTC site and risk of CVD events throughout more than 16 years of follow-up. These associations were statistically significant after adjustment for age, race/ethnicity, and baseline assessments of BMI, hypertension, hypercholesterolemia, diabetes, smoking, and probable PTSD. Furthermore, the HR of the highest vs lowest exposure group was comparable in magnitude to that of hypertension, which is an established risk factor for CVD.9 A 2010 update concluded that the body of evidence was “…consistent with a causal relationship between PM2.5 [aerodynamic diameter] exposure and cardiovascular morbidity and mortality.”12(p1)Traditional CVD risk factors include hypertension, hypercholesterolemia, diabetes, smoking, older age, and BMI. Environmental exposures to small, airborne particulate matter have increasingly been recognized as also contributing to CVD risk, including by a 2004 American Heart Association scientific statement.2.5], carbon monoxide levels, and ozone levels.34 It is not possible to distinguish specific WTC dust components, which included an extensive variety from organic and inorganic material ranging in size from 2.5 μm or less to larger than 53 μm. In a measured sample, approximately 0.88% to 1.98% of the total mass was PM2.5.35 With more than a million tons of WTC dust, even 1% would constitute an enormous amount of PM2.5. The highest concentration of dust occurred during and immediately after the collapse of the WTC towers, although dust became reaerosolized when disturbed during the recovery and cleanup effort.36 Furthermore, there is the possibility of gaseous and chemical inhalations beyond concerns about particulate matter of specific sizes.Previous non-WTC studies of air pollutants and CVD have focused on particulate matter less than 2.5 μm [PM15 Similarly, ecologic studies of CVD events immediately following the WTC disaster showed significant associations with WTC exposure.18 Potential mechanisms for short-term exposures and acute CVD outcomes may be different from mechanisms for longer-term exposures and CVD events occurring years later, since an event on the same or next day after exposure could more plausibly be linked to triggers related to pulmonary crises, stress-related spikes in blood pressure, or platelet aggregation.Ecologic studies of short-term exposures and acute CVD events typically link daily rates of measured particulate concentrations with concurrent CVD hospital admissions and deaths.5 The association between WTC exposure and CVD has also been observed in other WTC studies,19 although not in all.22 This difference may be owing to the high exposure levels experienced by FDNY firefighters compared with levels experienced by non-FDNY rescue and recovery workers. In a non-WTC study of the aftermath of an oil spill, those who worked on the cleanup for more than 180 days—similar to our duration exposure measure—showed a significantly greater long-term incidence of heart disease.37Both high-level acute exposure with arrival before noon on 9/11 and recurrent postacute exposure with prolonged duration of work at the site were significantly associated with long-term risk of the primary CVD outcome and all CVD. We found the risk was 44% greater among firefighters who arrived on the morning of 9/11 compared with those who arrived later. This finding suggests that discrete exposure to dust and products of combustion could have initiated persistent pathologic processes related, in part, to chronic inflammation that increased CVD risk years later. Increased risk for other health outcomes has been noted in this cohort.38 Although we included PTSD in our models, we did not observe a significant association with either CVD outcome measure. We performed a sensitivity analysis because we were concerned that the timing of our PTSD measure, obtained from the earliest post-9/11 survey, may have contributed to the observed lack of significance. Sensitivity analyses examined the association of PTSD as measured after 2006 (using PCL-17 score) with CVD; however, PTSD still did not achieve statistical significance. Future research will study the possibility that PTSD measured later during follow-up could act as a mediator between WTC exposure and CVD.Previous research from other WTC cohorts has shown an association between PTSD and CVD events.2.5 or other dust components. Similarly, work records were not available to determine the exact time of arrival or days of work at the site. Nonetheless, the measures we used have demonstrated external validity in studies of lung function decline, adverse pulmonary symptoms, and PTSD.29 In addition, hospital records were not available in all cases to confirm CVD outcomes, so misclassification is possible. However, the severity of these diagnoses is such that our program physicians typically require supporting documentation. Similarly, lack of the exact date of a CVD event can be expected to reduce precision of HR estimates, which would likely bias toward the null. It is possible that the long-term risk of CVD observed in these firefighters can be attributed to their stressful occupation, which also reexposed them to smoke and dust in subsequent fires. However, in this analysis, the reference groups were firefighters who likely had similar non-WTC exposures. The reference groups were still WTC exposed, albeit less exposed, rather than non-WTC exposed, suggesting that the true association of exposure might be greater than we observed.This study has several limitations. Our exposure variables are relative and do not quantify specific concentrations of PM38 These diagnoses, along with physicians’ notes, were clinically reviewed for classification as primary outcome events or all-CVD events. In addition, CVD diagnoses are not conditions whose medical care is covered under the James Zadroga 9/11 Health and Compensation Act. As a result, the likelihood of overreporting CVD for purposes of compensation is small. Furthermore, we observed associations of the traditional CVD risk factors consistent with what is known, possibly providing further evidence of external validity.This study also has considerable strengths. The FDNY WTC-exposed firefighter cohort, established before 9/11, has been extensively studied with consistency of results. At baseline, the few (<0.5%) participants with CVD were removed from analyses, leaving a healthy group that was followed up for as long as 16 years. The CVD outcomes were based on physician-documented diagnoses in the FDNY medical record rather than patient self-report that others have used.We observed that acute WTC dust exposure, as well as repeated exposures over the months of cleanup, may be associated with elevated CVD risk throughout 16 years of longitudinal follow-up. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters. Future studies are warranted to address whether identifying and addressing changes in other CVD risk factors can mitigate elevated CVD risk associated with disaster exposure.


N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a paraneoplastic limbic encephalitis, recently identified.Anti-To summarize our experience in the nursing care of patients with anti-NMDAR encephalitis managed with surgery and pharmacotherapy.This study included 45 patients treated between July 2015 and November 2016. Laparoscopic oophorocystectomy was performed in 11 female patients with teratomas. Eleven patients required tracheal intubation or tracheotomy and ventilation.The patients were hospitalized for an average of 25.2 days. The mental and neurological symptoms were significantly relieved 23.6 ± 4.8 days after surgery or immunotherapy. Near-normal function was restored in 11 patients, while 34 patients had varying degrees of dysfunction at discharge. After follow-up of 1 to 18 months, 24 patients were found to have permanent impairments.Appropriate symptomatic nursing care is required to ensure the safety of patients with anti-NMDAR encephalitis. Anti-NMDAR encephalitis is caused by antibodies against NMDA receptors on the surface of hippocampal neurons, and often occurs as a paraneoplastic syndrome associated with ovarian teratoma. It affects males and females of all ages. The condition is potentially fatal. In the United States, the incidence of anti-NMDAR encephalitis rivals that of viral encephalitis. In England, anti-NMDAR encephalitis accounts for 4% of all encephalitis cases. Anti-NMDAR encephalitis was reported for the first time in China by Xu et al in 2010.Anti- The nursing care of these patients is challenging because of the complex clinical manifestations, long disease duration, slow recovery, and high risk of recurrence and death. Furthermore, because of the limited information available on the disease, the management of the psychiatric symptoms in critically ill patients with anti-NMDAR encephalitis is difficult.Despite symptom severity, paraneoplastic anti-NMDAR encephalitis has a better prognosis than most other paraneoplastic encephalitis conditions. The symptoms can be alleviated by first-line treatments  or second-line treatments .The aim of this study was to report our experience in the nursing care of 45 patients with anti-NMDAR encephalitis from presentation to end of treatment. This study could improve our clinical understanding of this condition and the quality of nursing care offered to patients with anti-NMDAR encephalitis.22.1This retrospective study included 45 consecutive patients that underwent treatment for anti-NMDAR encephalitis at our hospital between July 2015 and November 2016. We recorded the treatments and nursing care provided to the patients, and assessed the clinical outcome, prognosis, complications, and permanent impairments. The study was approved by the ethics committee