Cost-effectiveness of early intervention in psychosis in low- and middle-income countries: economic evaluation from São Paulo, Brazil.

AIMS: The effectiveness and cost-effectiveness of early intervention for psychosis (EIP) services are well established in high-income countries but not in low- and middle-income countries (LMICs). Despite the scarcity of local evidence, several EIP services have been implemented in LMICs. Local evaluations are warranted before adopting speciality models of care in LMICs. We aimed to estimate the cost-effectiveness of implementing EIP services in Brazil. METHODS: A model-based economic evaluation of EIP services was conducted from the Brazilian healthcare system perspective. A Markov model was developed using a cohort study conducted in São Paulo. Cost data were retrieved from local sources. The outcome of interest was the incremental cost-effectiveness ratio (ICER) measured as the incremental costs over the incremental quality-adjusted life-years (QALYs). Sensitivity analyses were performed to test the robustness of the results. RESULTS: The study included 357 participants (38% female), with a mean (SD) age of 26 (7.38) years. According to the model, implementing EIP services in Brazil would result in a mean incremental cost of 4,478 Brazilian reals (R$) and a mean incremental benefit of 0.29 QALYs. The resulting ICER of R$ 15,495 (US dollar [USD] 7,640 adjusted for purchase power parity [PPP]) per QALY can be considered cost-effective at a willingness-to-pay threshold of 1 Gross domestic product (GDP) per capita (R$ 18,254; USD 9,000 PPP adjusted). The model results were robust to sensitivity analyses. CONCLUSIONS: This study supports the economic advantages of implementing EIP services in Brazil. Although cultural adaptations are required, these data suggest EIP services might be cost-effective even in less-resourced countries.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Gene expression alterations related to mania and psychosis in peripheral blood of patients with a first episode of psychosis.

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Association between gastroesophageal reflux and endobronchial carcinoid: a case report.

Children with neurological disorders may suffer from gastroesophageal reflux disease (GERD). Typical symptoms are vomiting, regurgitation and hematemesis. Patients present with respiratory symptoms only in cases with swallowing disorders causing chronic airway aspiration. We report the case of a patient affected by chromosome 8 p deletion syndrome with mental retardation, referred to our unit for suspected GERD. Chest X-ray, performed at admission for coexisting respiratory complaints, showed left lower lobe pneumonia; esophageal pH monitoring and upper endoscopy were normal for GERD. To rule out chronic airway aspiration, gastroesophageal 99 mTc scintigraphy with lung scan 18 to 24 h after a test meal and video fluoroscopy swallowing study were performed, both negative. Two months later, a second episode of left lower lobe pneumonia occurred. A chest CT scan was performed and showed an endobronchial mass; the biopsy taken during the broncoscopy was not conclusive. Surgical excision resulted in a diagnosis of pulmonary carcinoid. Bronchial carcinoids, although rare, should be taken into consideration as a potential cause of recurrent pneumonia even in the presence of demonstrated GERD where severe respiratory infections only occur with coexisting chronic pulmonary aspiration, even in neurologically impaired people.

Positive impact of blocking tumor necrosis factor alpha on the nutritional status in pediatric Crohn's disease patients.

BACKGROUND: TNFalpha seems to contribute to inflammation and malnutrition in Crohn's disease (CD) patients. In CD patients, the comparative effects on nutritional status of infliximab and traditional therapy have not yet been determined. The aim of our study was to assess the effects of infliximab as compared with those of standard therapy on nutritional status, disease activity, resting energy expenditure (REE), and food intake in CD children and adolescents. METHODS: From September 1999 to September 2005, all CD patients treated with infliximab (group A) were reviewed and matched with CD patients treated with traditional therapy (mesalazine and azathioprine) (group B). RESULTS: Fourteen CD patients from group A and 14 from group B were included; median interval before follow-up investigation was 10 months. Baseline and final values of weight, height, body mass index (BMI), pediatric CD activity index (pCDAI), REE, and food intake were studied. In treated patients, but not in control group, mean baseline weight (kg) and BMI values, 39.7 +/- 13.1 and 17.9 +/- 3.3, respectively, were significantly lower than their final values 42.6 +/- 13.2 and 18.9 +/- 3.1, and median pCDAI values 23.5 were significantly higher than their final values 10 (P < 0.05). Significant changes in height, REE, and food intake were not found in either group. CONCLUSIONS: In pediatric CD patients, infliximab seems to impact positively on the nutritional status as demonstrated by the improvement in weight and BMI, but not in linear growth; effects on nutritional status seem to be due to amelioration of disease activity, rather than to REE reduction or food intake increase.

