French protocol for the diagnosis and management of hematopoietic stem cell transplantation in autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document.

Infections occurring following IL6 blockade for the management of cytokine release syndrome in onco-hematology patients.

BACKGROUND: Cytokine release syndrome (CRS) is a common adverse event of CAR T cell or bispecific antibody (bsAb) therapy. Anti-IL6/IL6R drugs are used in the management of auto-immune diseases. Some reports showed increased risk of bacterial infection in this context. In onco-hematology, there are few data about the occurrence of infection after administration of an anti-IL6/IL6R for CRS. METHODS: We retrospectively reviewed all consecutive patients treated in Gustave Roussy Cancer Campus between 2018 and 2021, who received anti-IL6/IL6R for CRS due to bsAb in phase I clinical trials or adoptive cellular therapy (ACT). We constituted a control group including all the patients treated in the same clinical trials or standard of care ACT, naïve of anti-IL6/IL6R. RESULTS: Fifty-two patients have been included. In the anti-IL6/IL6R group (n = 26), five patients developed a grade 2 to 5 infection within a month after anti-IL6/IL6R treatment, including two grade 5 infections. In the control group (n = 26), only one patient had a grade 3 infection. The two patients who had grade 5 infections were treated for diffuse large B cell lymphoma (DLBCL), one with bsAb and the other with CAR T cell. Fifty percent (3/6) of DLBCL patients who received an anti-IL6/IL6R presented an infection, one of which was a grade 5. In solid tumor patients treated with bsAb and anti-IL6/IL6R, only one patient (/9, 11%) developed a grade 2 viral infection. CONCLUSION: It seems that the use of anti-IL6/IL6R in CRS secondary to bsAb administration in solid tumors patients does not significantly increase the risk of infection, as opposed to DLBCL patients where secondary infection might be a concern.

Estudio poblacional de casuística y morbimortalidad de la prostatectomía radical en España / Population based study of morbidity and mortality rates associated to radical prostatectomy cases in Spain

Introducción: No existe ningún estudio poblacional que contabilice en número de prostatectomías radicales (PR) realizadas España, ni la morbimortalidad de dicha intervención.Nuestro objetivo es estudiar la morbimortalidad de la PR en España desde el 2011 al 2015 y evaluar la variabilidad geográfica. Material y métodos: Diseñamos un estudio observacional retrospectivo de todos los pacientes intervenidos de PR en España durante cinco años consecutivos (2011-2015) a partir de los datos registrados en el Conjunto Mínimo Básico de Datos (CMBD).Hemos estudiado la distribución del número de casos y la variabilidad intercomunitaria en términos de morbilidad y de estancia hospitalaria, así como el impacto del volumen quirúrgico medio anual por cada centro en dichas variables. Resultados: Entre los años 2011-2015 se han realizado un total de 37.725 PR en 221 hospitales españoles públicos del sistema nacional de salud. La edad media de la serie fue 63,9 ± 3,23 años. El 50% de las PR se han realizado por vía abierta, y un 43,4% se han intervenido en hospitales de < 500 camas. Encontramos una gran variabilidad en la distribución de los casos intervenidos en las distintas Comunidades Autónomas (CCAA Las comunidades que realizan un mayor número de prostatectomías son Andalucía, Cataluña, Galicia y Madrid. La tasa de complicaciones a nivel nacional es de 8,6%, siendo las más frecuentes la hemorragia y necesidad de transfusión (5,3 y 4%, respectivamente). Encontramos importantes diferencias en las tasas de hemorragia y en la estancia hospitalaria entre las distintas CCAA, que se mantienen tras ajustar por las características del paciente y del tipo de hospital. Al estudiar el volumen quirúrgico anual de cada hospital vemos que el impacto en la tasa de hemorragia o transfusión es lineal sin embargo en la estancia a partir de 60 PR/año la estancia se mantiene estable en torno a cinco días. (AU)

Introduction: There is no population-based study that accounts for the number of radical prostatectomies (RP) carried out in Spain, nor regarding the morbidity and mortality of this intervention.Our objective is to study the morbidity and mortality of RP in Spain from 2011 to 2015 and to evaluate the geographic variation. Material and methods: We designed a retrospective observational study of all patients submitted to RP in Spain during five consecutive years (2011-2015). The data was extracted from the «Conjunto Mínimo Básico de Datos» (CMBD).We have evaluated geographic variations in terms of morbidity and hospital stay, and the impact of the mean annual surgical volume for each center on these variables. Results: Between 2011-2015, a total of 37,725 RPs were performed in 221 Spanish public hospitals. The mean age of the series was 63.9 ± 3.23 years. Of all RPs, 50% were performed through an open approach, and 43.4% have been operated on in hospitals with < 500 beds. We observed an important variability in the distribution of the cases operated on in the different regions. The regions that perform more RPs are Andalusia, Catalonia, Galicia, and Madrid. Our study shows a complication rate of 8.6%, with hemorrhage and the need for transfusion being the most frequent (5.3 and 4%, respectively). There are significant differences in bleeding rates and hospital stay among regions, which are maintained after adjusting for patient characteristics and type of hospital. When studying the annual surgical volume of each hospital, we find that the impact on the rate of hemorrhage or transfusion is linear; however, hospital stay remains stable at around 5 days from 60 RPs/year (AU)

Population based study of morbidity and mortality rates associated to radical prostatectomy cases in Spain.