of our hospital. Because of the risk to fertility, informed consent was obtained prior to surgery from all patients or their legal representatives.2.2Surgical treatment is the only treatment for ovarian teratoma. Routine preoperative care and examinations were carried out, including electrocardiography, chest radiography, blood tests, urine tests, stool tests, blood type, coagulation function, and pelvic B-mode ultrasound. Skin preparation of the abdominal and perineal regions was performed 1 day before operation. The umbilical skin was cleaned and disinfected or the patient was bathed. The patients were instructed to maintain personal hygiene. For vaginal preparation, a 1:40 iodine solution was used in the morning and evening on the day before the operation. The patients were fasted for 12 h before operation. Polyethylene glycol-electrolyte powder or 25% magnesium sulfate was prescribed for bowel preparation. The patient's history of drug allergy was recorded, and a drug allergy test was carried out before the operation. The surgical procedure and main points on which cooperation was required from the patient were explained to the patients, and their questions were answered to alleviate their doubts and concerns about the operation. The patients were instructed to practice deep breathing and effective coughing exercises, and learn how to relieve themselves on a bed before surgery in order to minimize postoperative micturition and defecation difficulties. The surgery was scheduled to avoid the menstrual period. The patients were offered easily digestible semi-fluid food 2 days before operation, and were given liquid food 1 day before surgery. Gas-producing foods (like milk and beans) were avoided. Vulvar and urethral cleaning were performed twice daily.2.3After returning to the ward, the nurses assessed the patients’ condition in details. The patients were asked to lie flat with the head turned to one side, without pillow, for 6 h. They were given low-flow oxygen. The respiratory tract and trachea were kept clean for tracheal intubation and tracheotomy. Blood pressure, pulse, respiration, and blood oxygen were monitored closely. The patients were monitored for hemorrhage from the operation wound or vagina. Care was taken to prevent undue strain on the abdominal cavity drainage tube, and to maintain its patency. The amount, color, and nature of the drainage fluid were noted.2 into the abdomen. The CO2 gas was suctioned from the abdominal cavity after operation to minimize postoperative distension.Subcutaneous emphysema is a specific complication of laparoscopic surgery. Owing to increased intra-abdominal pressure during laparoscopy, gas can diffuse from the stomach to the skin, or directly penetrate into the skin (in the case of pneumoperitoneum). Usually, this condition resolves by itself. Abdominal distension typically lasts for 12 to 24 h after surgery, and is mainly caused by the injection of COEarly mobilization helps intestinal function recovery after operation. Subcutaneous congestion is mainly observed during 12 to 48 h after surgery, and causes darkening of the skin around the incision. This complication is more obvious in patients with abdominal obesity, and is mostly due to the intraoperative pulling of the abdominal skin, which causes rupture of the subcutaneous capillaries. It resolves spontaneously without any treatment.2.4Early immunotherapy is crucial for good prognosis of anti-NMDAR encephalitis. IVIg was administered at 0.4 g/kg body weight/day for 5 days . Each patient received 2 to 4 cycles of IVIg treatment in combination with steroids . The IVIg solution was infused at l mL/min for the first 15 min. If no adverse reaction occurred, the infusion rate was gradually increased, not exceeding 3 mL/min. The occurrence of adverse reactions to immunoglobulins is 1%. Glucocorticoid therapy was administered in the form of high-dose methyl prednisone pulse therapy  or intravenous dexamethasone . Patients with high-blood pressure or high intraocular pressure were monitored for symptoms such as headache, dizziness, nausea, vomiting, severe eye irritation, and impaired vision. Blood pressure was monitored closely. Attention was paid to osteoporosis symptoms, ulcers, blood sugar changes, symptoms of endocrine disorders, and other side effects.Long-term treatment with high doses of hormones causes imbalances in water, electrolytes, carbohydrates, proteins, and lipids. This can result in Cushing syndrome , acne, hirsutism, atony, hypokalemia, edema, hypertension, and diabetes mellitus.In addition to the above first-line treatments, second-line treatment with rituximab  was administered if required. When rituximab was administered, the patient's temperature was monitored in order to promptly detect and treat allergic reactions and fever. Thirty minutes before rituximab administration, the patient was given intramuscular injections of 5 mg dexamethasone and 20 mg diphenhydramine along with acetaminophen and bupropion.Intravenous fluids were administered and the infusion rate was strictly controlled: 50 mg/h for the first 30 min, without exception, and subsequently increased to 50 mg/min. Visits were limited to prevent contagious diseases like colds. Heart rate and breathing were monitored for early detection of cardiac arrest or arrhythmia.2.5 A spatula was kept readily available at the bedside to prevent tongue biting and respiratory obstruction during seizures. Breathing was kept steady to reduce the risk of aspiration pneumonia due to vomiting and aspiration. The patient's head was tilted to one side, and oxygen was provided in a timely manner. In the event of status epilepticus, care was taken to handle the patient with care and not exert excessive pressure on the patient's body to avoid fractures or joint dislocation. Anti-epileptic drugs were administered as prescribed by the attending physician, including sodium phenobarbital 0.1 to 0.2 g i.m., diazepam 10 mg i.m., or 1 to 2 mL/mg/h midazolam i.v.Epileptic seizures may occur at any stage during the course of anti-NMDAR encephalitis, but their frequency and intensity decrease with recovery.2.6 Mental and behavioral disorders are the most common clinical manifestations of anti-NMDAR encephalitis, and are often misdiagnosed as psychosis or schizophrenia. No objects that could be used as a weapon were kept near the patient's bed to prevent self-injury and harm to others. Hot liquids were kept away from the patients to prevent burn wounds. Midazolam and propofol were used for sedation of restless patients. The sedative effect was greater when both drugs were used in combination.In patients with anti-NMDAR encephalitis, abnormal movements can be caused by psychosis, auditory and visual hallucinations, aggression, anxiety, depression, insomnia, catatonia, choreoathetosis, and complex and stereotypic movement disorders.2.7 This condition is characterized by difficult breathing, oxygen desaturation, apnea, decreased partial pressure of arterial blood oxygen, and increased partial pressure of CO2. Patients with difficult breathing, oxygen desaturation, or cyanosis of the face, lips, and nails were immediately given oxygen inhalation (mask). Breathing was kept steady, and the patient was laid flat with the head turned to one side to facilitate the discharge of respiratory secretions and vomiting. Artificial airway and mechanical ventilation were used in the event of severe respiratory failure.Central hypoventilation has been reported in some cases of brainstem or hypothalamic paraneoplastic syndromes.2.8The tracheal incision dressing was changed once a day. Proper elasticity and length of the catheter were verified. After the tracheal catheter was connected to the ventilator, the catheter was supported against gravity to prevent tracheal compression and necrosis. Long-term compression of the organs or mucous membrane by the tracheal catheter was prevented by discharging air from the catheter for 3 to 5 min every 3 to 4 h. Before air discharge, oropharyngeal suction was applied.2.9 hypersexuality, and hypersalivation. Untreated autonomic dysfunction can progress to death or permanent disability.In patients with anti-NMDAR encephalitis, autonomic dysfunction can manifest as hyperthermia, urinary and fecal incontinence, hypertension, severe cardiac dysrhythmia, clinically significant cardiac pauses,For patients with hypersalivation, the mouth and cheeks were cleaned. A disposable plastic bag was opened, placed 2 to 3 cm away from the mouth, and the head was tilted to one side to let the saliva flow in the plastic bag under gravity. The amount of saliva was recorded. The amount of saliva can reach 50 mL/h and 200 to 320 mL/day when the condition is severe.2.10Serum anti-NMDAR antibody and tumor markers were measured regularly. Patients were instructed to take their drugs on time after leaving the hospital. In particular, they were advised to never miss, reduce, or stop taking hormonal drugs, to use potassium and calcium supplements, to take rest, to avoid physical exertion, to undergo rehabilitation training, and to take safety precautions to prevent accidents. For female patients of >12 years of age, a pelvic MRI was carried out every 6 months for 4 years.33.1Of the 45 patients, 12 were male, and 33 were female. They were 11 to 58 years of age. Mean age at onset was 25.1 years. The average hospital stay was 25.2 days .3.2 The average interval between precursor symptoms and the initial mental and behavioral symptoms was 12 days. In 28 (62%) patients, mental and behavior disorders were the presenting symptoms.Precursor symptoms were present in 27 of the 45 (60%) patients, and mainly were symptoms of upper respiratory tract infection such as