Obesity effect on newly diagnosed and recurrent post-ablation atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The role of overweight and obesity in the development of atrial fibrillation (AF) is well established; however, the differential effect on the occurrence and recurrence of AF remains uncertain. The aim of this review is to compare the effect of underweight and varying degrees of obesity on onset of AF and in recurrent post-ablation AF, and, when possible, in relation to sex. METHODS: A systematic literature search was conducted in PubMed, Embase, and Cochrane Library from inception to January 31, 2023. Studies reporting frequency of newly-diagnosed AF and of recurrent post-ablation AF in different BMI categories, were included. 3400 records were screened and 50 met the inclusion criteria. Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were extracted from the manuscripts and were analyzed using a random effect model. The outcome was the occurrence of AF in population studies and in patients undergoing ablation. RESULTS: Data from 50 studies were collected, of which 27 for newly-diagnosed AF and 23 for recurrent post-ablation AF, for a total of 15,134,939 patients, of which 15,115,181 in studies on newly-diagnosed AF and 19,758 in studies on recurrent post-ablation AF. Compared to normal weight, the increase in AF was significant (p < 0.01) for overweight, obese, and morbidly obese patients for newly-diagnosed AF, and for obese and morbidly obese patients for recurrent post-ablation AF. Newly-diagnosed AF was more frequent in obese female than obese male patients. CONCLUSION: The effect of increased BMI was greater on the onset of AF, and obese women were more affected than men.

Staphylococcus aureus adlb gene is associated with high prevalence of intramammary infection in dairy herds of northern Italy: A cross-sectional study.

Staphylococcus aureus is a major mastitis pathogen in dairy cattle worldwide, responsible for substantial economic losses. Environmental factors, milking routine, and good maintenance of milking equipment have been described as important factors to prevent intramammary infections (IMI). Staphylococcus aureus IMI can be widespread within the farm or the infection can be limited to few animals. Several studies have reported that Staph. aureus genotypes differ in their ability to spread within a herd. In particular, Staph. aureus belonging to ribosomal spacer PCR genotype B (GTB)/clonal complex 8 (CC8) is associated with high within-herd prevalence of IMI, whereas other genotypes are generally associated with individual cow disease. The adlb gene seems to be strictly related to Staph. aureus GTB/CC8, and is a potential marker of contagiousness. We investigated Staph. aureus IMI prevalence in 60 herds in northern Italy. In the same farms, we assessed specific indicators linked to milking management (e.g., teat condition score and udder hygiene score) and additional milking risk factors for IMI spread. Ribosomal spacer-PCR and adlb-targeted PCR were performed on 262 Staph. aureus isolates, of which 77 underwent multilocus sequence typing. In most of the herds (90%), a predominant genotype was identified, especially Staph. aureus CC8 (30%). In 19 of 60 herds, the predominant circulating Staph. aureus was adlb-positive and the observed IMI prevalence was relevant. Moreover, the adlb gene was detected only in genotypes of CC8 and CC97. Statistical analysis showed a strong association between the prevalence of Staph. aureus IMI, the specific CCs, and carriage of adlb, with the predominant circulating CC and presence of the gene alone explaining the total variation. Interestingly, the difference in the odds ratio obtained in the models for CC8 and CC97 suggests that it is carriage of the adlb gene, rather than the circulation of these CCs per se, that leads to higher within-herd prevalence of Staph. aureus. In addition, the model showed that environmental and milking management factors had no or minimal effect on Staph. aureus IMI prevalence. In conclusion, the circulation of adlb-positive Staph. aureus strains within a herd has a strong effect on the prevalence of IMI. Thus, adlb can be proposed as a genetic marker of contagiousness for Staph. aureus IMI in cattle. However, further analyses using whole-genome sequencing are required to understand the role of genes other than adlb that may be involved in the mechanisms of contagiousness of Staph. aureus strains associated with high prevalence of IMI.

Rhinomyiasis by Oestrus ovis in a tourist returning from Corsica.

