Adición de melatonina a terapia con hipotermia para encefalopatía hipóxico-isquémica neonatal / Addition of melatonin to hypothermia therapy for neonatal hypoxic-ischemic encephalopathy

Introducción La encefalopatía hipóxico-isquémica neonatal es una patología caracterizada por una disfunción neurológica aguda, de severidad variable, causada por un episodio asfíctico perinatal. Se presenta en uno a seis de cada 1000 recién nacidos de término, asociándose a una alta morbimortalidad neonatal y a desenlaces neurológicos adversos. El uso de hipotermia es considerado como la terapia estándar para esta condición. Sin embargo, debido a su limitada eficacia clínica, se han propuesto diferentes opciones terapéuticas adyuvantes, incluyendo el uso de fármacos como la melatonina. Existe controversia sobre si la terapia combinada con melatonina es superior a la monoterapia con hipotermia. Métodos Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta-análisis y preparamos una tabla de resumen de los resultados utilizando el método Grading of Recommendations Assessment, Development and Evaluation, GRADE Resultados Identificamos dos revisiones sistemáticas que en conjunto incluyeron dos estudios primarios, ambos ensayos aleatorizados. Se incluyeron los dos ensayos aleatorizados en el análisis del presente trabajo. Conclusiones No es posible establecer con claridad si la adición de melatonina disminuye la mortalidad o la probabilidad de presentar alteraciones reflejadas en la resonancia magnética cerebral, debido a que la certeza de la evidencia existente ha sido evaluada como muy baja. Por otro lado, adicionar melatonina a la terapia con hipotermia, comparado con la monoterapia con hipotermia, podría aumentar la probabilidad de que el examen neurológico sea normal a los seis meses, y que la cognición sea normal a los 18 meses. Finalmente, la adición de melatonina a la terapia con hipotermia probablemente disminuya la probabilidad de presentar convulsiones.

Introduction Neonatal hypoxic-ischemic encephalopathy is caused by perinatal asphyxia, resulting in an acute neurological dysfunction of variable severity. It occurs in one to six of every 1000 full-term newborns and is associated with high neonatal morbimortality and adverse neurological outcomes. The use of hypothermia is considered the standard therapy for this condition. However, different adjuvant therapeutic options have been proposed due to limited clinical efficacy, including drugs like melatonin. There is controversy about whether combined therapy with melatonin is superior to monotherapy with hypothermia. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, and Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of the findings table using the GRADE approach. Results We identified two systematic reviews that included two primary studies, both randomized trials. The two randomized trials were included in the analysis of the present work. Conclusion It is not possible to establish whether the addition of melatonin decreases mortality or the probability of alterations in brain magnetic resonance imaging because the certainty of the existing evidence has been assessed as very low. On the other hand, the addition of melatonin to hypothermia therapy, compared to hypothermia monotherapy, may increase the probability of normal neurological examination at six months and the probability of normal cognition at 18 months. Finally, adding melatonin to hypothermia therapy likely reduces the probability of seizures.

Utilidad del tromboelastograma en pediatría: correlación con pruebas habituales de la coagulación / Usefulness of the thromboelastogram in children: correlation with habitual coagulation tests