headache, fever, runny nose, and sore throat.Of the 45 patients in this study, 34 were agitated, were shouting, and showed anxiety, irritability, tension, insomnia, and auditory and visual hallucinations. During hospitalization, one patient exhibited a jealousy delusion; he firmly believed that his spouse was being unfaithful, and showed aggressive behavior toward her. Nine patients had urinary and fecal dysfunction such as incontinence, dysuria, and constipation. Five patients had tachycardia . The symptoms are shown in Table 3.32O (1 mm H2O = 0.0098 kPa). The cytological and biochemical changes in the CSF of patients with anti-NMDAR encephalitis resembled those observed in patients with viral encephalitis. Both CSF pressure and white blood cell count were increased, as was the percentage of multinucleated and mononuclear cells. The protein levels were normal or slightly elevated, while the sugar and chloride levels were mostly normal or slightly low. All 45 patients underwent brain magnetic resonance imaging (MRI) and video EEG after disease onset. The MRI and EEG findings are shown in Table Lumbar puncture was performed in all 45 patients. No cerebrospinal fluid (CSF) abnormality was detected in 15 patients Table . The CSF3.4All 33 female patients underwent pelvic computed tomography (CT) or transvaginal ultrasound for preoperative tumor screening. Imaging was suggestive of an ovarian teratoma in 11 (24%) patients, all of whom underwent laparoscopic oophorocystectomy. Postoperative pathological examination of the specimen confirmed the presence of ovarian teratoma. One of those patients had bilateral tumors, while the remaining 10 patients had unilateral tumor. In one of these 11 patients, a right ovarian teratoma was found during cesarean section 1 year before disease onset. In another patient, a left ovarian teratoma was resected 6 years before disease onset. Among the 11 patients, seven and four tumors were on the left and right side, respectively. The average tumor diameter was 3.8 cm. Only one patient had an immature grade I teratoma; all other patients had mature teratomas. Mature brain tissue was found in the pathological sections in nine patients.3.5Drainage tubes were used after operation in five patients and for 1 to 2 days. Dressings were changed for two patients with capillary hemorrhage. All patients received first-line immunotherapy, and five patients received second-line treatment with rituximab after initial therapy because of no improvement. The treatments and outcomes of all 45 patients are shown in Table dl-lysine injection was prescribed for 12 patients.Twelve patients who were clearly and continuously restless were given intravenous midazolam or propofol. The 19 patients with fever  were given physical cooling . These treatments were ineffective in three patients, who were provided with ice blankets. Aspirin-4 In a cohort of 577 patients with anti-NMDAR encephalitis, Titulaer et al found that the highest frequency of teratoma-associated disease was among patients of 12 to 45 years of age, with 52% of females >12 years of age having a teratoma. NMDAR antibodies are present in the serum and CSF; occasionally, antibodies are only detectable in the CSF. The main target epitopes are in the NR1/NR2 heteromers of the NMDA receptors. Since the development of the NMDAR assay, some cases of encephalitis of unknown etiology have been reclassified as autoimmune conditions. Over 500 cases of anti-NMDAR encephalitis have been reported in the literature. The California Encephalitis Project (CEP) found that among individuals aged ≤30 years, anti-NMDAR encephalitis is more common than each viral etiologies of encephalitis. Within a 3.5-year period, 32 of 761 (4.2%) cases of encephalitis of uncertain etiology were found to be anti-NMDAR encephalitis. In another study of encephalitis in England, a similar proportion (4.4%) of cases was determined to have been caused by antibodies against NMDA receptors. Although antibodies have been identified in men, approximately 80% of the patients are female. Most tumors are found in females of 12 to 45 years of age. In a recent report, 78% of anti-NMDAR patients in California were white Hispanics and Asian/Pacific Islanders, and 6% were non-Hispanic Caucasians. In addition, tumors associated with anti-NMDAR encephalitis were found more often in Asian and black patients, which suggests a possible genetic risk associated with anti-NMDAR encephalitis.This study aimed to summarize our experience in the nursing care of patients with anti-NMDAR encephalitis. Anti-NMDAR encephalitis is a potentially fatal syndrome that presents with severe psychiatric and neurologic symptoms. Until 5 years ago, limbic encephalitis was considered as a paraneoplastic phenomenon, frequently encountered with lung and testis cancers, and associated with antibodies against neuronal antigens. Thus, psychiatrists must be aware of this condition. Involuntary mouth and limb movements (27% patients) were present for 1 to 2 months in our patients. Of the seven patients with obvious hypersalivation, two showed redness of the cheek and neck skin during the initial stages. Salazar et al reported one case of anti-NMDAR encephalitis associated with involuntary movements and hypersalivation; the symptoms were controlled with narcotics and high-dose sedation, and were aggravated after dose reduction. In 2010, Taguchi et al reported a case of anti-NMDAR encephalitis in a 17-year-old patient with ovarian teratoma. The clinical manifestations included abundant salivary secretion for 42 days, described as the “bubbles of a crab,” which was reduced with an anesthetic drug. Salazar et al suggested that hypersalivation may be caused by changes in hypothalamic neurotransmitter levels leading to excessive stimulation of the parasympathetic neurons in the central nervous system. In the present study, 13 patients had pulmonary ventilation deficiency and CO2 retention symptoms, including 11 patients with respiratory failure. This is much lower than the frequency of central ventilation failure reported by Dalmau et al (66%). We found that 42% of our patients had fever, which is consistent with the literature (48–86%). Among our patients, 24% had teratomas, of which 91% were benign; the incidence of teratomas in previous reports is 56%.In most of our patients (62%), the presenting symptoms were mental and behavioral abnormalities, and 40% of our patients were first admitted in a mental hospital and diagnosed with mental disease. Anti-NMDAR encephalitis is often misdiagnosed as mental illness or viral encephalitis. reported a recurrence rate of 15% during a mean follow-up of 18 months , including cases of single and multiple recurrences. Only one recurrence occurred among the 11 patients with teratoma in our study, which is consistent with previous reports. Compared with patients with tumors, patients without tumors have higher recurrence rates.In the present study, 20% of the patients had recurrence, including six patients with one recurrence each, and three patients with two recurrences each. Consistent with this, Dalmau et al While 38% of our patients had abnormal MRI findings, Dalmau et al reported that 55% of their anti-NMDAR encephalitis patients have MRI abnormalities, which are located in the temporal lobe, hippocampus, corpus callosum, cerebral and cerebellar cortex, frontal lobe, basal ganglia, and brainstem abnormalities. In the present study, 62% of the patients were without MRI abnormalities, and their clinical manifestations included severe mental disorder, epilepsy, involuntary limb movements, and lack of central ventilation, indicating that MRI findings are not always related to clinical severity. Thus, the specific mechanisms underlying anti-NMDAR encephalitis warrant further study.Brain MRI in patients with anti-NMDAR encephalitis may be either normal or abnormal.Considering the long duration, complex clinical manifestations, and life-threatening nature of anti-NMDAR encephalitis, patients with this condition must be treated in an intensive care unit. The disease involves multiple systems and organs, leading to symptoms widely varying among patients, and requiring the intervention of specialists from multiple disciplines. Thus, multidisciplinary communication is crucial to the management of these patients, as this will enable the timely detection and treatment of all types of complications. Psychologists and psychiatrists should be aware of the existence of anti-NMDAR encephalitis in order to avoid misdiagnoses such as viral encephalitis or mental illness. The symptoms of anti-NMDAR encephalitis include hypersalivation, involuntary movements, respiratory impairment, fever, headache, vomiting, mental disorder, and epilepsy. For patients with suspicion of anti-NMDAR encephalitis, lumbar puncture should be performed as early as possible for the detection of anti-NMDA receptor antibody in the CSF. Table 4.1This was a single-center study with a small sample size, and may thus be subject to selection bias. The continuous care of patients after discharge from hospital is the key to the nursing of these patients and a worthy topic for future research.5Anti-NMDAR encephalitis should be considered among the possible differential diagnoses in patients with an abrupt alteration in mental status. Once a diagnosis is established, patients should be quickly screened for underlying tumors and receive immunosuppressant therapy. Most patients experience sustained remission and near-baseline functioning after rapid, aggressive, and continued immunosuppressant treatment.None.Conceptualization: Li Yang, Haixin Bo.Data curation: Li Yang, Qian Jiang, Hongzhi Guan.Writing – original draft: Qian Jiang, Hongzhi Guan, Haixin Bo.