Clinical efficacy and safety of parenteral nutrition in adolescent girls with anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) is a common chronic disorder characterized by severe malnutrition and psychological disturbances. Parenteral nutrition (PN) is not usually used in nutritional rehabilitation of AN. The aim of our study was to retrospectively evaluate the indications, clinical efficacy, and safety of PN as assessed by short- and long-term outcomes in AN inpatient girls. METHODS: During the last 10 years a total of 198 inpatients were included in our study: 104 (53%) received oral and parenteral refeeding (group A) and 94 (47%) oral refeeding alone (group B). For each nutritional treatment, clinical efficacy was evaluated by short- and long-term outcomes, and safety was assessed by complication rate. RESULTS: Short-term outcome assessment indicated weekly weight gain and maximum caloric intake to be higher in PN-treated patients. Long-term outcome evaluation showed rehospitalization and recovery rate to be similar in the two groups, but failure of first nutritional rehabilitation requiring PN significantly greater in group B (17.5%) than in group A (3%) (p = .01). The number of complications was significantly higher in group A than in group B (p = .004), although all complications resolved. CONCLUSION: Among all nutritional rehabilitation strategies, PN offers an alternative and safe way to successfully treat AN patients. Presence of clinical complications and reduced compliance with individual, group, and family therapy seem to be the main indications for PN, as it promptly improves nutritional status. At pediatric and adolescent ages, psychological disturbances can also contraindicate the use of enteral nutrition, and therefore represent an additional indication for PN.

[Erdheim-Chester disease: a non-Langerhans cell histiocytosis. A clinical-case and review of the literature]. / La malattia di Erdheim-Chester una istiocitosi a cellule non Langerhans. Rewiew della letteratura e descrizione di un caso clinico.

We make a retrospective evaluation of clinical and radiologic features, treatment, and outcome of Erdheim-Chester disease, a rare non-Langerhans cell histiocytosis. We report a case of Erdheim-Chester disease and review 60 cases from the literature. These cases are consider to have Erdheim-Chester disease when they have either typical bone radiographs (symmetrical long bones osteosclerosis) and/or histologic criteria disclosing histiocytic infiltration with distinctive immunohistochemical phenotype of the non-Langerhans cell histiocytes with positive staining for CD68 and negative staining for S-100 protein and CD1a. Our patient undergoes chemiotherapy according to the LCH-II stratification and therapy plan (Vinblastine, Etoposide and Prednisone) and thereafter receives Carboplatin and Etoposide, and Somatostatin. She is alive and clinically well 33 months after onset of symptoms and the lesions don't appear to progress at imaging examinations. In conclusion, Erdheim-Chester disease may be confused with Langerhans cell histiocytosis as it sometimes shares the same clinical (exophthalmos, diabetes insipidus) or radiologic (osteolytic lesions) findings. However, the characteristics radiological pattern of Erdheim-Chester disease together the immunohistochemical phenotype of hystiocytic infiltration supports the theory that Erdheim-Chester disease is a unique disease entity distinct.

Cerebellar influences on saccade plasticity.