INTRODUCCIÓN: Los exámenes habituales de coagulación evalúan distintos elementos de la hemostasia en forma par cial, y no traducen las interacciones celulares, lo que es especialmente sensible en pacientes críticos. Las técnicas viscoelásticas, como el tromboelastograma (TEG) muestran el proceso de coagulación completo, y están siendo evaluadas como exámenes de la coagulación global. OBJETIVO: determinar la correlación de los exámenes habituales de coagulación con los valores del TEG, en niños atendidos en una unidad de cuidados intensivos (UCI). PACIENTES Y MÉTODO: Se revisaron 238 TEG de pacientes <18 años, con evidencia de alteración de coagulación clínica y/o de laboratorio, hospitalizados en UCI. Se correlacionaron los valores de los parámetros del TEG con cada uno de los valores de los exámenes habituales de coagulación. Los exámenes se obtuvieron según protocolo, utilizando una muestra de sangre de 4,5 ml para TEG con equipo TEG® 5000 Thrombelastograph Hemostasis Sys tem, mediante un transductor electromagnético que permite la medición de la resistencia durante la formación y lisis del coágulo. El recuento de plaquetas se obtuvo utilizando método automatizado o microscopía con contraste de fase; el fibrinógeno, tiempo de protrombina y de tromboplastina parcial activada por métodos nefelométricos. RESULTADOS: 201 TEGs correspondientes a 59 pacientes. Se evidenció una correlación moderada a baja en todos los parámetros medidos. No se encontró co rrelación entre porcentaje de lisis del coágulo, ni firmeza del coágulo. CONCLUSIONES: Existe una baja correlación entre la información entregada por TEG y los exámenes de coagulación habituales, esto sugiere que el TEG aporta información diferente acerca del estado de coagulación de los pacientes críticos evaluados.

INTRODUCTION: Usual coagulation tests partially evaluate different elements of hemostasis, and do not translate cell interactions, which is an especially sensitive issue in critically ill patients. Viscoelastic measurement techniques, such as thromboelastogram (TEG) show the complete coagulation pro cess and are being evaluated as global coagulation tests. OBJECTIVE: To determine the correlation of the usual coagulation tests with the TEG values, in children treated in an intensive care unit (ICU). PATIENTS AND METHOD: We reviewed 238 TEGs of patients under 18 years of age, with evidence of clinical and/or laboratory coagulation alterations, who were hospitalized in the ICU. The TEG para meter values were correlated with each of the usual coagulation test values. The tests were obtained according to the protocol, using a 4.5 ml blood sample for TEG with TEG® 5000 Thrombelastograph Hemostasis System, through an electromagnetic transducer that allows the measurement of resis tance during the clot formation and lysis. Platelet count was obtained using an automated method or phase-contrast microscopy, and fibrinogen levels, prothrombin time, and partial thromboplastin time activated by nephelometric methods. RESULTS: 201 TEGs corresponding to 59 patients were re viewed. A moderate to low correlation was observed in all the measured parameters. No correlation was found between the percentages of clot lysis or clot firmness. CONCLUSIONS: There is a low corre lation between the information provided by TEG and the usual coagulation tests. This suggests that the TEG provides different information about the coagulation status of the evaluated critical patients.

Usefulness of the thromboelastogram in children: correlation with habitual coagulation tests. / Utilidad del tromboelastograma en pediatría: Correlación con pruebas habituales de la coagulación.

INTRODUCTION: Usual coagulation tests partially evaluate different elements of hemostasis, and do not translate cell interactions, which is an especially sensitive issue in critically ill patients. Viscoelastic measurement techniques, such as thromboelastogram (TEG) show the complete coagulation pro cess and are being evaluated as global coagulation tests. OBJECTIVE: To determine the correlation of the usual coagulation tests with the TEG values, in children treated in an intensive care unit (ICU). PATIENTS AND METHOD: We reviewed 238 TEGs of patients under 18 years of age, with evidence of clinical and/or laboratory coagulation alterations, who were hospitalized in the ICU. The TEG para meter values were correlated with each of the usual coagulation test values. The tests were obtained according to the protocol, using a 4.5 ml blood sample for TEG with TEG® 5000 Thrombelastograph Hemostasis System, through an electromagnetic transducer that allows the measurement of resis tance during the clot formation and lysis. Platelet count was obtained using an automated method or phase-contrast microscopy, and fibrinogen levels, prothrombin time, and partial thromboplastin time activated by nephelometric methods. RESULTS: 201 TEGs corresponding to 59 patients were re viewed. A moderate to low correlation was observed in all the measured parameters. No correlation was found between the percentages of clot lysis or clot firmness. CONCLUSIONS: There is a low corre lation between the information provided by TEG and the usual coagulation tests. This suggests that the TEG provides different information about the coagulation status of the evaluated critical patients.

[Oral transmission of Chagas' disease]. / Transmisión de la enfermedad de Chagas por vía oral.