INTRODUCTION: There is no population-based study that accounts for the number of radical prostatectomies (RP) carried out in Spain, nor regarding the morbidity and mortality of this intervention. Our objective is to study the morbidity and mortality of RP in Spain from 2011 to 2015 and to evaluate the geographic variation. MATERIAL AND METHODS: We designed a retrospective observational study of all patients submitted to RP in Spain during five consecutive years (2011-2015). The data was extracted from the «Conjunto Mínimo Básico de Datos¼ (CMBD). We have evaluated geographic variations in terms of morbidity and hospital stay, and the impact of the mean annual surgical volume for each center on these variables. RESULTS: Between 2011-2015, a total of 37,725 RPs were performed in 221 Spanish public hospitals. The mean age of the series was 63.9±3.23 years. Of all RPs, 50% were performed through an open approach, and 43.4% have been operated on in hospitals with <500 beds. We observed an important variability in the distribution of the cases operated on in the different regions. The regions that perform more RPs are Andalusia, Catalonia, Galicia, and Madrid. Our study shows a complication rate of 8.6%, with hemorrhage and the need for transfusion being the most frequent (5.3 and 4%, respectively). There are significant differences in bleeding rates and hospital stay among regions, which are maintained after adjusting for patient characteristics and type of hospital. When studying the annual surgical volume of each hospital, we find that the impact on the rate of hemorrhage or transfusion is linear; however, hospital stay remains stable at around 5 days from 60 RPs/year. CONCLUSIONS: In national terms, morbidity and mortality rates after RP are comparable to those described in the literature. This study reveals a clear dispersion in the hospitals that carry out this intervention, showing clear differences in terms of morbidity and hospital stay between the different regions.

[Autologous hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyneuropathy]. / Carrefour des spécialités : autogreffe de cellules souches hématopoïétiques périphériques pour la prise en charge thérapeutique des polyradiculonévrites inflammatoires démyélinisantes chroniques.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a dysimmune neuropathy with sensory and/or motor symptoms due to destruction of the myelin sheat secondary to an auto-immune attack. A quarter to a third of patients do not respond to immunomodulatory first line recommended therapies. No second line treatment has shown its effectiveness with a sufficient level of evidence. Autologous hematopoietic stem cell transplantation (AHSCT) is a promising therapy for autoimmune disease, especially for CIDP in recent works. We present in this article an update on the diagnosis of CIDP, its conventional treatments as well as the results of AHSCT in this indication, which was the subject of French recommendations under the aegis of the SFGMTC and neuromuscular disease french faculty (FILNEMUS) as a third line therapy after failure of two first-line and one second-line treatments.

Neuropsychological development in the child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder: A two-year follow-up comparative study.

There has been growing scientific evidence in recent years that schizophrenia and bipolar disorder share clinical, cognitive, neuroimaging and genetic characteristics. This overlap might also be present in their offspring, who have an increased risk of developing both disorders. Comparing the characteristics of these samples may have important implications for understanding etiological processes. This study aimed to assess the development of cognitive functions over two years in a sample of child and adolescent offspring of patients diagnosed with schizophrenia (SZoff) or bipolar disorder (BDoff), comparing them with a community control group (CCoff). METHODS: 90 BDoff, 41 SZoff and 107 CCoff aged between 6 and 17 years were included at baseline. At the two-year follow-up, 84.9% of the sample was re-assessed (78 BDoff, 32 SZoff and 92 CCoff). All subjects were assessed with a comprehensive neuropsychological test battery at baseline and at the two-year follow-up to evaluate: intelligence quotient, working memory, processing speed, verbal memory and learning, visual memory, executive functions and sustained attention. RESULTS: Processing speed, verbal memory and executive functions showed different developmental patterns among the SZoff, BDoff and CCoff groups. The SZoff group maintained baseline performances in the three variables over time, while the BDoff group presented improved processing speed and executive functioning and the CCoff group showed improvements in verbal memory and executive functions at follow-up. CONCLUSIONS: These findings suggest that the development of some cognitive functions might differ between child and adolescent SZoff and BDoff, indicating different trajectories during neurodevelopment.

