Significant Clinical Worsening Research Articles

A longitudinal characterization of the adaptive and behavioral profile in Sotos syndrome.

Delineation of a developmental and behavioral trajectory is a key-topic in the context of a genetic syndrome. Short- and long-term implications concerning school outcome, independent living, and working opportunities are strictly linked to the cognitive and behavioral profile of an individual. For the first time, we present a longitudinal characterization of the adaptive and behavioral profile of a pediatric sample of 32 individuals with Sotos Syndrome (SoS) (18 males, 14 females; mean age 9.7 ± 4 years, eight carrying the NSD1 5q35 microdeletion and 24 with an intragenic mutation). We performed two clinical assessments: at baseline (T0) and at distance evaluation (T1) of adaptive and behavioral skills with a mean distance of 1.56 ± 0.95 years among timepoints. Our study reports a stability over the years-meant as lack of statistically significant clinical worsening or improvement-of both adaptive and behavioral skills investigated, regardless the level of Intellectual Quotient and chronological age at baseline. However, participants who did not discontinue intervention among T0 and T1, were characterized by a better clinical profile in terms of adaptive skills and behavioral profile at distance, emphasizing that uninterrupted intervention positively contributes to the developmental trajectory.

Author Response: Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial.

We appreciate the comment by Kang et al. on our research.1 While we acknowledge findings of toxicity in a mouse model of elevated cellular dopamine due to overexpression of the dopamine transporter,2 such toxicity has not been observed in rodent or primate models of Parkinson disease (PD) in which the aromatic L-amino acid decarboxylase (AADC) gene therapy was tested.3,4 Moreover, in our observations of these participants 3 years after AADC therapy,1 we did not see evidence of significant clinical worsening, which would be expected if the AADC gene therapy was causing injury to medium spiny neurons.

First vs second wave of COVID-19 pandemic in patients with obsessive compulsive disorder: A multicentre report from tertiary clinics in Northern Italy

IntroductionAmong patients with mental illness, those with obsessive compulsive disorder (OCD) showed a significant clinical worsening by the COVID-19 pandemic. The effects of the COVID-19 pandemic on OCD have been shown to worsen symptoms severity, with serious clinical consequences. However, the persistence of COVID-19 pandemic in OCD patients has been poorly investigated. The purpose of the present study was to assess the impact of the second wave of the COVID-19 pandemic in a sample of OCD patients and to compare the results with those obtained during the first wave on the same OCD sample. Methods116 OCD outpatients attending three OCD tertiary clinics in Northern Italy and previously included in a report on the impact of COVID-19, were followed-up in order to investigate sociodemographic and clinical features. Appropriate statistical analyses for categorical and continuous variables were conducted. ResultsThe 43 OCD patients with a clinical worsening (OW) reported a significant development of new obsessions/compulsions and the recurrence of past OC symptoms, higher rates of psychiatric comorbidities and sleep disturbances compared to patients without symptom worsening. Moreover, an increase in avoidance behaviors, suicidal ideation, Internet checking for reassurance, and job difficulties emerged in OW patients. Also, lower rates of pharmacological stability, and higher rates of therapy adjustment were observed. In terms of sex differences, males showed higher rates of past obsessions occurrence, while females showed a rise in Internet checking behaviors. When comparing OW patients between the first and the second wave, the latter showed significantly higher rates of past obsession occurrence and lower rates of pharmacological stability. Moreover, patients with OW showed a significantly older age during the second wave. ConclusionThe persistence of the COVID-19 pandemic showed a globally impaired clinical picture in the analyzed OCD sample. A further worsening between the two waves timepoints emerged, mainly involving older patients with OCD. The concordance between our results and those existing in literature highlights the importance of an accurate long-term monitoring of OCD patients in light of COVID-19 pandemic persistence.