Inaccurate saccades adapt to become more accurate. In this experiment the role of cerebellar output to the oculomotor system in adapting saccade size was investigated. We measured saccade adaptation after temporary inactivation of saccade-related neurons in the caudal part of the fastigial nucleus which projects to the oculomotor brain stem. We located caudal fastigial nucleus neurons with single unit recording and injected 0.1% muscimol among them. Two monkeys received bilateral injections and two monkeys unilateral injections. Unilateral injections made ipsiversive saccades hypermetric (gains >1.5) and contraversive saccades hypometric (gains approximately 0.6). Bilateral injections made both leftward and rightward saccades hypermetric (gains >1.5). During unilateral inactivation neither ipsiversive nor contraversive saccade size adapted after approximately 1,000 saccades. During bilateral inactivation, adaptation was either small or very slow. Most intact monkeys completely adapt after approximately 1,000 saccades to similar dysmetrias produced by intrasaccadic target displacement. After the monkeys receiving bilateral injections made >1,000 saccades in each horizontal direction, we placed them in the dark so that the muscimol dissipated without the monkeys receiving visual feedback about its saccade gain. After the dark period, 20-degree saccades were adapted to be 12% smaller, and 4-degree saccades to be 7% smaller. We expect this difference in adaptation because during caudal fastigial nucleus inactivation, monkeys made many large overshooting saccades and few small overshooting saccades. We conclude from these results that: (1) caudal fastigial nucleus activity is important in adapting dysmetric saccades; and (2) bilateral caudal fastigial nucleus inactivation impairs the relay of adapted signals to the oculomotor system, but it does not stop all adaptation from occurring.

Visual error is the stimulus for saccade gain adaptation.

Saccade accuracy is fundamental to clear vision. The brain maintains saccade accuracy by altering commands for saccades that are consistently inaccurate. For example, saccades that consistently overshoot their targets gradually become smaller. The signal that drives the adaptation of saccade size is not well understood. Previous reports propose that corrective movements and visual errors, both generated after inaccurate saccades, could be responsible for a change in saccade size. Here we show that we can elicit normal reductions in saccade size while eliciting few or no correction saccades. These normal reductions in saccade size indicate that visual errors, not correction saccades, drive the adaptation of saccades.

Effect of visual background on saccade adaptation in monkeys.

The brain maintains saccade accuracy by modifying saccades that are consistently inaccurate (e.g. hypermetric). To determine whether this adaptation is influenced by the visual background we used several different target and background movements to elicit changes in saccade gain. In almost all cases, the target spot drove gain changes. The background had no effect on, or slightly reduced, adaptation. We conclude that the saccade adaptation mechanism is driven almost entirely by stimuli on or near the fovea and is affected very little by visual stimuli falling more peripherally.

Temporal characteristics of error signals driving saccadic gain adaptation in the macaque monkey.

Saccadic gain (saccade amplitude/target amplitude) can be reduced gradually by repeatedly stepping the target backward during the saccade. The gain reduction produced by this paradigm is thought to be driven by an error signal created by the backstep. We investigated the effects of varying the timing of this error signal relative to the end of the saccade by using two different paradigms in macaques. In the brief backstep paradigm, the target was stepped backward 30% during the saccade but extinguished after different durations. For very short backstep durations (32 ms), little gain reduction occurred. As backstep duration increased, the amount of gain reduction also increased. When backstep duration reached 80 ms, the amount of gain reduction was just under that achieved during the conventional adaptation paradigm in which the backstep remained visible for 1000-1200 ms. In the delayed backstep paradigm, as the saccade occurred, we extinguished the target and then, after a delay, illuminated it for 1 s at the backstep location. In most experiments with short delay times of 16-64 ms, the saccadic gain reduction reached that achieved during conventional adaptation. At delays of 112-208 ms, the amount of gain reduction decreased to approximately 75% of that reached during conventional adaptation. With still longer delays, the amount of gain reduction decreased more gradually. At delays of 750 ms, average gain reduction was 10%. By delays of 1.5 s, gain reduction had fallen essentially to zero. Taken together, these data suggest that the error signal must be present for a limited time ( approximately 80-100 ms) after the saccade to produce the most robust saccadic gain adaptation. However, errors present as long as 750 ms after the saccade still can produce a significant gain reduction.