In the Mediterranean basin, one of the most important agents of myiasis is Oestrus ovis Linnaeus 1758 (Diptera, Oestridae). Herein, we report a rare case of nasal myiasis with a secondary infection complication in a patient from northern Italy who had been visiting Corsica. A healthy, 39-year-old Italian woman spent 2 weeks of vacation in Corsica in June 2018. During her stay, she suddenly felt a foreign body inside her nose, followed by cough, pain, burning at the pharyngeal level, cephalalgia, and nasal congestion with secretions from the nostrils. The clinical examination showed a hyperemic and irritated mucosa and endoscopic examination of the patient's nose and right maxillary sinus revealed three tiny mobile larvae, morphologically and molecular identified as L1 instar larvae of Oestrus ovis. The patient's infestation was probably imported from Corsica, as Mediterranean islands are ideal geographical areas for the development of O. ovis, and the timing of infestation match with the period of O. ovis larviposition. Although rhinomyiasis is rare, it should be considered in people returning from abroad presenting with an acute-onset and foreign body sensation in the nose.

Attention-deficit/hyperactivity disorder symptoms and psychological comorbidity in eating disorder patients.

PURPOSE: There is some evidence that eating disorders (ED) and Attention-deficit/hyperactivity disorder (ADHD) share common clinical features and that ADHD might contribute to the severity of eating disorders. A greater understanding of how the presence of comorbid ADHD may affect the psychopathological framework of eating disorder seems of primary importance. The aim of our study was to evaluate rates of ADHD in three ED subgroups of inpatients: anorexia nervosa restricting type (AN-R), anorexia nervosa binge-eating/purging type (AN-BP) and bulimia nervosa (BN). The secondary aim was the evaluation of the associated psychological characteristics. METHOD: The sample consisted of 73 females inpatients (mean age 28.07 ± 7.30), all with longstanding histories of eating disorder (ED). The presence of a diagnosis of ADHD was evaluated in a clinical interview based on DSM-IV-TR criteria. The following psychometric instruments were used: the eating attitude test (EAT-40), the Bulimic Investigatory Test, Edinburgh (BITE), the Eating Disorder Inventory (EDI-2), the Wender Utah Rating Scale (WURS), the Brown Attention Deficit Disorder Scale (BADDS), the Hamilton scales for Anxiety (HAM-A) and Depression (HAM-D), and the Barrat Impulsivity Scale (BIS-10). RESULTS: Among the three ED subgroups, 13 patients reported comorbidity with ADHD; three in the AN-R subtype, nine in the AN-BP and one in the BN. The remaining 60 patients (n = 34 AN-R; n = 19 AN-BP; n = 7 BN) presented only a diagnosis of ED. The EAT (p = 0.04) and HAM-A (p = 0.02) mean scores were significantly higher in patients with comorbid ADHD. CONCLUSIONS: In our study the comorbidity between ADHD and ED appeared to be frequent, particularly among patients with AN-BP. ED inpatients with higher level of anxiety and more abnormal eating attitudes and bulimic symptoms should be assessed for potentially associated ADHD.

Exploring patient safety culture in preventive medicine settings: an experience from Northern Italy.

INTRODUCTION: Patient safety and quality in healthcare are inseparable. Examining patient safety culture in staff members contributes to further develop quality in healthcare. In Italy there has been some experience in assessing patient safety culture in staff working in hospital. In this pilot study we explored patient safety culture in public health staff working in Italian Local Health Authorities. METHODS: We carried out a descriptive cross sectional study in four Italian territorial Prevention facilities in Northern Italy. We administrated an adapted Italian version of the US Hospital Survey of Patient Safety Culture to all the staff within these facilities. The survey consisted of 10 dimensions based on 33 items, according to the results of a previous psychometric validation. RESULTS: Seventy per cent of the staff responded to the survey (N = 479). Overall, six out of the 10 dimensions exhibited composite scores of positive response frequency for patient safety culture below 50%. While "communication openness" (65%) was the most developed factor, "teamwork across Units" (37%) was the least developed. The work areas with the highest composite scores were Management and the Public Health Laboratory, while in terms of professional categories, Physicians had the highest scores. Patient safety culture in the staff participating in this study was lower than in hospital staff. DISCUSSION: Our descriptive cross sectional study is the first to be carried out in Preventive medicine settings in Italy. It has clearly indicated the need of improvement. Consequently, several interventions with this aim have been implemented.

Water safety in healthcare facilities. The Vieste Charter.