Outcomes of an enhanced recovery after radical cystectomy program in a prospective multicenter study: compliance and key components for success.

OBJECTIVE: To investigate the effect of an Enhanced Recovery After Surgery (ERAS) program on complications and length of stay (LOS) after radical cystectomy (RC) and to assess if the number and type of components of ERAS play a key role on the decrease of surgical morbidity. MATERIALS AND METHODS: We analyzed the data of 277 patients prospectively recruited in 11 hospitals undergoing RC initially managed according to local practice (Group I) and later within an ERAS program (Group II). Two main outcomes were defined: 90-day complications rate and LOS. As secondary variables we studied 90-day mortality, 30-day readmission and transfusion rate. RESULTS: Patients in Group II had a higher use of ERAS measures (98.6%) than those in Group I (78.2%) (p < 0.05). Patients in Groups I and II experienced similar complications (70.5% vs. 66%, p = 0.42). LOS was not different between Groups I and II (12.5 and 14 days, respectively, p = 0.59). The risk of having any complication decreases for patients having more than 15 ERAS measures adopted [RR = 0.815; 95% confidence interval (CI) 0.667-0.996; p = 0.045]. Avoidance of transfusion and nasogastric tube, prevention of ileus, early ambulation and a fast uptake of a regular diet are independently associated with the absence of complications. CONCLUSIONS: Complications and LOS after RC were not modified by the introduction of an ERAS program. We hypothesize that at least 15 measures should be applied to maximize the benefit of ERAS.

Development and psychometric properties of the "Suicidality: Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales" in adolescents.

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity-the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test-retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS-the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = - 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents.

Psychosocial risk factors for suicidality in children and adolescents.

Suicidality in childhood and adolescence is of increasing concern. The aim of this paper was to review the published literature identifying key psychosocial risk factors for suicidality in the paediatric population. A systematic two-step search was carried out following the PRISMA statement guidelines, using the terms 'suicidality, suicide, and self-harm' combined with terms 'infant, child, adolescent' according to the US National Library of Medicine and the National Institutes of Health classification of ages. Forty-four studies were included in the qualitative synthesis. The review identified three main factors that appear to increase the risk of suicidality: psychological factors (depression, anxiety, previous suicide attempt, drug and alcohol use, and other comorbid psychiatric disorders); stressful life events (family problems and peer conflicts); and personality traits (such as neuroticism and impulsivity). The evidence highlights the complexity of suicidality and points towards an interaction of factors contributing to suicidal behaviour. More information is needed to understand the complex relationship between risk factors for suicidality. Prospective studies with adequate sample sizes are needed to investigate these multiple variables of risk concurrently and over time.

Transición de vigilancia activa a observación en pacientes mayores de 75 años con cáncer de próstata en una serie de largo seguimiento / Transition from active surveillance to observation in prostate cancer patients older than 75 years. A long follow-up series

Introducción: La población mundial va envejeciendo y la esperanza de vida va siendo cada vez mayor; esta situación va a conllevar un gran impacto en el manejo de los pacientes con cáncer de próstata, sobre todo en aquellos de bajo riesgo susceptibles de un manejo conservador mediante la vigilancia activa (VA). En estos pacientes es necesario responder a las preguntas de hasta cuándo se ha de continuar con el esquema de VA, con qué pruebas y si es posible realizar una transición a observación con seguridad oncológica. El objetivo de este trabajo es analizar aquellos pacientes con cáncer de próstata que han estado en VA con 75 años o más y valorar la seguridad de la observación en una serie de VA con un largo seguimiento. Material y métodos: Se analizó nuestra cohorte prospectiva de pacientes en VA entre los años 1999 y 2018, seleccionando aquellos que hubieran estado bajo seguimiento con 75 años o más. Se ofreció tratamiento con intención curativa cuando existían criterios de progresión y paso a observación a criterio del urólogo. Se incluyeron algunos pacientes de riesgo intermedio en el análisis. Los cambios de comorbilidad se analizaron teniendo en cuenta el Charlson a la entrada y salida de VA. Se estudió la progresión y la mortalidad en los pacientes según el manejo por el que se hubiera optado. Resultados: De un total de 347 pacientes en VA, 90 cumplían los criterios mencionados anteriormente, de los cuales 15 (16,7%) eran de riesgo intermedio. La mediana de seguimiento era de 6,4 años y 73 (81,1%) tenían baja comorbilidad (Charlson < 2). Hubo 40 (44,4%) pacientes que salieron de VA, de los cuales 17 (18,9%) pasaron a observación; del resto, 21 (23,3%) recibieron tratamiento curativo. Se observó una diferencia significativa en el cambio de comorbilidad, medida por el índice de Charlson, a la entrada y salida de VA (p < 0,05) entre los pacientes sometidos a tratamiento activo y los sometidos a observación. No se observó ningún caso de muerte dependiente del cáncer ni progresión en el grupo de observación. Conclusión: La transición desde un programa de VA a observación del cáncer de próstata en pacientes añosos, así como la decisión de llevar a cabo un tratamiento con intención curativa, resulta controvertida. En nuestra serie esta transición en pacientes mayores de 75 años no aumenta el riesgo oncológico