Short-term outcomes of surgical atrial ablation and septal myectomy

Background. Hypertrophic cardiomyopathy is one of the most common types of cardiomyopathy. The appearance of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy is associated with significant clinical worsening. Outcomes of surgical ablation and septal myectomy in these patients are limited.Aim. This retrospective study aimed to evaluate short-term outcomes of concomitant surgical ablation and septal myectomy in patients with obstructive hypertrophic cardiomyopathy and atrial fibrillation.Methods. Fifty-five patients with hypertrophic obstructive cardiomyopathy and atrial fibrillation who underwent concomitant surgical ablation and septal myectomy between 2014 and 2019 were analysed. Patients with paroxysmal atrial fibrillation predominantly underwent left atrial ablation, and those with nonparoxysmal atrial fibrillation predominantly underwent the Maze IV procedure. Surgical ablation was performed using cryoablation alone (83.6%) or in combination with radiofrequency energy (16.4%).Results. Hospital mortality was 1.8%. Incidence of major adverse events was 3.6%. Sinus node dysfunction and atrioventricular block occurred in 7.3% and 1.8% of patients, respectively. Bleeding requiring revision occurred in 2 (3.6%) patients. Forty-nine (89.1%) patients had stable sinus rhythm and five (9.1%) were on dual-chamber pacemaker stimulation at the time of discharge.Conclusion. Concomitant septal myectomy and surgical ablation are feasible and safe in patients with hypertrophic obstructive cardiomyopathy and atrial fibrillation.Received 5 April 2021. Revised 16 May 2021. Accepted 17 May 2021.Funding: The study did not have sponsorship.Conflict of interest: The authors declare no conflicts of interests.Contribution of the authorsConception and study design: A.S. Zalesov, A.V. Bogachev-ProkophievData collection and analysis: A.S. Zalesov, S.A. Budagaev, A.V. SapeginStatistical analysis: A.S. Zalesov, A.V. Afanasyev, R.M. SharifulinDrafting the article: A.S. ZalesovCritical revision of the article: A.V. Bogachev-Prokophiev, S.I. Zheleznev, I.I. DeminFinal approval of the version to be published: A.S. Zalesov, A.V. Bogachev-Prokophiev, A.V. Afanasyev, R.M. Sharifulin, A.V. Sapegin, S.A. Budagaev, S.I. Zheleznev, I.I. Demin

Mucosal Kaposi's sarcoma in HIV-negative patients: a large case series from a single, tertiary referral center in Italy.

Mucosal involvement in HIV-negative Kaposi's sarcoma (KS) is uncommon but has potentially serious repercussions on patient care. Evidence regarding its epidemiology and optimal management is limited. Invasive endoscopic staging at diagnosis and periodically during follow-up is currently recommended by major guidelines. We reviewed the clinical records of 1,308 HIV-negative KS patients followed at our dedicated KS outpatient service. Demographics, clinical characteristics, and treatment outcomes for cases with biopsy proven mucosal lesions were collected. Mucosal involvement was documented in 53 patients (4.1% of our cohort), being present at diagnosis in 28 (52.8%) and occurring at a later time in the remaining 25 (47.2%) patients, with a mean latency of 8years (±7.7). Oral cavity (43.4%) and glans penis (39.6%) were the most frequently involved anatomical sites. Of those with available treatment response data, complete response (CR) of mucosal KS was appreciated in 41 cases (93.2%), while partial response (PR) and stable disease (SD) were documented in one (2.3%) and two cases (4.5%), respectively. Same-site recurrences were noticed in seven patients (17.1%). Mucosal involvement in HIV-negative KS is rare, and its recurrence, if properly treated, appears to be infrequent. Thus, routine invasive monitoring in this setting may be unnecessary. We propose a tailored approach based on the clinical manifestations of each patient, limiting the indication of invasive procedures to the first evaluation and in case of significant clinical worsening or to monitor known mucosal localizations.