The Study Group on Hospital Hygiene of the Italian Society of Hygiene, Preventive Medicine and Public Health (GISIO-SItI) and the Local Health Authority of Foggia, Apulia, Italy, after the National Convention "Safe water in healthcare facilities" held in Vieste-Pugnochiuso on 27-28 May 2016, present the "Vieste Charter", drawn up in collaboration with experts from the National Institute of Health and the Ministry of Health. This paper considers the risk factors that may affect the water safety in healthcare facilities and reports the current regulatory frameworks governing the management of installations and the quality of the water. The Authors promote a careful analysis of the risks that characterize the health facilities, for the control of which specific actions are recommended in various areas, including water safety plans; approval of treatments; healthcare facilities responsibility, installation and maintenance of facilities; multidisciplinary approach; education and research; regional and national coordination; communication.

Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular (CV) disease. Several large clinical trials have shown that the risk for patients with diabetes of developing CV complications is only partially reduced by early, intensive glycaemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles (i.e. exosomes and microvesicles) could be harnessed to restore a 'physiological' signature capable of preventing or delaying the harmful systemic effects of T2DM.

A path analysis of patient dependence and caregiver burden in Alzheimer's disease.

BACKGROUND: The concept of dependence has been proposed as an integrative measure to assess the progression of Alzheimer's disease (AD).This study aimed to investigate the association of patient's dependence level with the caregiver burden within a general theoretical model that includes other well-established determinants. METHODS: Observational and cross-sectional multicenter study. The sample consisted of patients with AD recruited in outpatient consultation offices by a convenience sampling procedure stratified by dementia severity. Cognitive and functional status, behavioral disturbances, dependence level, medical comorbidities, and caregiver burden were assessed by using standardized instruments. A path analysis was used to test the hypothesized relationships between the caregiver burden and its determinants, including the level of dependence. RESULTS: The sample consisted of 306 patients (33.3% mild, 35.9% moderate, 30.7% severe), the mean age was 78.5 years (SD = 7.8), and 66.2% were women. The model fit was acceptable and explained 29% of the caregiver burden variance. Primary stressors were the level of dependence and the distress related to behavioral disturbances. Caregiver's age, gender, and co-residence with the patient were the contextual factors related to caregiver burden. The job status of the caregiver was a significant secondary stressor, functional disability was indirectly associated with caregiver burden via dependence, and frequency of behavioral disturbances was indirectly associated with the caregiver burden via distress. CONCLUSIONS: Dependence was, apart from behavioral disturbances, the most important primary stressor directly related to caregiver burden irrespective of the disease severity.

Prevalence and spatial distribution of bovine brucellosis in San Luis and La Pampa, Argentina.

BACKGROUND: Bovine brucellosis (BB) is a zoonotic disease caused by Brucella abortus. BB is endemic in Argentina, where vaccination with Brucella abortus strain 19 is compulsory for 3-to-8 month-old heifers. The objectives of this study were to quantify the prevalence of BB and to identify factors associated with its occurrence, along with the spatial distribution of the disease, in the provinces of La Pampa and San Luis. A two-stage random sampling design was used to sample 8,965 cows (3,513 in La Pampa and 5,452 in San Luis) from 451 farms (187 in La Pampa and 264 in San Luis). RESULTS: Cow and herd prevalence were 1.8 % (95 % CI: 1.3-2.2; n = 157) and 19.7 % (95 % CI: 17.0-22.4; n = 89), respectively. Both cow-level and herd-level prevalence in La Pampa (2.4 and 26.0 %, respectively) were significantly higher than in San Luis (1.4 and 15.5 %, respectively). There were not differences between the proportions of reactive cattle compared to that obtained in a survey conducted in 2005. However, herd prevalence in La Pampa was significantly (P < 0.05) higher compared to that study. Disease was found to be spatially clustered in west La Pampa. The lower the bovine density and the calf/cow ratio, the higher odds of belonging to the cluster. CONCLUSIONS: The increase of farm prevalence in the last five years suggests that the disease is spreading and that control measures should be applied in the region. The cluster of infected farms was located in the west region of La Pampa. There, farms have lower animal densities and smaller cow/calf indices compared to the rest of the province. Although western La Pampa has more infected herds, within-farm prevalence was not higher, which suggests that the control program has been relatively successful in controlling the disease at the farm level, and/or that low animal density inherently results in low disease prevalence. Our results provide baseline information on the epidemiology of BB and its potential pattern of transmission in Argentina, which will ultimately help to improve BB control programs in the country.