There is strong association between inflammatory processes and their main metabolic mediators, such as leptin, adiponectin secretion, and low/high-density lipoproteins, with the cancer risk and aggressive behavior of solid tumors. In this scenario, cancer cells (CCs) and cancer stem cells (CSCs) have important roles. These cellular populations, which come from differentiated cells and progenitor stem cells, have increased metabolic requirements when it comes to maintaining or expanding the tumors, and they serve as links to some inflammatory mediators. Although the molecular mechanisms that are involved in these associations remain unclear, the two following cellular pathways have been suggested: 1) the mesenchymal-epithelial transition (MET) process, which permits the differentiation of adult stem cells throughout the acquisition of cell polarity and the adhesion to epithelia, as well to new cellular lineages (CSCs); and, 2) a reverse process, termed the epithelial-mesenchymal transition (EMT), where, in pathophysiological conditions , the differentiated cells can acquire a multipotent stem cell-like phenotype. The molecular mechanisms that regulate both EMT and MET are complex and poorly understood. Especially, in the thyroid gland, little is known regarding MET/EMT and the role of CCs or CSCs, providing an exciting, new area of knowledge to be investigated. This article reviews the progress to date in research on the role of inflammatory mediators and metabolic reprogramming during the carcinogenesis process of the thyroid gland and the EMT pathways. Epithelial thyroid cancer (ETC) is the most common malignancy of the endocrine system, which affects the follicular cells of the gland. These tumors are twice as common in women as in men, but male tumors are associated with a poor prognosis. Additional important risk factors include a history of childhood head and neck irradiation, large nodule size (>4 cm), evidence for local tumor fixation or invasion into lymph nodes, and the presence of metastases. Moreover, this neoplasia increases with the age, plateauing after about age 50 years; it represents an important prognostic factor for thyroid cancer at a young age (<20), or in older persons (>45), and it is associated with a worse prognosis .There are two main types of ETC based on the cells’ differentiated characteristics:Well-Differentiated thyroid cancer (WDTC) arises from thyroid follicular epithelial cells and it accounts for the overwhelming majority of thyroid cancers. Of the differentiated cancers, papillary thyroid cancer (PTC) comprises about 85% of cases when compared with about 10%, which have follicular histology, referred to as follicular thyroid cancer (FTC), and 3–5% of the type FTC correspond to the Hürthle cell or oxyphil tumors characteristic.Although PTC and FTC have a good prognosis, in the case of PTC, some histological subtypes, such as tall cell variant, columnar cell variant, and diffuse sclerosing variant, show aggressive behavior with a worse prognosis. In FTC tumors, 11% of patients have an aggressive tumor at diagnosis . In the PTC tumors show multifocality and they are able to invade tissues near the gland; the major tumoral dissemination is through the lymphatic system, but also hematogenously (bone and lung). Most of these tumors (80%) are classified as stages I or II, with a good prognosis and only 1% of them lose the differentiated characteristic, with a fatal prognosis (stage IV).In the case of FTC, epidemiological studies show that iodine-deficiency is a key factor in the development of these types of tumors, and most of them appear as a nodule in the gland with a slow growth before the metastatic process. The histological diagnosis sometimes is difficult, because it presents a normal follicular pattern to anaplastic form without follicles or colloid .The tumors with a nodule are less aversive and present low risk for infiltrating the tissues closer or local adenopathy. Nevertheless, tumors with high risk show capsular invasion, high growing in the local structures (strap muscles or trachea), making their resectability difficult. The prognosis varies in function of the degree of invasion .FTC tends to invade locally and metastasize distantly, rather than to local nodes; they are especially prone to metastasizing to the bone or lung. In a Massachusetts General Hospital series , one-halde novo in the patients. The diagnosis of is difficult, because they show a different histological pattern  with differences in their growing. However, all of them have poor prognosis and lymph node metastasis and distant metastasis is frequent . In. In21]. The WNT/β-catenin signaling pathway plays a well-established role in cell growth and proliferation, as well as in the differentiation of cell progenitors, and its constitutive activation is frequently seen in the oncogenic processes. β-catenin facilitates the transcription of diverse tumor-promoting genes through its upregulation by the WNT signaling pathway . In the In terms of the HIF1α signaling pathway, it is well-known that hypoxia is a strong stimulus for tumor metabolism, growth, and progression. HIF1α is a critical mediator of a response to hypoxia, which binds to HIF1β  to form the transcription factor HIF1; this factor induces the expression of diverse genes that are associated with cell metabolism and tumor angiogenesis—a critical process in solid tumor progression and the intratumoral response to hypoxia. VEGFA induces this process, where HIF1 upregulates the expression . HIF1α i2+-inositol 1,4,5-triphosphoolipase Cβ-mediated signaling by Gs or G11 . There is a clinical association between elevated TSH levels and an elevated risk of malignant thyroid nodules in men .,77.66,77The AdipoR1 and AdipoR2 receptors are expressed in macrophages, dendritic cells (DCs), and lymphocytes of various tissues and organs. These two classical Acrp30 receptors share 67% identity of their protein sequence . They beIt seems that Acrp30 exerts antineoplastic effects via two mechanisms: First, it can directly act on CCs by stimulating receptor-mediated signaling pathways. Second, it may act indirectly by modulating insulin sensitivity at the target tissue site, regulating inflammatory responses, and influencing tumor angiogenesis . This reThe evidence suggests that most of the effects of Acrp30 are related to the inhibition of carcinogenesis through AMPK, as well as the inhibition of leptin-induced JAK2 activation and STAT-3 transcriptional activity via increasing the PTP1B protein ,82. For Acrp30 binds to AdipoR1 or AdipoR2, initiating a downstream signaling pathway . Bax is Acrp30 has a negative effect on PI3K/Akt activation. Thus, Akt, which promotes cell proliferation and survival, remains inactivated. PTEN acts as an inhibitor of PI3K signaling, and cell line-specific PTEN deficiency may determine whether AMPK or Akt prevails in regulating mTOR activation. Furthermore, Acrp30 inhibits thioredoxin and the thioredoxin reductase-mediated inhibition of PTEN, thereby influencing PI3K/Akt signaling  78]..78].The mediators of the MAPK, cascade, such as JNK, p38, and ERK1/2, can also be related to Acrp30. In different types of cancers, treatment with Acrp30 led to increased JNK activity, resulting in Caspase-3-mediated apoptosis. It seems that AMPK plays a crucial role in JNK phosphorylation. Furthermore, Acrp30 treatment resulted in decreased levels of c-myc, cyclin D, and Bcl-2, while increasing the expression of p53 and Bax, thereby promoting cell cycle arrest and apoptosis  78]. In. In78]. An EPIC cohort’s study that was published by Dossus et al.  comparedp = 0.049). Thus, MMPs and TIMPs are all expressed in ETC and could be important in promoting recurrence [In relation to MMPs and tissue inhibitor of MMPs (TIMPs), their role in inducing EMT has been well reported, as well as their part in the migration and invasion processes in ETC ,87,88. Icurrence ,87,88. Mcurrence . Thus, icurrence . Sun et currence  revealedIn ETC, Cheng et al.  found thSignificant evidence supports the key role of lipid pathways in cancer development ,93. TumoThe LDL receptor (LDLR) gene resides on chromosome 19 at the band 19p13.2, which encodes for a cell-surface receptor of 839 amino acids . IncreasUnder conditions of oxidative stress, LDL can be oxidatively modified, which results in the formation of lipid peroxidation metabolites, which are closely associated with carcinogenic processes . The levThese studies show the importance of LDL-related pathways in controlling EMT processes and cancer aggressiveness. However, the impact of LDL and oxLDL on EMT processes that are related with thyroid CCs is unknown.A few studies have addressed the relationship between HDL transporters and EMT in CCs, with divergent results. The gene SCARB1, located in 12q24.31, encodes the scavenger receptor class B, type I (SR-BI), which is the main HDL receptor. This integral membrane protein has 509 amino acids and contains N- and C-terminal cytoplasmic domains, two transmembrane domains, and a large extracellular domain that contains multiple sites for N-linked glycosylation . SR-BI wThe ABCA1 gene, located in 9q31.1, encodes the ATP binding cassette (ABC) A1 (ABCA1), which is the main cholesterol efflux transporter from cells to HDL. It is ubiquitously expressed as a 220-kDa protein, and it can activate multiple signaling pathways, including the JAK/STAT, PKA, and PKC pathways . Indeed,It is noteworthy that apoAI overexpression or exogenous human apoAI, which is the main HDL protein, reduced the malignant properties of colorectal CCs are driven by ABCA1 overexpression . HDL maiThe incidence of ETC, especially PTC, has rapidly increased in recent decades, in parallel with the increase in the prevalence of obesity and other inflammatory diseases. Some reports indicate that inflammatory mediators, such as adipokines, can contribute to cell proliferation and the dedifferentiation of the follicular thyroid epithelium, especially in circumstances of greater genetic susceptibility. These cytokines can induce EMT processes in human PTC cell lines; furthermore, the link between inflammation and tumor metastasis progression in these types of tumors has been demonstrated. However, significant evidence has not been offered regarding the causal mechanisms of these associations and the link between these pathologies. As of yet, neither the risk of ETC nor the molecular mechanism that regulates both EMT and MET are completely understood.In conclusion, inflammatory mediators, like adipokines and metabolite of cholesterol, can contribute to promoting the aggressive behaviours of thyroid tumors, and the molecular mechanism that controls this process should be investigated.