Flexibility of saccade adaptation in the monkey: different gain states for saccades in the same direction.

Saccadic accuracy, measured as the ratio of the size of a saccade to the size of the target step that elicits it, i.e., saccade gain, can be altered by jumping the target surreptitiously during the targeting saccade. The gain change produced by this paradigm does not generalize or transfer to saccades of all sizes. Instead, the amount of transfer decreases the more the tested saccade differs in amplitude and direction from that adapted. Here, we tested the limits of this saccade-size specificity by attempting to impose quite different gain states on saccades in the same direction. We altered the saccadic gain by intrasaccadic target jumps of 30% of the initial target step, either forward to produce a gain increase or backward to produce a gain decrease. Three different conditions were studied: (1) saccades to target steps of 20 degrees or 7 degrees were adapted in individual sessions with backward and forward jumps, respectively; (2) saccades to target steps of 20 degrees caused backward target jumps during the same session in which saccades to 7 degrees target steps caused forward steps; (3) the target jumps accompanying 20 and 7 degrees saccades were the same as in (2), but in addition, there were intermediate-sized saccades to 13.5 degrees target steps with no intrasaccadic target jumps. Saccadic gain adaptation was quite flexible. In condition 2, we could simultaneously increase the gain of saccades to 7 degrees target steps while decreasing the gain of saccades to 20 degrees steps in the same direction. Intermediate horizontal saccades to 13.5 degrees target steps experienced gain reductions (average: 6.9%), which were not the sum of gain changes expected from separate 20 degrees gain decreases and 7 degrees gain increases alone, as predicted from condition 1. If adaptation at 20 degrees and 7 degrees occurred while an animal also tracked a non-adapting 13.5 degrees target step (paradigm 3), the gain reduction of saccades to the 13.5 degrees step was reduced considerably (3.4%). Thus, the mechanism that adapts saccade size can support a robust gain increase for saccades of one size while simultaneously supporting a robust gain decrease for saccades only 13 degrees larger. Furthermore, the presence during adaptation of a non-adapted target step with a size intermediate to the two adapting steps reestablishes a nearly normal gain within only 6.5 degrees of a robust gain increase and decrease. These data indicate that saccadic gain adaptation can set very different gain states for saccades with rather similar vectors.

[Combined vaginal and laparoscopic surgical treatment of genito-urinary prolapse]. / Trattamento chirurgico combinato vaginale e laparoscopico del prolasso genito-urinario.

BACKGROUND: A new combined technique for vaginal prolapse and cystocele using minimal access surgery is presented and evaluated. METHODS: Thirty-five patients (mean age 57.1) with genitourinary prolapse (II-IV degree Baden-Walker) without urinary incontinence underwent surgery between January 98 and December 99 with 4-24 months of follow-up (mean 14.6 months). The surgical stages include total vaginal hysterectomy with bilateral adnexectomy, wide opening of the vagina without excessive removal of the vaginal mucosa; the bladder is loosened and the polypropylene mesh (PPM) is lightly fixed to the bladder and stitched to the anterior and posterior vaginal wall. The PPM is introduced into the abdomen and laparoscopically fixed to the sacral promontory with titanium spirals having checked vaginally the right tension of the mesh. Accurately laparoscopic peritonization of the PPM ends the surgical procedure. RESULTS: The operation time was 90'-140' (mean 112') followed by 3-7 days of hospitalization (mean 4.3). Vaginal prolapse and cystocele were corrected in all cases. No surgical complications, de novo urinary incontinence, prolapse recurrence or inconvenience to sexual activity have been observed. There was one erosion of the vaginal wall by the PPM 45 days after the operation. CONCLUSIONS: Initial studies suggest that laparoscopic sacrocolpopexy and cystocele repair with PPM is an effective treatment for genitourinary prolapse. If subsequent studies will confirm these findings, the development of minimal access techniques for genitourinary prolapse will represent a significant surgical advance.