Hyperglycemia following recovery from hypoglycemia worsens endothelial damage and thrombosis activation in type 1 diabetes and in healthy controls.

BACKGROUND AND AIMS: Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation. METHODS AND RESULTS: In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production. CONCLUSION: This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.

Newest therapeutic strategies impacting on rarest thoracic malignancies: The clinical case report of biphasic pleural mesothelioma.

A caucasian 62-year-old woman, diagnosed with biphasic pleural mesothelioma (PM) of II stage and BAP1 loss, was treated with therapies included in clinical trial and Early Access Programmes (EAP). During her clinical history, radiological images presented an unusual representation of the disease, with a pseudo progression discussed many times by several specialists. The patient's overall survival improved as a result of the multidisciplinary team and the availability of medicines outside of clinical practice.

Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B.

Niemann-Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.

Pathology of enteric infections induced by the acanthocephalan Profilicollis chasmagnathi in Olrog's gull, Larus atlanticus, from Argentina.

Acanthocephalans can be pathogenic helminths of marine birds. Every year during the breeding season, there is variable mortality among prefledged chicks from the largest known Olrog's gull (Larus atlanticus) colony. Mortality has been associated with infection by the acanthocephalan Profilicollis chasmagnathi. Our aim was to study the role of chicks' size as a risk factor for intensity of infection and severe pathology, and to expand upon previous pathological findings reported in acanthocephalan-infected chicks. Size of the chick was associated with intensity of infection and number of intestinal perforations, which increased by 6.9% and 4.1%, respectively, for each millimetre increment in chick size. Infection was associated with inflammatory enteritis and granulomatous peritonitis. Complete intestinal perforations were observed in 85% and 97.3% of the studied chicks in 2005 and 2006, respectively, and they were observed very early during the post-hatching period. Our results show: (1) the presence of advanced pathology associated with acanthocephalan infections in chicks, beginning very early in the post-hatching period; and (2) significant increases in the intensity of infection and the associated pathology as a function of size of chicks, in dead chicks during this period.

Management of preeclampsia with severe features in a patient with relapsing polychondritis affecting the tracheobronchial tree.

Relapsing polychondritis is a rare disease that affects cartilaginous structures throughout the body. Progressive destruction of the laryngeal structures and the tracheobronchial tree occurs in 50% of patients, potentially leading to loss of patency and collapse of the airway. Respiratory involvement in relapsing polychondritis includes airway stenosis, tracheomalacia and recurrent lung infections due to chronic inflammation caused by the destruction of upper and lower airway cartilage. Pregnancy and preeclampsia can worsen pharyngolaryngeal oedema, while treatment with magnesium sulphate can affect neuromuscular function, exacerbating the degree of airway collapse in the most serious cases of relapsing polychondritis, possibly altering obstetric outcomes. Here, we present the management of a pregnant woman with relapsing polychondritis who presented with features of severe preeclampsia at 29 weeks and 6 days gestation. We believe that this is the first published case of the combination of the two disorders, complicated by acute respiratory failure after treatment with magnesium sulphate.

Epidemiology of acanthocephalan infections in crabs from the Bahía Blanca Estuary, Argentina.

This study was conducted in two populations of crabs, Cyrtograpsus angulatus and Neohelice granulata from the Bahía Blanca Estuary, in Argentina, to identify risk factors for infection by the acanthocephalan Profilicollis chasmagnathi and to assess the association between infection and mortality of these hosts. Cyrtograpsus angulatus and N. granulata crabs were sampled seasonally over the course of a year, and spring sampling included collection of dead crabs predated by Olrog's gulls in a nearby breeding colony. Potential risk factors for infection were assessed and the number of cystacanth larvae per crab was counted. In C. angulatus, the odds of infection increased by 7% for each millimetre increase in carapace length, and were nearly 17 times greater in crabs sampled from the Olrog's gull feeding area compared with those sampled from nests in the breeding colony. For every millimetre increase in carapace length in N. granulata, the odds of infection increased by 13% in crabs from the breeding colony, and by 32% in crabs from the feeding area. Mean intensity of infection in N. granulata increased by 16.5% for each additional millimetre of carapace width. The level of parasite aggregation was lowest in the largest C. angulatus and highest in N. granulata predated by Olrog's gull. The results show that host size is the most important factor influencing infection prevalence in both crab species and intensity of infection in N. granulata, and suggest the presence of parasite-induced mortality in the populations studied.