Supplemental Digital Content is available in the text Aripiprazole is widely used in the management of tic disorders (TDs), we aimed to assess the safety of aripiprazole for TDs in children and adolescents.A systematic literature review was performed in the databases of MEDLINE, Embase, the Cochrane Library and 4 Chinese databases, from inception to February 2019. All types of studies evaluating the safety of aripiprazole for TDs were included. The quality of studies was assessed using the Cochrane Risk of Bias tool, the Newcastle–Ottawa Scale tool, the National Institute of Clinical Excellence, the CARE (Case Report) guidelines according to types of studies. Risk ratio (RR) and incidence rate with a 95% confidence interval (CI) were used to summarize the results.A total 50 studies involving 2604 children met the inclusion criteria. The result of meta-analysis of randomized controlled trials showed that there was a significant difference between aripiprazole and haloperidol with respect to rate of somnolence , extrapyramidal symptoms , tremor , constipation , and dry mouth . There was a significant difference between aripiprazole and placebo in the incidence rate of adverse events (AEs) for somnolence . The meta-analysis of incidence of AEs related to aripiprazole for case series studies revealed that the incidence of sedation was 26.9% , irritability 25% , restlessness 31.3% , nausea and vomiting 28.9% , and weight gain 31.3% .Aripiprazole was generally well tolerated in children and adolescents. Common AEs were somnolence, headache, sedation, nausea, and vomiting. Further high-quality studies are needed to confirm the safety of aripiprazole for children and adolescents with TDs. There are 3 kinds of TD: transient tic, chronic tic, and Tourette syndrome with prevalence rates 2.99%, 1.61%, and 0.77%, respectively. In general, the severity of TDs wanes in late adolescence, and the prevalence rates of TDs in adulthood become much lower. There are various comorbid psychiatric conditions with TDs, such as obsessive–compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and sustained social problems. TDs and these comorbidities are associated with many serious impairments in social functioning as well as emotional and educational impairment, which can have serious negative impacts on quality of life.–5Tic disorders (TDs) are very common neurodevelopmental condition in children and adolescents,7Currently, pharmacological treatment is the most common intervention for patients with TDs, including typical antipsychotics , atypical antipsychotics , analgesics , anticonvulsants , antidepressants , among others. However, the use of these treatments is associated with several adverse events (AEs), including tardive dyskinesia, extrapyramidal syndrome, and electrocardiographic abnormality.,9 It is extensively used in the management of TDs in the United States, China, and other countries. Yang et al reviewed 12 trials including 935 participants aged between 4 and 18 years, involving aripiprazole for children with TDs. Those authors confirmed that aripiprazole appears to be a new treatment approach for children with TDs; the systematic review also pointed out that drowsiness, increased appetite, nausea, and headache were common AEs with use of aripiprazole for tics. However, that study only included randomized controlled trials (RCTs) and did not include a quantitative analysis of safety; therefore, the safety of aripiprazole was not well evaluated.Aripiprazole, a dopamine agonist and 5-HT1A receptor, could act as a dopamine D2 partial agonist based on local dopamine system surroundings.–14 However, several new reports have been published demonstrating that the findings for the relative safety of aripiprazole in children and adolescents need to be updated.A considerable number of trials have researched the efficacy and safety of aripiprazole for patients with TDs; these studies have provided evidence of the comparative efficacy and safety of aripiprazole for TDs.Therefore, to provide additional information on the safety of aripiprazole, we included all types of studies and performed a meta-analysis to assess the safety of aripiprazole for TDs in children and adolescents.2This meta-analysis was conducted strictly according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines, and the ethical approval and informed consent were unnecessary since the meta-analysis was aimed to summarize the previous studies.2.1A systematic literature review was performed in the databases of MEDLINE, Embase, the Cochrane Library, the Chinese Biomedical Literature Database, China Knowledge Resource Integrated Database, VIP Database, and Wanfang Database, from inception to March 2018. Citations of relevant studies were searched for appropriate articles as well. The search terms included “aripiprazole,” “Tourette syndrome,” “tic disorders,” and “tics.” According to the specific requirements of the database, the terms were combined into different retrieval expressions. .2.2The inclusion criteria were developed using the PICOS  framework, as follows:1.Population: aged <18 years old, with a clinical diagnosis of TD2.Intervention: aripiprazole3.Comparison: placebo or other types of pharmacotherapies4.Outcome: prevalence rate of all types of AE5.Study design: all types of studies, including RCT, non-RCT, cohort study, case-control study, case series study, and case report, with data extraction and quality assessmentMeanwhile, we restricted the language of publications English or Chinese. Through reading the title, abstract, and full text, we judged whether studies met the inclusion criteria.Data were extracted by 1 author and checked by another author using an Excel form, which included the following information: study information, age, sex, intervention, control, treatment period, time of follow-up, diagnostic criteria, and prevalence rate of AEs.www.cochranehandbook.org): Random sequence generation; Allocation concealment; Blinding of participants; Blinding of outcome assessment; Incomplete outcome data; Selective reporting; Other sources of bias. The qualities of case-control studies and cohort studies were assessed using the Newcastle–Ottawa Scale tool. Assessment of risk of bias in case series was based on the recommendations of the National Institute of Clinical Excellence (NICE): Case series in more than 1 center, that is, multicenter study; Is the hypothesis/aim/objective of the study clearly described? Are the inclusion and exclusion criteria (case definition) clearly reported? Is there a clear definition of the outcomes reported? Were data collected prospectively? Is there an explicit statement that patients were recruited consecutively? Are the main findings of the study clearly described? Are outcomes stratified? . Quality appraisal of case reports was conducted according to the CARE (CAse REport) guidelines: Title; Keywords; Abstract; Introduction; Patient Information; Clinical Findings; Timeline; Diagnostic Assessment; Therapeutic Intervention; Follow-up and Outcomes; Discussion; Patient Perspective; Informed Consent.The quality of all RCTs and non-RCTs was assessed using the Cochrane Risk of Bias tool according to the Cochrane Handbook for Systematic Reviews of Interventions . Risk ratio (RR) and incidence rate with a 95% confidence interval (CI) were used to summarize the results. The significance of evidence was evaluated using the Z-test. We used the Q test and I2 statistic to assess the percentage of heterogeneity.33.1Our initial database search yielded 211 studies. After reading the title, abstract, and full text, 50 studies met the inclusion criteria  used an adequate method of random sequence generation; the remaining studies did not mention any method or used an inappropriate allocation method. Three studies (17.6%) implemented allocation concealment. Similarly, blinding of participants and outcome assessment were not specified; 3 studies (17.6%) described blinding of participants and outcome assessment, and 2 studies (12.5%) were judged to be prone to a high risk of bias. The risk of bias regarding incomplete outcome data was judged to be high in 1 report (6.3%). Reporting bias was not detected in any of the included studies, and no other bias was found.In the assessment of methodology quality of non-RCTs, none of these studies described appropriate random sequence generation. Five studies (50%) described as open-label trials had adequate allocation concealment; the remaining 5 studies (50%) did not include sufficient information to evaluate this item, leading to the determination of unclear risk. For blinding, 3 studies (30%) were assessed as having high risk of bias in the blinding of participants and personnel. Similarly, 3 studies (30%) were judged to be prone to high risk of bias in the blinding of outcome assessment; the remaining studies (70%) could not be evaluated because of insufficient information. In terms of incomplete outcome data, 4 studies (40%) were described as unclear risk of bias, and the remainder (60%) showed low risk of bias. Reporting bias was not detected in any of the included studies; no other bias was found.Case studies had a mean score of 5.67 points according to the NICE guidelines checklist. Only 2 studies were multicenter studies, and outcomes were not stratified in either study; the remaining indicators demonstrated fair good quality.We assessed the methodological quality of case reports based on the 13 items of the CARE guidelines. All case reports described the items of title, patient information, clinical findings, time line, therapeutic interventions, follow-up and outcomes, and discussion. Six studies included the items of introduction and diagnostic assessment, and 5 studies comprised the items keywords and abstract. Only 2 reports had a low risk of informed consent. All reports had a high risk of patient perspective. The quality assessment of the included studies is summarized in Table 3.3The most common AEs with aripiprazole in RCTs were somnolence (17.2%), increased appetite (13.5%), sedation (13.2%), dyspepsia (9.7%), and nasopharyngitis (9.1%).3.3.13.3.1.1P = .014), extrapyramidal symptoms , and tremor . The differences for the remaining