The traditional transmission pathways of Chagas' disease are vectorial, transfusional, transplacental and organ transplantation. However, oral transmission is gaining importance. The first evidence of oral transmission was reported in Brazil in 1965. Nowadays the oral route is the transmission mode in 50% of cases in the Amazon river zone. Oral infection is produced by the ingestion of infected triatomine bugs or their feces, undercooked meat from infested host animals and food contaminated with urine or anal secretion of infected marsupials. Therefore travelers to those zones should be advised about care to be taken with ingested food. In Chile, this new mode of transmission should be considered in public health policies.

Transmisión de la enfermedad de Chagas por vía oral / Oral transmission of Chagas' disease

The traditional transmission pathways of Chagas' disease are vectorial, transfusional, transplacental and organ transplantation. However, oral transmission is gaining importance. The first evidence of oral transmission was reported in Brazil in 1965. Nowadays the oral route is the transmission mode in 50 percent of cases in the Amazon river zone. Oral infection is produced by the ingestion of infected triatomine bugs or their feces, undercooked meat from infested host animals and food contaminated with urine or anal secretion of infected marsupials. Therefore travelers to those zones should be advised about care to be taken with ingested food. In Chile, this new mode of transmission should be considered in public health policies.

Introducción precoz de sustitutos de lactancia materna e incidencia de lactancia materna exclusiva al mes de vida / Breast milk substitutes at one month of life and breastfeeding suspension risk

Healthy term newborn feeding choice at the Maternity Ward may determine exclusive breastfeeding (EB) duration. Objective: Determine prospectively if early introduction of breast milk substitutes (BMS) or other liquids in healthy term newborns is associated to a reduction of EB incidence at 1 month of age. Methods: Concurrent cohort study of 211 healthy term neonates born in Hospital Clínico Universidad Católica during October 2007-June 2007, 108 non-supplemented and 103 supplemented with milk formula or dextrose 5 percent during the time they stayed at the Maternity Ward. Crude and adjusted risk of EB cessation between both groups was estimated at 1 month of age. Results: One month after birth, 40/100 (40.0 percent) of supplemented newborns and 26/101 (25.7 percent) non-supplemented newborns were not receiving exclusive breastfeeding (crude RR =1.55 (CI95 percent 1.03-2.34)). Adjusted by maternal characteristics (age, education, breastfeeding experience, education in breastfeeding, EB time projection and paternal support) and newborn characteristics (type of delivery and birth weight), EB cessation risk was 55 percent higher in supplemented neonates (adjusted RR = 1.55, CI95 percent 1.01-2.35). Conclusion: Early supplementation in healthy term newborns with BMS is associated to a higher risk of EB cessation at 1 month of age.

Introducción: La forma de alimentación de un recién nacido de término (RNT) durante su estadía en la Maternidad puede condicionar la duración de la lactancia materna exclusiva (LME). Objetivo: Determinar prospectivamente si la introducción precoz de SLM (sustitutos de lactancia materna) u otros líquidos a RNT sanos se asocia a una reducción de la incidencia de LME al mes de vida. Métodos: Estudio de cohorte concurrente. Se conformó una cohorte de 211 RNT sanos cuyo parto fue atendido en la Maternidad del Hospital Clínico Universidad Católica en el período octubre 2006-junio 2007, 108 no-suplementados y 103 suplementados con fórmula láctea o suero glucosado al 5 por ciento durante su estadía en la Maternidad. Se estimó el riesgo crudo de cesación de LME al mes de vida entre los grupos no-suplementado vs suplementado, y ajustado por diversas variables confundentes. Resultados: Transcurrido un mes de vida, 40/100 (40,0 por ciento) recién nacidos suplementados y 26/101 (25,7 por ciento) recién nacidos no-suplementados habían dejado de recibir LME, siendo el RR crudo = 1,55 (IC95 por ciento 1,03-2,34). Ajustado por características maternas (edad, educación, experiencia previa de lactancia, educación en lactancia, proyección LME y apoyo paterno) y del recién nacido (vía de parto y peso de nacimiento), el riesgo de cesación de LME al mes de vida fue 55 por ciento mayor en los RNT suplementados vs. no-suplementados (RR ajustado = 1,54; IC95 por ciento 1,01-2,35). Conclusión: La suplementación precoz de RNT sanos con SLM asocia a un mayor riesgo de cese de LME al mes de vida.