Introduction. The world population is ageing, and life expectancy is increasing. This situation will have a great impact on the management of patients with prostate cancer, especially in those of low risk, susceptible to a conservative management under active surveillance (AS). Regarding these patients’ profile, it is necessary to answer the following questions: ¿for how long to continue with the AS scheme?, ¿which tests will be required?, ¿is it possible to carry out a transition to observation with oncological safety? The objective of this work is to analyse those patients with prostatic cancer who have been in AS with 75 years of age or more and assess the safety of the observation in an AS series with a long follow-up. Material and methods: We analysed our prospective cohort of AS patients between the years 1999 and 2018,including those who had been in follow-up with 75 years or more. They were offered treatment with curative intent when there were progression criteria and transition to observation under the urologist's decision. Some intermediate risk patients were included in the analysis. Comorbidity changes were analysed with the Charlson comorbidity index at entry and exit of AS. The progression and mortality of the patients were studied according to the management they received. Results: From 347 AS patients, 90 patients fulfilled the afore mentioned criteria and 15 (16.7%) were intermediate risk. The median follow-up was 6.4 years and 73 (81.1%) had low comorbidity (Charlson < 2).There were 40 (44.4%) patients who left AS, 17 (18.9%) of them went to observationand the rest, 21 (23.3%), received curative treatment. There was a significant difference in comorbidity, measured by the Charlson index, at entry and exit of AS (P < .05) among patients receiving active treatment and the ones submitted to observation.No case of cancer-specific death or progression was observed in the observation group. Conclusion: The transition from an active surveillance management to observation of prostate cancer elderly patients, as well as the decision to carry out a treatment with curative intent, seems controversial. In our series, this transition in patients older than 75 years does not increase the oncological risk

Transition from active surveillance to observation in prostate cancer patients older than 75 years. A long follow-up series. / Transición de vigilancia activa a observación en pacientes mayores de 75 años con cáncer de próstata en una serie de largo seguimiento.

INTRODUCTION: The world population is ageing, and life expectancy is increasing. This situation will have a great impact on the management of patients with prostate cancer, especially in those of low risk, susceptible to a conservative management under active surveillance (AS). Regarding these patients' profile, it is necessary to answer the following questions: ¿for how long to continue with the AS scheme?, ¿which tests will be required?, ¿is it possible to carry out a transition to observation with oncological safety? The objective of this work is to analyse those patients with prostatic cancer who have been in AS with 75 years of age or more and assess the safety of the observation in an AS series with a long follow-up. MATERIAL AND METHODS: We analysed our prospective cohort of AS patients between the years 1999 and 2018,including those who had been in follow-up with 75 years or more. They were offered treatment with curative intent when there were progression criteria and transition to observation under the urologist's decision. Some intermediate risk patients were included in the analysis. Comorbidity changes were analysed with the Charlson comorbidity index at entry and exit of AS. The progression and mortality of the patients were studied according to the management they received. RESULTS: From 347 AS patients, 90 patients fulfilled the afore mentioned criteria and 15 (16.7%) were intermediate risk. The median follow-up was 6.4 years and 73 (81.1%) had low comorbidity (Charlson<2).There were 40 (44.4%) patients who left AS, 17 (18.9%) of them went to observationand the rest, 21 (23.3%), received curative treatment. There was a significant difference in comorbidity, measured by the Charlson index, at entry and exit of AS (P<.05) among patients receiving active treatment and the ones submitted to observation.No case of cancer-specific death or progression was observed in the observation group. CONCLUSION: The transition from an active surveillance management to observation of prostate cancer elderly patients, as well as the decision to carry out a treatment with curative intent, seems controversial. In our series, this transition in patients older than 75 years does not increase the oncological risk.

Vacuna triple vírica como tratamiento de verruga subungueal recalcitrante / Mumps, Measles, and Rubella Vaccine for the Treatment of a Recalcitrant Subungual Wart

No disponible

Panarteritis nudosa con patrón de respuesta inflamatoria sistémica: respuesta a anti-TNF / Polyarteritis Nodosa with a Systemic Inflammatory Response Pattern: Effectiveness of anti-TNF

No disponible

Liquen plano palmoplantar: espectro de manifestaciones clínicas en un paciente / Palmoplantar Lichen Planus: The Spectrum of Clinical Manifestations in a Single Patient

No disponible

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.