AEs showed no statistical significance (P > .05).We compared aripiprazole with haloperidol, risperidone, and sulfur with respect to various types of neurological and psychiatric AEs. The results of the meta-analysis showed that there was a significant difference between aripiprazole and haloperidol in the rates of somnolence . Although the rate of AEs with use of aripiprazole with respect to the digestive system was lower than those with use of risperidone and sulfur, there was no statistical difference (P > .05).The included studies reported that the occurrence of gastrointestinal AEs with aripiprazole was significantly lower than those with haloperidol for constipation .Four types of AEs of the cardiovascular system  were reported among the aripiprazole and haloperidol groups. Nevertheless, the differences were not statistically significant (3.3.4P > .05).Only 2 studies reported AEs affecting the urinary system. There were no urinary AEs with aripiprazole; the use of sulfur had 1 reported case of urinary AEs. Nocturia occurred with risperidone in 4 cases; however, there were no significant differences (3.3.5P < .05). As for upper respiratory infection, we found no significant differences.The included studies reported that the occurrence of nasopharyngitis with aripiprazole was significantly lower than that with placebo (3.3.6P > .05). A significant difference was observed in the incidence rate of dry mouth between aripiprazole and haloperidol treatment groups .Meta-analysis of 1 study (n = 60) that compared the occurrence of blurred vision and itching between aripiprazole and risperidone showed that there were differences, but without statistical significance (3.3.7P > .05) in the incidence rate of AEs between aripiprazole and placebo, except for somnolence , as shown in Table We retrieved 2 RCTs (n = 194) that reported AEs in a positive control group and placebo group. The results of meta-analysis showed that there was no significant difference , sedation (10.9%), nausea and vomiting (8.4%), extrapyramidal symptoms (6.9%), and gastrointestinal disturbance (6.4%).The results of meta-analysis revealed that there was no significant difference in the rate of AEs between aripiprazole and haloperidol, risperidone, sulfur, and pimozide. Similar statistical differences were found for the incidence of AEs between 2 aripiprazole treatment groups with different administration frequency (aripiprazole q.i.d. vs aripiprazole q.d.), as shown in Table 3.5P < .05). There were no significant differences for tiredness; stomach discomfort; or muscle, bone, or joint pain/conditions (P > .05) , irritability , restlessness , nausea and vomiting , and weight gain  (3.6Five of 8 cases (62.5%) mentioned or described AEs, which included convulsions, mania, fidgeting, trembling, inarticulate speech, slow motion, dizziness, muscle cramps, nystagmus, torticollis, and insomnia.3.7In regard to the primary outcome, after excluding trials with low-quality RCTs which did not report appropriate randomized method and allocation, no material change of the pooled estimated effects in sensitivity analysis was found Table . The min3.8Finally, funnel plots were not used because the number of included studies in 1 comparison had insufficient statistical power, according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.4In this study, we evaluated the safety of aripiprazole for TDs in the wider context. To our knowledge, this is the first and most comprehensive meta-analysis of this topic. Our analyses were based on 50 studies  including 2604 children with TDs.Results from the meta-analysis showed that the rate of AEs with aripiprazole was significantly lower than those with haloperidol in some fields. In terms of neurological and psychiatric symptoms, only the comparison of aripiprazole with haloperidol and aripiprazole with placebo showed a significant difference in RCTs; the other studies showed nonsignificant differences. In terms of AEs of the digestive system, only the comparison of aripiprazole and haloperidol showed a significant difference in RCTs. In terms of respiratory system AEs, a significant difference was found only between aripiprazole and placebo in RCTs; other studies showed a nonsignificant difference. In terms of AEs of the cardiovascular, urinary, and motor systems, we found nonsignificant differences between aripiprazole and other pharmacotherapies. Overall, the results of our systematic review favored the clinical use of aripiprazole, which can be considered an excellent treatment option for TDs as aripiprazole shows good tolerability in children and adolescents. Our findings agreed with those of previous relevant studies. Considering that the quality of studies included here was poor, it is necessary to confirm our findings in future studies. Second, to ensure the coverage of all relevant AEs, a comprehensive search of the literature was conducted in which we included any type of study, to reduce the possibility of publication bias. Third, 2 independent authors were involved in the phases of study retrieval, data extraction, and quality assessment. In addition, another author checked the consistency of the results and resolved disagreements. Fourth, the tools used in this review to assess the risk of bias are the most widely used and accepted.There are some strengths that should be noted in our meta-analysis. First, this study is based on the PRISMA reporting recommendations.Several important limitations of this review also emerged. First, although the report retrieval was comprehensive, it is still possible that unpublished reports were not found. In addition, we failed to search several websites of special agencies that report adverse drug events. Second, some of our results focused on short-term outcomes, which cannot be generalized to long-term safety. Third, the measures and definition of some AEs might differ among the included studies, which might cause clinical heterogeneity. Fourth, no protocol was established before the study was carried out. Fifth, we could not combine data from different dose arm. It is difficult to separate different dose arm, because every study gave the appropriate dose for patients according to the weight and age.5In conclusion, we found that aripiprazole had clinically relevant tolerability in children and adolescents. Aripiprazole might be viewed as an important treatment option for patients with TDs in these age groups. The common AEs were somnolence, headache, sedation, and nausea and vomiting. There is a need for further studies to confirm the use of aripiprazole in children and adolescents with TDs.The authors thank Group of People with Highest Risk of Drug Exposure of International Network for the Rational Use of Drugs, China for providing support to coordinate circulation of the manuscript to all co-authors and collect comments from all coauthors.YCS, YQS, ZLL, CH, and MJP contributed to planning, supervision, writing, and analysis of the study; YCS, YQS, and ZLL independently selected titles, abstract and full text; YCS, YQS, CH, and MJP each contributed to data collection, writing the manuscript and review of the literature. All authors have read and approved the final manuscript.Conceptualization: Jianping Mao.Methodology: Chunsong Yang, Lingli Zhang, Hao Cui.Software: Jianping Mao.Validation: Hao Cui.Visualization: chunsong yang.Writing – original draft: chunsong yang, qiusha yi.Writing – review & editing: chunsong yang.


Multiple myeloma is a plasma cell dyscrasia characterized by transformation of B cells into malignant cells. Although there are data regarding the molecular pathology of multiple myeloma, the molecular mechanisms of the disease have not been fully elucidated.To investigate the gene expression profiles in bone marrow myeloma cells via RNA-sequencing technology.Cell study.Myeloma cells from four patients with untreated multiple myeloma and B cells from the bone marrow of four healthy donors were sorted using a FACSAria II flow cytometer. The patient pool of myeloma cells and the control pool of B cells were the two comparative groups. A transcriptome analysis was performed and the results were analyzed using bioinformatics tools.In total, 18.806 transcripts (94.4%) were detected in the pooled multiple myeloma patient cells. A total of 992 regions were detected as new exon candidates or alternative splicing regions. In addition, 490 mutations (deletions or insertions), 1.397 single nucleotide variations, 415 fusion transcripts, 132 frameshift mutations, and 983 fusions, which were reported before in the National Center for Biotechnology Information, were detected with unknown functions in patients. A total of 35.268 transcripts were obtained (71%) (25.355 transcripts were defined previously) in the control pool. In this preliminary study, the first 50 genes were analyzed with the MSigDB, Enrichr, and Panther gene set enrichment analysis programs. The molecular functions, cellular components, pathways, and biological processes of the genes were obtained and statistical values were determined using bioinformatics tools and are presented as a supplemental file.EEF1G, ITM2C, FTL, CLPTM1L, and CYBA are identified as possible candidate genes associated with myelomagenesis. Multiple myeloma (MM) is a cancer of plasma cells in which abnormal types of immunoglobulins are produced that can be measured in blood and urine . MM is aThe etiology of MM depends on many factors, such as the environment, chemical agents, viruses, and genetic factors . MM is cin silico tools. Our transcriptomic profile obtained data to evaluate differential expression of all transcripts, alternative new splicing variants, mutations, and fusion genes. These results will contribute to the understanding of myeloma pathogenesis and provide valuable information for prognostication and new therapies.In the present study, we provide comprehensive insight into the transcriptomes of patients with MM and healthy donors. Many of the genes were determined in transcriptome profiles of pooled myeloma cells and were determined to play a role in MM pathogenesis via intracellular pathways, gene expression patterns, biological functions, and protein-protein interactions using