Changes in the survival of patients with systemic lupus erythematosus in childhood: 30 years experience in Chile.

The objective of this study was to analyse the survival rate and cause of death in children with systemic lupus erythematosus (SLE) during the past 30 years in Chile. A retrospective analysis was performed between 1969 and 2000 on patients attending pediatric rheumatology centres in Santiago, Chile. Survival and causes of death in 31 children followed from 1969 to 1980 fulfilling the 1982 American College of Rheumatology criteria for SLE and treated with oral steroids were compared with 50 other patients who were treated with oral steroids and an aggressive treatment of IV bolus of cyclophosphamide (38 patients) and azathioprine (12 patients). Global survival at five and 10 years follow-up for the patients studied from 1969 to 1980 was 68 and 40%, respectively. During the second study period these values were significantly improved and global survival reached 95% at five years and 90% at 10 years follow-up (P < 0.05). Survival at 10 years follow-up for patients with lupus nephropathy increased from 28% (study period 1964-1980) to 86% (study period 1984-2000). Twelve children died (38%) during the 1964-1980 study period. The causes of death were six due to kidney failure, three due to infectious conditions and another three of unknown causes. During the 1980-2000 study period mortality reached 6% (three cases), two cases died of a lupus flare-up and one case due to infection. In the last three decades, we have seen an important increase in the survival of children with SLE, especially in those patients with renal involvement. Management with immunosuppressive drugs, such as IV cyclophosphamide or azathioprine has changed the prognosis in these children. These results demonstrate that our children with SLE increased their life expectancy but are now faced with new types of morbidity because of the sequelae related to the disease itself.

Tratamiento de la asfixia perinatal con hipotermia corporal total (caso clínico) / Treatment of perinatal asphyxia with total body hypothermia: a clinical case

El manejo del RN de termino asfixiado, ha mejorado gracias a la mayor disponibilidad de terapia intensiva, sin embargo, es poco lo que se ha progresado en su neuroprotección. Caso clínico: Recién nacido (RN) gravemente asfixiado, sometido a hipotermia corporal total. Madre de 38 años, diabética, inducida a las 38 semanas, desarrolla signos de sufrimiento fetal agudo. Se extrae un recién nacido con un peso de 4.545 g. Apgar 1-3-5. Requiere intubación y ventilación mecánica por apnea, un gas arterial a los 30 min muestra acidosis metabólica severa. A las 2 h de vida presenta signos de encefalopatía hipóxica isquémica grave y depresión difusa del voltaje en el electroencefalograma. Se somete a hipotermia corporal total a una temperatura rectal de 33° C a 34° C, durante 72 h no hubo efectos colaterales importantes. Se da de alta a los 10 días en buenas condiciones neurológicas. El seguimiento se realiza por 2 años. El test de Bailey da un puntaje de 82 en la escala motora y 95 en la escala mental. Este caso demuestra que este tipo de tratamiento es factible de realizar, si se selecciona adecuadamente al paciente, se inicia precozmente y cuentan con las condiciones de equipamiento y enfermería especializadas.

Alta precoz vigilada en infecciones respiratorias agudas bajas: campaña de invierno, servicio de pediatría, Hospital San Juan de Dios, 1999 / Early surveilled discharge in low acute respiratory tract infections: winter campaing: pediatric service, San Juan de Dios Hospital, 1999