Characteristics of simian adaptation fields produced by behavioral changes in saccade size and direction.

The gain of saccadic eye movements can be altered gradually by moving targets either forward or backward during targeting saccades. If the gain of saccades to targets of only one size is adapted, the gain change generalizes or transfers only to saccades with similar vectors. In this study, we examined the spatial extent of such saccadic size adaptation, i.e., the gain adaptation field. We also attempted to adapt saccade direction by moving the target orthogonally during the targeting saccade to document the extent of a direction or cross-axis adaptation field. After adaptive gain decreases of horizontal saccades to 15 degrees target steps, >82% of the gain reduction transferred to saccades to 25 degrees horizontal target steps but only approximately 30% transferred to saccades to 5 degrees steps. For the horizontal component of oblique saccades to target steps with 15 degrees horizontal components and 10 degrees upward or downward vertical components, the transfer was similar at 51 and 60%, respectively. Thus the gain decrease adaptation field was quite asymmetric in the horizontal dimension but symmetric in the vertical dimension. Although gain increase adaptation produced a smaller gain change (13% increase for a 30% forward adapting target step) than did gain decrease adaptation (20% decrease for a 30% backward adapting target step), the spatial extent of gain transfer was quite similar. In particular, the gain increase adaptation field displayed asymmetry in the horizontal dimension (58% transfer to 25 degrees saccades but only 32% transfer to 5 degrees saccades) and symmetry in the vertical direction (50% transfer to the horizontal component of 10 degrees upward and 40% transfer to 10 degrees downward oblique saccades). When a 5 degrees vertical target movement was made to occur during a saccade to a horizontal 10 degrees target step, a vertical component gradually appeared in saccades to horizontal targets. More than 88% of the cross-axis change in the vertical component produced in 10 degrees saccades transferred to 20 degrees saccades but only 12% transferred to 4 degrees saccades. The transfer was similar to the vertical component of oblique saccades to target steps with either 10 degrees upward (46%) or 10 degrees downward (46%) vertical components. Therefore both gain and cross-axis adaptation fields have similar spatial profiles. These profiles resemble those of movement fields of neurons in the frontal eye fields and superior colliculus. How those structures might participate in the adaptation process is considered in the DISCUSSION.

A rare complication due to sulfuric acid ingestion.

The authors present a case of pyloric and duodenal obstruction in an 8-year-old child, resulting from accidental ingestion of sulfuric acid. A marked pyloric and duodenal cicatrizing stenosis resulting from ingestion of sulfuric acid is seen infrequently, especially in pediatric age. Sulfuric acid produces a coagulation necrosis of the gastric mucosa and submucosa, and the process may involve the entire thickness of the gastric wall, with subsequent ulceration and fibrosis. This dynamic pathophysiologic event imposes postponement of surgical intervention because of various time length between ingestion of acid and onset of gastric outlet obstruction (17 days to 5 years). Clinical features included postprandial epigastric distress, repeated non-bilious vomiting, and marked weight loss. The authors also discuss the various surgical procedures that were employed to relieve the obstruction. Notwithstanding a potential risk of malignant evolution, a gastro-jejunostomy is the treatment of choice because of the age of the patient, and good postoperative results are confirmed by barium studies.

[A multicenter epidemiological study of burns of the head in childhood in the period of 1986-1990]. / Studio epidemiologico multicentrico delle ustioni nell'estremo cefalico in età pediatrica nel periodo 1986-1990.

A retrospective study was performed over the children admitted to three regional pediatric burn units, over a 5-year period (1986-1990). Out of 695 pediatric patients, 270 (38.8%) were admitted with burns of the head and neck. This whole childhood age group (up to 14 years of age) was examined epidemiologically. The age group presenting the highest incidence was within 0-3 years (71%); scalds were involved in high percentage (68%) and many injuries occurred at home (93%). Epidemiological aspects of the report are discussed with particular consideration of preventive programs.