This study was approved (2010/108-28) by the Ethics Committee of İstanbul University Faculty of Medicine. Written informed consent Helsinki Declaration and ethics committee documents was obtained from all patients and healthy donors. We performed RNA-seq using the Ion Torrent Personal Genome Machine (PGM) platform to compare the transcriptome profiles of four newly diagnosed patients with untreated MM and four healthy donors. Bone marrow was aspirated from the hip bones of all patients and donors. The bone marrow samples were subjected to Ficoll gradient centrifugation (1.077 g/mL Ficoll), and the mononuclear cells were collected. The viability and absolute cell counts were determined by the Vi-CELL™ XR Cell Counter .Myeloma cells  and healthy B cells  were selected from bone marrow mononuclear cells using a gating strategy by simultaneously specifying cell surface markers, and by determining forward and side light scattering characteristics on the FACSAria II Cell Sorter  , 2. The RNA was extracted from the sorted cells using the PureLink RNA Microkit . Before proceeding to rRNA depletion, the quantity and quality of total RNA was evaluated using the RNA 6000 Pico kit on the Agilent 2100 Bioanalyzer . After checking the quantity and quality of the RNA, we pooled the RNA samples from the four untreated MM patients and four healthy donors. The workflow of the study is summarized in rRNA depletion was performed using the Eukaryotic Ribominus kit . The quantity and quality of the mRNA was evaluated using the RNA 6000 Pico kit on Agilent 2100 Bioanalyzer.® 2.0.The RNA-sequencing libraries were prepared from the pooled RNA of the patients and healthy donors. The libraries were constructed using the Ion Total RNA-seq V2 kit protocol for transcriptome profiling of low-input RNA samples (April 2011). The quality of the libraries was validated using the Agilent High Sensitivity DNA kit on the Agilent 2100 Bioanalyzer . The finThe Ion PGM™ system was cleaned and initialized before sequencing. Sequencing was accomplished using the Ion PGM™ 200 Sequencing v2 kit  according to the manufacturer’s instructions. Pooled samples were sequenced with a semiconductor-based sequencing system using the Ion 318™ Chip .The pooled RNA from the patients with MM and that from the controls was subjected to massively parallel cDNA sequencing at İstanbul University Whole Genome Sequencing Laboratory Aziz Sancar Institute of Experimental Medicine. The sequencing data were analyzed with the PSSC Labs Big Data Server . The quality of the raw sequencing data was checked and the data were preprocessed according to two criteria: adaptors and low quality sequences (readings with ambiguous N’s) were removed, and data with a quality score (Qscore) <30 was trimmed.The trimmed sequencing reads were aligned to the UCSC human reference genome (build GRCh37/hg19) using TopHat v2.0.6, which incorporates Bowtie v0.12.8 software to build the alignment. The expression level for each transcript was normalized to the reads per kilobase of the exon model per million mapped reads (RPKM)  and alsoThe cDNA libraries from the patients with MM and the control group were subjected to massively parallel transcriptome sequencing. Of the 18,806 total transcripts obtained by the transcriptome analysis, 17,760 were reported previously in pooled patients with MM. These transcripts were used in the downstream analysis.EEF2) gene was the most significantly expressed gene among the MM and normal cells according to our RPKM results. Our analysis included the majority of annotated human genes. The analysis of the whole transcriptome data revealed different expression levels of several genes, such as JAK1, JAK2, JAK3, RAF, IL6R, NCAM (CD56), WHSC1, MCL1, BCL2, and IGF1, which showed myeloma pathogenesis as reported previously. These 50 genes were subjected to the GSEA using MSigDB. As a result, 11 of these genes had increased expression in plasma cells from patients with MM that significantly overlapped between EEF1A1, UBC, UBB, CALR, CXCR4, JUND, FOS, PIM2, JUN, GAPDH, and HSP90B1 and were previously reported as upregulated in the Munshi_multiple _myeloma data set   in the control pool. Qscore values of about 35% on average for each chromosome were calculated. We measured the transcript values and identified the differentially expressed genes between the two groups using Cuffdiff/Cuflink. In total, we detected 12,453 expressed genes by calculating reads per kilobase million (RPKM) values and analyzed the data from the first 50 highly expressed selected genes in the pooled MM cells  and compdata set . The biodata set ,6,7. Thedata set . We perfJUN was in the oncogene family; FOSB, JUN, JUNB, JUND, and KLF were in the transcription factor family; PIM2 and SIK1 were in the protein kinase family; and CXCR4, CD74,ICAM3, and SDC1 were cell differentiation markers. In particular, the first 50 genes supported that the ubuquitin genes, such as UBB, UBC, EEF2, were related to the pathogenesis of MM. The ubiquitin cascade system is a central contributor to cellular processes that regulate protein stability, trafficking, and activation  pathway. In addition to gallbladder cancer, it operates as a biomarker and promotes increased degradation of ceramides, ensuring a survival advantage to cancer cells . Another related gene is calreticulin. This gene produces a calcium-binding protein that is a major component of the endoplasmic reticulum and has been shown in various cell types to be involved in regulating calcium homeostasis, as a ligand for integrins, and as a component of phagocytic synapses (CLPTM1L) gene is overexpressed in lung cancer and knockdown of this gene prevents 95-D lung cancer cells from migrating and invading . Using in silico tools, we identified significant overlaps between EEF1A1, UBC,UBB, CALR, CXCR4, JUND, FOS, PIM2, JUN, GAPDH, and HSP90B1, which were previously reported to be upregulated in MM according to the Munıshı_ MM data set (The enriched pathways for these upregulated genes are involved in peptide transport from the cytosol into the endoplasmic reticulum, antigen processing, peptide trimming, and assembly of the major histocompatibility complex class I loading complex . Leone egnancies . Our ressynapses . Upregulsynapses . The cisinvading . Althougpoptosis . Anotherrylation . Our resma cells . The resdata set . The Pandata set ,6,7. Anadata set . This trEEF1G, ITM2C, FTL, CLPTM1L, and CYBA are possible candidate genes associated with myelomagenesis.In conclusion,


Tursiops truncatus) from the Aeolian Archipelago . Thirteen skin mark types were identified and their origin, prevalence and permanence time were examined. The pattern of skin marks was assessed for the abundance, richness, distribution and severity in six body regions and compared among age classes, sex and degree of dolphins’ interaction with trammel nets (DIN). Our results showed higher prevalence, abundance, richness and distribution of skin marks in adults than in the younger age classes, with the exception of black marks and white ring lesions. The prevalence and abundance of skin marks were higher in males than females, with the exception of scratches and white patches. Moreover, gunshot wounds, mutilations and irregular dorsal fin edges were found only on adult males. Since males showed higher DIN than females and, in dolphins with higher DIN, skin marks were more abundant and frequently distributed in different body regions, the skin mark pattern in regard to DIN seems to be sex-related. The more severe marks were observed on adults, males and dolphins with higher DIN, namely skin disorder, tooth rake marks, small shallow indentations, deep indentations and mutilations. On the contrary, the severity of scratches, white patches and dark ring lesions was higher in females than males, but not significantly related to DIN and age of the individuals. Our results showed that photo-id data provide an efficient and cost-effective approach to document the occurrence of skin marks in free-ranging bottlenose dolphin populations, a critical step toward understanding the cause and supporting the conservation strategies.Skin marks occur frequently in many cetacean species across the globe revealing a broad spectrum of causes, including social interactions, infectious diseases and injuries produced by anthropogenic factors. The current study used photo-id data from 2005–2014 to estimate the skin mark pattern on resident bottlenose dolphins ( Cetacean skin marks have been widely reported –3 and reThe skin mark pattern has been studied in bottlenose dolphins via photo-id techniques , 32–37. Since 2005 a photo-id study was performed on an endangered small population of bottlenose dolphins in the Aeolian Archipelago  , 45, 50.The current study used photo-id data to assess and quantify the types of skin marks in bottlenose dolphins interacting with artisanal trammel nets in the Aeolian Archipelago. Skin marks were identified and classified according to their origin, prevalence in the population and time of permanence in different body regions. The abundance, richness, distribution and severity of skin marks were also assessed and compared among groups of dolphins with different age, sex and degree of interaction with trammel nets.2 of coastal area around Filicudi island, in the Aeolian Archipelago . Dedicated boat surveys were performed from June to September in 2005–2014. The surveys were carried out from 6.00 a.m. to 14.00 p.m., limited to sea states of Beaufort 3 or less and in good light conditions (visibility > 300 m) [The study area covered 280 km> 300 m) , 45, 50.