En 1994 se iniciaron las Campañas de Invierno con el fin de disminuir las complicaciones y mortalidad infantil por infecciones respiratorias agudas. En su perfeccionamiento gradual surgió la estrategia del alta precoz, otorgada con criterios definidos y con seguimiento en Consultorio de Enfermedades Respiratorias Infantiles. Se pretende evaluar esta actividad en el Servicio de Pediatría de nuestro hospital durante el invierno de 1999. 143 pacientes calificaron para el estudio, de estos, 140 tenían bronconeumonía, que correspondieron a un 40 por ciento de los egresos por IRA. El virus más detectado fue el VRS en 57 niños. Destaca que un 41 por ciento tenía patología asociada a la causa de hospitalización. El 87,4 por ciento de los niños fue seguido en consultorio de Broncopulmonar. Se detectó complicaciones postalta en el 16 por ciento de los niños: atelectasia en 42 por ciento de ellos; síndrome bronquial obstructivo persistente, 31 por ciento; sobreinfección bacteriana, 27 por ciento, que fueron manejados ambulatoriamente. La tasa de reingresos fue del 6,3 por ciento. La evaluación de los criterios para ingresar niños al programa de alta precoz mostró un predominio de criterios clínicos, que fueron menos exigentes que los preestablecidos. Este esfuerzo permitió detectar oportunamente a los portadores de patología crónica y definir la necesidad de recurso humano para el programa. Deben perfeccionarse los criterios de alta precoz y de vigilancia para mejorar el programa dado que éste incide en la optimización de los recursos y la calidad de atención

The Chilean version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Chilean language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Chilean CHAQ-CHQ were derived from the European Spanish version with changing of the few words whose use is different in the 2 countries. A total of 126 subjects were enrolled: 72 patients with JIA (29% systemic onset, 39% polyarticular onset, 4% extended oligoarticular subtype, and 28% persistent oligoarticular subtype) and 54 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the JIA patients having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the JIA patients having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Chilean version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Childhood stroke associated with protein C or S deficiency and primary antiphospholipid syndrome.

Two girls, 22 months and 12 years of age, presented with repeated cerebral infarctions in association with primary antiphospholipid syndrome. The younger patient also suffered from protein C deficiency, while the other one had protein S and complement C4 deficiencies. All other causes of cerebral infarction were excluded; however, vasculitis remains a possibility in one patient. Both girls developed spastic tetraparesis as a sequela of the previous infarctions. The two patients were treated with aspirin and prednisone, with remission of the infarctions during the next 8 months of observation. A primary deficiency of protein C or S is proposed which would produce cerebral thrombosis with exposure of phospholipids; this thrombosis then, like antigens, would generate antibodies acting on the thrombin-thrombomodulin complex, exacerbating the thrombotic process. The association of complement C4 deficiency is an additional risk factor.

Antihypertensive activity of once daily metoprolol alone and with chlorthalidone and comparison with a twice daily regimen.

In a multicentre, double-blind (DB), within-patient study, the antihypertensive effectiveness and tolerability of two oral administration schedules of metoprolol (M) 100 mg b.i.d. versus 200 mg once daily (o.d.), were investigated in 103 outpatients with mild to moderate essential hypertension. The study lasted 14 weeks and was divided into 3 periods: a) a weeks of single-blind (SB) placebo wash-out; b) 4 weeks of SB administration of M 100 mg b.i.d.; at the end of the second week of this period, chlorthalidone (C) 25 mg was added in patients with a recumbent diastolic blood pressure (BP) still greater than 95 mmHg and was continued throughout the following period; and c) DB cross-over administration of M 200 mg/d for 4 weeks on a b.i.d. schedule and 4 weeks on a once daily schedule. In comparison with pretreatment values, heart rate and systolic and diastolic BP were reduced (p less than 0.001) by both M administration schedules; there was no differences between the once and twice daily treatment regimens. During M once daily, betablockade was still maintained over 24 hours or longer, as the heart rate remained significantly lower than the basal value. In 57 patients, C was added at the end of the second week of SB M administration, and a further decrease in BP was observed; again, there was no significant change during once and twice daily M administration. Unwanted effects during M treatment were of minor severity, and the majority occurred when C, too, was added.

A fixed combination of oxprenolol slow-release and chlorthalidone once daily in treatment of mild to moderate hypertension.