Peritoneopericardial Diaphragmatic Hernia in a Persian Cat

Background: Peritoneopericardial diaphragmatic hernia is a congenital defect characterized by an anomalous communication between the abdominal cavity and pericardial sac, which can lead to displacement of the abdominal viscera into the thoracic cavity. The occurrence in felines is higher among long-haired breeds, mainly the Persian breed, possibly based onan autosomal recessive inheritance. The diagnosis of PPDH is performed by means of chest radiography with or without contrast, in association with other imaging tests such as ultrasonography and echocardiography. Our objective in this study was to report the occurrence and macroscopic changes in a case of peritoneopericardial diaphragmatic hernia in a Persian feline. Case: A 9-year-old male Persian cat weighing 3.4 kg was referred to the HPET-Private Veterinary Clinic, Salvador, Bahia, with an history of weight loss and chronic intermittent vomiting during the preceding 6 months, with lateral decubitus and breathing difficulties. Ultrasonography revealed findings suggestive of an infiltrative process in the stomach and duodenum, enlarged gastric lymph nodes, and some nodular images indicating slight displacement of the liver. Chest radiography revealed a cardiac silhouette with markedly enlarged dimensions associated with a dorsal deviation of the terminal trachea, and echocardiography revealed a small amount of pericardial effusion. The patient showed initial clinical improvement after blood transfusion; however, after 2 days, he exhibited significant clinical worsening and was therefore euthanized with the owner's consent. Post mortem evaluation revealed partial herniation of the liver and gallbladder into the chest cavity through a diaphragmatic hernia ring. The heart was partially surrounded by the left medial lobe of the liver, which was displaced into the pericardial sac. Herniated hepatic lobes had an irregular capsular surface with evident lobulation and tension lipidosis. In the abdominal cavity, the remainder of the liver (right lateral and medial lobes) was observed to be slightly enlarged, with an irregular surface, diffusely reddish with intense evidence of the lobular pattern and white and firm multifocal areas (fibrosis). In the duodenum, close to the pylorus, there was a nodule measuring 2.8 x 2.5 x 1.0 cm, with a whitish and ulcerated surface. When cut, it was soft and exhibited a homogeneous, whitish compact surface.Histopathological examinationshowed marked proliferation of fibrous connective tissue, which for the most part separated the lobes by septa and surrounded the portal space (fibrosis), a marked diffuse chronic inflammatory infiltrate composed of lymphocytes and plasma cells. In addition, marked bile duct hyperplasia and multifocal areas of fatty degeneration (steatosis).Discussion: The diagnosis was based on the association of clinical and pathological findings. Considering the age and clinical signs presented by the patient in this report, as well as the presence of few radiographic signs that were indicative of PPDH, the first differential diagnosis thought was pericardial neoplasia. Peritoneopericardial diaphragmatic hernia in felines is always of congenital origin and may occur asymptomatically depending on the number and involvement of herniated viscera. In this case, the patient's diagnosis of peritoneopericardial hernia was a necropsy finding; the fact that in agreement with previous reports of high rates of incidental diagnoses reinforces the importance of performing necropsy for confirmation or diagnosis of unexpected pathologies. In the present case, peritoneopericardial diaphragmatic hernia in isolation may not have led to severe anemia that culminated in the patient's death. The anatomopathological findings were compatible with biliary cirrhosis and multifocal liver fibrosis, accompanied by the presence of anemia and consequent hypovolemia. Keywords: congenital diaphragmatic hernia, congenital abnormalities, cats. Título: Hérnia Diafragmática Peritoneopericárdica em um Felino da Raça PersaDescritores: hérnia diafragmática congênita, anomalias congênitas, felinos.

Clinical worsening due to inappropriate automatic mode switch during biventricular pacing: What is the mechanism?

We describe a case of a 65-year-old gentleman with nonischemic cardiomyopathy and left bundle branch block who underwent cardiac resynchronization therapy device. After becoming a responder initially, he experienced significant clinical worsening on follow-up. Device interrogation revealed several long episodes of inappropriate automatic mode switch (AMS) entry due to far-field R wave oversensing resulting in loss of atrioventricular synchrony. Moreover, pacing in VVI mode with consistent VA conduction taking place during the AMS episodes was also found to be detrimental, which helped in sustaining the episodes and produced pacemaker syndrome like phenomenon. Attempts made to resolve the issue by prolonging the post-ventricular atrial blanking period was unsuccessful, hence we adjusted the atrial channel sensitivity to troubleshoot the problem.

Hemifacial Spasm Associated with Chiari Type I Malformation: Surgical Considerations and Case Report

AbstractHemifacial spasm (HS) is a movement disorder characterized by paroxysmal and irregular contractions of the muscles innervated by the facial nerve. Chiari malformation type I (CM I) is a congenital disease characterized by caudal migration of the cerebellar tonsils, and surgical decompression of foramen magnum structures has been used for treatment. The association of HS with CM I is rare, and its pathophysiology and therapeutics are speculative. There are only a few cases reported in the literature concerning this association. The decompression of the posterior fossa for the treatment of CM I has been reported to relieve the symptoms of HS, suggesting a relation between these diseases. However, the possible complications of posterior fossa surgery cannot be underrated. We report the case of a 66-year-old patient, in ambulatory follow-up due to right HS, no longer responding to botulinum toxin treatment. Magnetic resonance imaging (MRI) of the skull revealed compression of the facial nerve and CM I. The patient underwent surgery for HS by neurovascular microdecompression of the facial nerve via right lateral suboccipital craniectomy, but presented significant clinical worsening in the postoperative period even though the cerebellum edema related to surgical manipulation was mild. Due to the clinical worsening, the patient underwent a median suboccipital craniectomy with decompression of the foramen magnum structures. After this second surgery, the patient had progressive improvement and was discharged from the hospital for ambulatory care.