> 300 m)  with ins> 300 m)  and phot> 300 m) . No spec> 300 m) . If a fo> 300 m) . Each in> 300 m) , 45. Eve> 300 m) . The degAs bottlenose dolphins are sexually dimorphic  and geneAge classes were attributed as follows , 46: (1)For each photo-identified dolphin in the catalogue, high-resolution photographs of dorsal fin, right and left flanks, back, head, tail and flukes were visually screened for the detection of skin marks, and sorted according to standard protocols, using nicks, notches, scars, patches, injuries and other clear lesions or traumata. Skin marks were analysed and classified, according to previous data  and grouAccording to the descriptions in previous scientific papers, skin marks were also divided into: (1) Skin lesions, including marks due to infectious diseases such as bacterial, viral or parasitic infections , 57, 58;In order to better describe the skin marks pattern according to age, sex, DIN, the “power” and the effect of every single mark on each individual, different parameters were calculated and analysed.In particular, the prevalence and permanence time of each skin mark type were assessed for each individual. The prevalence was calculated as the number of dolphins with the mark type compared to the number of all marked and not marked individuals. Separately, the prevalence of each mark type was calculated according to (a) all marked individuals only (independently of the mark category), (b) all marked males/females/adults/juveniles and calves, (c) all individuals recorded with that mark type. The permanence was the time of persistence of each mark type on the animal’s body from the first year when it was visible as a fresh or old mark to the last year when it was not visible anymore. In details, the permanence time was calculated by analysing the photographs of different body regions for each individual and counting the number of years (from 0 to 10) when the mark type occurred. If the same mark type was found in different body regions or in more individuals, the longest time of permanence among them was retained for the analyses. A time of permanence on the body ≤ 4 years was classified as “temporary”, while a time of permanence > 4 years was classified as “permanent” .In order to assess if the skin marks pattern was related to age, sex and DIN, the abundance, richness and distribution of skin marks were also calculated. In particular, the abundance was the total number of skin marks (independently of the relative abundance of each type) among the marked individuals with at least one skin mark type; the richness was the number of skin mark types (from 0 to 13) recorded over the whole body of the individual; the distribution was the number of body regions  where each skin mark type was located. The abundance, richness and distribution were calculated for dolphins with different age class  and for males and females separately. In addition, since the DIN was different for males and females, the abundance, richness and distribution were also calculated for males with DIN higher or lower than 40% and for females with DIN higher or lower than 20%. Normal distributions of parameters were checked using Shapiro-Wilk tests and the homogeneity of variances using Levene’s test. Kruskal-Wallis test was used to investigate the differences between these groups of data.Finally, the severity of each mark type was calculated in order to estimate the degree of threat to the population. For each dolphin (a) “low” severity was assigned to benign marks, i.e. superficial, short and limited to a little part of the skin in all occurrences, (b) “high” severity was assigned to marks that were deeper, larger, found on several body locations and/or that could affect swimming, like a mutilation and (c) “medium” severity was assigned to marks with intermediate severity. In order to understand if more severe marks may affect specific groups of individuals, a Principal Component Analysis (PCA) was performed on the severity data and for distinct groups . Kruskal-Wallis tests were conducted on the scores  of the leading principal components (e.g. explaining more than 60% of data variance). A score plot on the leading principal components was produced, representing each dolphin according to identified sex and DIN classes. The loadings, the Pearson correlation coefficients between the leading principal components and variables (i.e. severity of skin marks types), were used to identify correlations between marks and components as these were related to the variance explained by such a component. These analyses were performed using the software PAST.Four hundred surveys were carried out over 564 hours for a total of 6.204 km surveyed from 2005 to 2014. A total of 185 sightings were recorded, corresponding to 120.55 hours spent with the dolphins . The dolphin groups covered 1.320 km at an average (± St. Dev.) speed of 10.74 ± 2.45 km/h.The data used in this study were obtained from digital photo-id photographs taken during 135 sightings.p = 0.001) or among years . In particular, photographs of dorsal fins were obtained for 38 dolphins (100%) while photographs of flanks (right and left indistinctly) for 97.4% (n = 37), of the head for 57.9% (n = 22) and of the tail, flukes and back for 52.6% (n = 20).Only good quality photographs were selected and analysed for photo-id (n = 5046) and the number of good quality photographs did not differ between early (n = 3042) and late summer (n = 2004) , juvenile  and calf . For two dolphins (5.3%) age class was not determined. Of these individuals, 14 were classified males  and 9 females , while the remaining 15 dolphins  were not classified.The DIN was estimated in adults and juveniles only. In particular, 29 dolphins (76.3%) were sighted in the proximity of trammel nets: for 27.6% of them (4 adults and 4 juveniles) the DIN was < 20%, while 34.5% (6 adults and 4 juveniles) had the DIN ≥ 40%.In addition, the DIN was estimated for males and females separately. A DIN ≥ 40% was estimated in 50% of photo-id males (6 adults and 1 juvenile) and a DIN from 25% to 40% for the other males (6 adults and 1 juvenile). Five females  had a DIN from 0–25% and 4 females (44.4%) a DIN over the 25%.Thirteen skin marks were identified and classified  with varThe skin mark types were classified in: (1) skin lesions  or (2) traumata  . On the In order to analyse if the skin marks pattern was related to age and sex of the individuals, the prevalence (%) of each mark type was calculated for the three age classes   and for The skin mark types LW, SC, SD, SSI, TR and WP had the highest prevalence in males and females among marked dolphins , betweenp < 0.05), but homogeneous . In addition, adult dolphins were found to be more marked than the younger classes according to the Kruskal-Wallis tests  were higher than in calves; finally, only the distribution was higher in adults than juveniles .Skin mark abundance (but not richness and distribution) was higher in males than females as when considering only adult dolphins . Finallyp > 0.01) and Levene’s test of homogeneity of variance showed no significant differences among distinct groups of dolphins . Both Factor 1 and Factor 2 were significant as for differences between males and females  and between adult males and adult females . Only Factor 1 was significant for differences among age classes , between dolphins with DIN more than 40% or less than 20%  and between adult dolphins with DIN more than 40% or less than 20% . On the Factor 1 vs Factor 2 score plot, each dolphin was represented according to identified sex and DIN threshold . The scores on the leading principal components (Factor 1 and Factor 2) were normally distributed  according to dolphins’ age, sex and DIN. In particular, the more severe marks for adult dolphins, males and dolphins with DIN > 40% were SD (loading on Factor 1 = 0.64), TR (loading on Factor 1 = 0.38), SC (loading on Factor 1 = 0.33), SSI (loading on Factor 1 = 0.27), DI (loading on Factor 1 = 0.13) and MU (loading on Factor 1 = 0.12) . On the Epidermal marks are common in all bottlenose dolphin populations , 62, 68 In this study, thirteen mark types were identified in Aeolian bottlenose dolphins exposed to a wide range of natural and anthropogenic conditions, especially fishing activities. All skin marks were classified according to previous descriptions , 68, 71.Grampus griseus  [Pennella spp.), rubbing with inanimate objects, fishing gears or rocky sea bottom or interacting with other species, such as fish and molluscs [Our study showed higher prevalence in transient marks  compared to the permanent ones , with the exception of small shallow indentations (84%) and skin disorders 70%) , 16. Thevalence) . As thesmolluscs , 69, 71,molluscs , 63, 72,% , 16. Tmolluscs –81 and wmolluscs , 32, 63.molluscs , 82. Formolluscs , 70, whimolluscs , 32, 83 Different studies analysed photo-identification data to estimate the prevalence of skin marks on cetacean populations in order to assess the causes of injuries or diseases –76, 82. The prevalence of marks and marked dolphins were often used for demography studies , 76–78, In this study, different parameters were used to assess the skin marks pattern. Marks’ prevalence and abundance based on population features were already reported for bottlenose dolphins in different areas  and for The results of this study showed that the richness and distribution of skin marks were similar in both sexes and in the same body regions. On the other hand, males had more skin marks  than females, with the exception of scratches and white patches. In particular, tooth rakes, linear wounds, skin disorders and small shallow indentations were higher in males than females, accounting for 30% of the total prevalence of marks in the population, and gunshot wounds, mutilations and irregular dorsal fin edge were found only in male individuals. These sex differences may be explained by variations in the behaviour among sexes , 45, 50,Previous studies on bottlenose dolphins and other species described an association between mark occurrence and fishery interaction and the prevalence of skin marks increased with increasing interactions , 74, 75.In conclusion, this is the first work that analysed the skin marks pattern in bottlenose dolphins from one Mediterranean area using different parameters estimated from photo-identification data. The results of this study showed that the skin marks pattern of the Aeolian bottlenose dolphin population is strongly related to age, sex and degree of interaction with trammel nets. Our results also provided a new efficient and cost-effective approach to document the occurrence of skin marks in free-ranging populations, which is important to suggest cause-effect relationships with significant consequences in terms of conservation strategies , 56, 77.