Body dissatisfaction is improved but the ideal silhouette is unchanged during weight recovery in anorexia nervosa female inpatients.

OBJECTIVE: Few studies have examined the impact of weight gain on body image disturbance (BID) in patients suffering from anorexia nervosa (AN). This study aims to explore the evolution of body distortion and body dissatisfaction following inpatient treatment. METHOD: Sixty-four women suffering from AN enrolled in our inpatient Cognitive and Behavioural Therapy programme and undertook a body image perception test and completed the Eating Disorder Inventory (EDI). Thirty-four participants completed a total of four evaluations over a three-month period. RESULTS: Patients' weight gain following treatment was significant. Weight regain was accompanied by significant reductions in both body distortion and body dissatisfaction. These reductions were complemented by improved scores for both EDI Drive for Thinness and Body Dissatisfaction. Perceived body image differed significantly between the onset and the completion of inpatient treatment whereas ideal body image did not. DISCUSSION: The high severity of the included patients and the significant attrition rate should limit our conclusions for a subgroup of patients. New approaches are needed to facilitate changes in the way patients assess their ideal body image.

Giant congenital melanocytic naevi: review of literature.

Giant congenital pigmented naevi is a great reconstructive challenge for the pediatric and plastic surgeons. Due to the increased risk of malignant transformation in such lesions, many procedures have been used to remove giant congenital naevi like dermoabrasion, laser treatment or surgical excision combined with reconstruction through skin expansion or skin grafting; among these, only a complete excision can offer an efficacious treatment. In our centre we use the "tissue expansion" technique in order to achieve a sufficient quantity of normal skin to perform a both staged and radical excision of these giant lesions.

The level of associated depression and anxiety traits improves during weight regain in eating disorder patients.

We assessed whether re-nutrition and weight gain have an influence on comorbid depression and anxiety in patients hospitalised for chronic eating disorders (ED). Seventy-five inpatients agreed to participate by completing the Eating Attitudes Test (EAT-40), the Beck Depression Inventory (BDI-13), and the State-Trait Anxiety Inventory (STAI-Y) before, during and after three months of treatment. Patients suffering from either anorexia nervosa or bulimia nervosa successfully regained weight during treatment. This weight gain was accompanied by statistically significant reductions in ED symptoms. Anxiety and, to a lesser extent, depressive symptoms diminished, but remained at pathological levels, with between diagnostic subtype differences. Improvement of depressive (r=0.77) and anxiety (r=0.64) levels were significantly (p<0.001) and positively correlated with the reduction of eating attitudes (EAT). These results are discussed in the context of re-orienting the therapeutic strategies aimed at reducing emotional suffering in patients with ED.

Mindfulness-based cognitive therapy added to usual care improves eating behaviors in patients with bulimia nervosa and binge eating disorder by decreasing the cognitive load of words related to body shape, weight, and food.

BACKGROUND: This study aimed to investigate the effectiveness of mindfulness-based cognitive therapy (MBCT) as a complementary approach in patients with bulimia nervosa (BN) or binge eating disorder (BED), and to assess how the reduction of the cognitive load of words related to eating disorders (ED) could constitute an intermediate factor explaining its global efficacy. METHODS: Eighty-eight women and men participated in clinical assessments upon inscription, prior to and following 8-week group MBCT. Mindfulness skills were assessed using the five facet mindfulness questionnaire; eating behaviors were assessed using the Three Factor Eating Questionnaire (TFEQ); comorbid pathologies were assessed using the beck depression index and the state-trait anxiety inventory. The cognitive load of words associated with ED was assessed through a modified version of the Stroop color naming task. RESULTS: Mindfulness skills improved significantly (p < .05) after group MBCT. The improvement of TFEQ scores was accompanied by reduced levels of depressive mood and trait anxiety. The positive impact of MBCT on TFEQ score was directly related to an improvement of the performance in the Stroop task. CONCLUSIONS: MBCT represents an interesting complementary therapy for patients with either BN or BED, at least when cognitive and behavioral domains are concerned. Such efficacy seems to be mediated by the reduction of the cognitive load associated with ED stimuli, which offers a possible explanation of how MBCT could reduce binge-eating behaviors. Other studies are needed, in independent centers, to focus more directly on core symptoms and long-term outcome.