MRI features suggestive of gadolinium retention do not correlate with Expanded Disability Status Scale worsening in Multiple Sclerosis.

Different studies showed correlations between gadolinium-based contrast agent (GBCA) administrations and dentate nucleus (DN) T1-weighted hyperintensity. The clinical impact of gadolinium retention, however, is still largely unknown. The aim of this study was to investigate relations between MRI and clinical disability in relapsing-remitting multiple sclerosis (RR-MS) patients. In this retrospective study, clinical data were obtained from 74 RR-MS patients at baseline and after a mean follow-up time of 3.6years, including the expanded disability status scale (EDSS) score and its change (ΔEDSS). Patients were considered showing clinical worsening if they score a ΔEDSS ≥ 1 (for baseline EDSS ≤ 5.5) or ΔEDSS ≥ 0.5 (for baseline EDSS > 5.5). From the MRI data, the presence of bilateral DN hyperintensity was recorded along with the calculation of longitudinal relaxation rate (R1) maps. Patients with DN hyperintensity showed similar ΔEDSS change compared to those without visible changes on T1-weighted images (p = 0.32). Similarly, no DN-R1 difference was found comparing stable patients with those showing a significant clinical worsening (p = 0.54). Finally, no significant effect of DN-R1 values explained the variance in ΔEDSS (p = 0.76), thus suggesting their independence from the clinical outcome. MS patients with DN hyperintensity show similar EDSS changes compared to subjects without DN high-signal intensity. Furthermore, mean DN-R1 values of patients with significant clinical worsening were comparable to those of stable subjects and were unrelated to clinical disability. Taken together, these findings suggest that gadolinium retention in the brain of MS patients does not affect their clinical worsening, expressed by the EDSS change.

Stressful life events at the onset and during the evolution of systemic sclerosis

Objective: Stressful life events, such as Childhood Adverse Events (CAE) and Recent Stressful Events (RSE) may play a role in the pathogenesis of autoimmune disorders. The present study investigated their occurrence in Systemic Sclerosis (SSc). Methods: 110 SSc patients and 110 controls were enrolled. Stressful events assessment included a semi-structured interview and the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). A normative evaluation of RSE was made by means of the Paykel’s scoring of life events. The clinical status of patients with a very early diagnosis of Systemic Sclerosis (VEDOSS) during the first year after the diagnosis was evaluated in order to detect patients with a significant clinical worsening. Results: All investigated CAE were more frequently reported in SSc patients compared to controls, although with a significant difference only for the events “loss of mother” (p<0.05) and “sexual abuse” (p<0.05). SSc patients reported higher occurrence of at least one RSE (p<0.01), number of RSE (p<0.01), and stress load (mean total Paykel’s score) (p<0.01) in the year prior to the diagnosis compared to the year prior to the interview for controls. This was particularly true for severe and independent RSE (p<0.001). VEDOSS subjects who worsened during the first year after the diagnosis, compared to those who did not, reported a higher impact of severe and independent RSE in the same year (p<0.05). Conclusions: CAE may represent potential predisposing factors for SSc, while the occurrence of RSE may play a role in the onset and worsening of the disease.

PERSISTENT COMPROMISED HEMODYNAMIC FUNCTION, DUE TO SINGLE VENTRICULAR EPICARDIAL PACING, AFTER AORTIC VALVE REPLACEMENT SURGERY: A CASE REPORT

We report the case of a 69-year old woman, who was admitted to the cardiac surgery intensive care unit (ICU) of a tertiary hospital, after surgical aortic valve replacement, due to severe aortic stenosis. During the early postoperative period, the patient was hemodynamically stable and her cardiac rhythm was supported by temporary epicardial ventricular pacing. One hour after her ICU admission, the woman presented compromised hemodynamics, characterized by severe hypotension with poor response to aggressive inotropic, vasopressor and fluid therapy. After 15 minutes of her significant clinical worsening, the change of the pacing mode from single ventricular to single atrial effected immediate hemodynamic stabilization, improved arterial blood pressure and optimum patient cardiovascular function. This could be explained by the significantly reduced cardiac output in the absence of atrial contraction to assist ventricular preloading, which characterized some patients with impaired ventricular function, as those with severe aortic stenosis.