In a multicenter, single-blind, interpatient study, 103 outpatients with mild to moderate hypertension were given, after 2 weeks of placebo wash-out, 160 mg oxprenolol slow-release in fixed combination with chlorthalidone (20 mg per tablet) (SROC 160) once daily or conventional oxprenolol (80 mg) in fixed combination with chlorthalidone (10 mg per tablet) (COC 80) twice daily for 8 weeks. Throughout the study 22 of 51 patients on SROC 160 and 24 of 51 on COC 80 received 1 tablet once daily and, respectively, 1 tablet twice daily. The remaining patients of both groups double the corresponding dosage after the first 4 weeks. Systolic and diastolic blood pressure decreased on both treatments without and difference observed between the groups. Diastolic blood pressure normalization was achieved in both groups in the same number of patients (35). Minor side effects occurred on both treatments: only one patient on SROC 160 interrupted the study due to severe dizziness and fatigue. The advantages are discussed as regards patient's compliance with administration of fixed combination SROC 160 once daily in treatment of mild to moderate hypertension.

[A comparative evaluation of metoprolol and methyldopa in hypertension therapy (author's transl)]. / Valutazione comparativa del metoprololo e della metildopa nella terapia dell'ipertensione arteriosa.

The antihypertensive effect and the tolerability of the cardioselective beta-blocking drug metoprolol, in comparison to methyldopa, were assessed in 119 hypertensive patients (73 WHO stage 1 and 46 WHO stage 2). After 2 weeks of placebo wash-out, the patients were randomly allocated to treatment with either of the two drugs: metoprolol up to 200 mg bid, and methyldopa up to 500 mg bid, for 6 weeks. Periodical clinical, biochemical, haematological, radiological and electrocardiographical measurements were performed. In respect to pre-treatment values, heart rate, both in lying and standing position, was significantly reduced (P less than 0.01) only in the metoprolol group, while systolic and diastolic blood pressures were significantly reduced (P less than 0.01) with both drugs in both positions. Asymptotic regression analysis showed that velocity of blood pressure reduction was comparable with both drugs. In the lying position, the diastolic blood pressure reduction obtained with metoprolol was significantly greater (P less than 0.05) in respect to that obtained with methyldopa. In general, side effects were few and of mild severity: mainly bradycardia in the metoprolol group and dizziness and fatigue in the methyldopa group. After the formal end of the double-blind trial, 36 patients, 14 in the metoprolol group and 22 in the methyldopa group, were treated in open conditions with metoprolol alone; after an average period of 6.5 weeks, diastolic blood pressure was significantly reduced (P less than 0.05) only in the group previously treated with methyldopa. In conclusion, metoprolol is a well tolerated and effective antihypertensive agent, which may be safely used in patients with mild to moderate hypertension.

Antihypertensive activity of a fixed combination of oxprenolol and chlorthalidone in mild to moderate arterial hypertension.

In a multicentre double-blind study, 92 out-patients with mild to moderate hypertension who had a resting blood pressure greater than or equal to 160/100 mmHg after a two-weeks' placebo wash-out were treated for 6 weeks with a fixed combination of oxprenolol 80 mg + chlorthalidone 10 mg per tablet or chlorthalidone alone (1 tablet = 10 mg). Five patients were drop-outs, 19 out of 44 patients on fixed combination and 7 out of 43 on chlorthalidone were given only 1 tablet b.i.d. throughout the study; the remaining doubled the corresponding dosage after the first 2 weeks. Resting and standing systolic and diastolic blood pressure decreased on both treatments, the reductions being significantly more marked on fixed combination in comparison to chlorthalidone alone (p < 0.01 and p < 0.05). The systolic blood pressure decrease was significantly greater on fixed combination from the first week of treatment (p < 0.05). Normalization of diastolic blood pressure was reached more frequently on fixed combination (73%) than on chlorthalidone (49%) (p < 0.05). Side-effects were recorded in 14 out of 44 patients treated with fixed combination and in 14 out of 43 treated with chlorthalidone. The advantages of treating patients with mild to moderate hypertension with a fixed combination of beta-blocker and diuretics are discussed.