Significant clinical worsening after natalizumab withdrawal: Predictive factors

We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.

AB0643 The Ψ-Reuma Project: Role of Early and Recent Life Events on Systemic Sclerosis (SSC) Clinical Presentation and Course

BackgroundStressful Life Events (SLEs) may play a role in the etiopathogenesis of autoimmune diseases, especially during childhood (early SLEs) and in the year prior to the onset of the disease...

Oral Sildenafil Therapy for Chinese Patients With Pulmonary Arterial Hypertension: A Multicenter Study

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

Sildenafil therapy for pulmonary hypertension: a prospective study

To explore the safety and efficacy of oral sildenafil therapy for pulmonary arterial hypertension (PAH), and to provide evidence for sildenafil treatment for Chinese patients with PAH. In this 12-week, prospective, open-label, uncontrolled study, 56 patients with PAH were given oral sildenafil (25 mg, tid). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by 6 min walk (6MW) test. Secondary end points included changes in WHO class and cardiopulmonary hemodynamics. Clinical worsening was defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH, such as intravenous epoprostenol or oral bosentan. After 12 weeks, the compliance was good in 56 patients. Significant improvement was seen in NYHA heart function class and WHO class as compared to baseline (P < 0.01): from class IV to class III in 2, from class III to class II in 8 and to class I in 2 cases, and from class II to class I in 5 cases. No NYHA heart function class and WHO PAH function class deterioration were observed. Oral sildenafil increased 6MW distance, from (352 ± 80) m to (396 ± 78) m, with a change of (44 ± 70) m (P < 0.01). Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, P < 0.01; cardiac index, P < 0.01; pulmonary vascular resistance, P < 0.01) at week 12 as compared with baseline. Mean right atrial pressure decreased (3 ± 11) mm Hg (1 mm Hg = 0.133 kPa), mean pulmonary arterial pressure decreased (6 ± 14) mm Hg, cardiac output increased (1.1 ± 2.0) L/min, cardiac index increased (0.7 ± 1.1) L×min(-1)×m(-2), and total pulmonary resistance decreased (490 ± 831) Dys×s×cm(-5). Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients. Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension.

PERFORATION OF SIGMOID COLON AFTER EXTRACORPOREAL LITHOTRIPSY

A 32-year-old white man presented with an 8 mm. renoureteral calculus on the left side. He was placed in the ventral decubitus position and underwent ESWL with 3,000, 7 kV. shock waves. The patient had symptoms of nephritic colic on the left side and on day 5 after ESWL he complained of indistinct pain in the left iliac fossa along with 6 episodes of diarrhea in 24 hours. Symptoms improved after receiving analgesics but on day 7 significant clinical worsening was characterized by signs of septicemia and an acute abdomen. An x-ray of the abdomen revealed pneumoperitoneum with the right diaphragmatic cupula and bilateral disappearance of the psoas muscle line (fig. 1). With the diagnostic hypothesis of perforative acute abdomen due to the use of antiinflammatory drugs the patient underwent laparotomy. The surgical finding was diffise pustular peritonitis and a blocked 1 cm. perforation in the distal sigmoid colon in the mesocolic margin. No diverticulum or foreign body was identified in the colon or in the cavity. In the distal urethral projection an intense organized inflammatory process was identified. The patient elected resection of the perforated intestinal segment following terminal colostomy of the sigmoid, rectal stump closure, washing of the abdominal cavity and broad-spectrum antibiotic therapy (fig. 2). On pathological examination a perforative process was observed in a segment of the sigmoid with infiltrating polymor

Early Combination of Selegiline and Low-Dose Levodopa as Initial Symptomatic Therapy in Parkinson's Disease

Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age, 57.3 years; mean Parkinson's disease duration, 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage, 2; mean motor scores, 11.4) were given selegiline (Deprenyl), 10 mg daily, and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet, 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy, seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa, with significant decreases in their rated motor scores, such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%, compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose, 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild, transient, abnormal involuntary movements, and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)