Validez diagnóstica del ratio sFlt-1/PlGF en la identificación de la preeclampsia: una revisión sistemática / Diagnostic validity of the sFlt-1/PlGF ratio in the identification of preeclampsia: A systematic review

La preeclampsia (PE) es un desorden multisistémico que se produce durante el embarazo. Implica alteraciones que conllevan una elevada morbimortalidad en la madre y el neonato. Se ha demostrado que la etiología de la PE está vinculada a factores angiogénicos y antiangiogénicos, específicamente los niveles séricos de la tirosincinasa 1 soluble similar a fms (sFlt-1) se encuentran elevados en embarazadas con PE, mientras los niveles libres circulantes del factor de crecimiento placentario disminuyen. En este trabajo se ha realizado una revisión sistemática de la literatura para evaluar la validez del ratio sFlt-1/factor de crecimiento placentario para el diagnóstico de PE. Se han seleccionado 7 estudios: un metaanálisis, 4 estudios prospectivos, 2 de casos y controles y 2 de cohortes; y 2 estudios retrospectivos. La conclusión de esta revisión es que el ratio sFlt-1/factor de crecimiento placentario tiene una precisión diagnóstica moderada y es útil como técnica de apoyo en el diagnóstico y seguimiento de gestantes con sospecha de PE, especialmente para poder descartar el desarrollo de esta

Pre-eclampsia (PE) is a multisystem disorder that occurs during pregnancy. It involves alterations that lead to high morbidity and mortality in mother and newborn. It has been shown that the aetiology of PE is linked to angiogenic and anti-angiogenic factors, specifically the serum levels of soluble tyrosine kinase 1 similar to fms (s-Flt1) are elevated in pregnant women with PE, while the circulating levels of the free placental growth factor decrease. In this work, a systematic review of the literature has been carried out to evaluate the validity of the s-Flt1 / placental growth factor ratio for the diagnosis of PE. Seven studies have been selected: one meta-analysis, 4 prospective studies, 2 case-control studies and 2 cohort studies; and 2 retrospective studies. The conclusion of this review is that the sFlt-1 / placental growth factor ratio has a moderate diagnostic accuracy, and is useful as a support technique in the diagnosis and follow-up of pregnant women with suspected PE, especially to rule it out

Electroquimioterapia para el tratamiento del melanoma cutáneo locorregionalmente avanzado irresecable. Revisión sistemática / Electrochemotherapy for the treatment of unresectable locoregionally advanced cutaneous melanoma: a systematic review

La electroquimioterapia (EQT) es una modalidad de tratamiento de lesiones cutáneas y subcutáneas originadas por melanoma u otros tumores. El procedimiento consiste en la administración de agentes antineoplásicos, seguido de impulsos eléctricos locales, para conseguir un efecto conocido como electroporación, que permite la entrada al citosol de medicamentos que no difunden a través de la membrana celular. El objetivo de esta revisión es establecer la evidencia que sustenta la incorporación de la EQT como estrategia terapéutica en el melanoma. Además, se ha llevado a cabo una revisión sistemática de la literatura con síntesis cualitativa. Se ha realizado una búsqueda cualificada de la literatura en bases de datos referenciales y a texto completo. Fueron seleccionados 7 estudios: 3 revisiones sistemáticas y 4 series de casos. La calidad de la evidencia encontrada no es buena, pero la coincidencia de sus resultados en algunas las variables le da consistencia. Los metaanálisis muestran resultados a favor de la EQT frente a la quimioterapia. La EQT parece un procedimiento efectivo en el tratamiento local de nódulos tumorales malignos (nivel medio o bajo de calidad de la evidencia). Es un tratamiento fácil de administrar, económico y bien tolerado con el que se consigue respuesta objetiva en circunstancias determinadas. No hay evidencia de que pueda afectar el curso natural de la enfermedad, por lo que debe considerarse un tratamiento paliativo. Con un nivel de la evidencia 1- (1 menos), puede recomendarse la incorporación de la EQT para el tratamiento paliativo del melanoma locorregionalmente avanzado irresecable (fuerza de la recomendación: B)

Electrochemotherapy is a therapeutic option for the treatment of cutaneous and subcutaneous metastases from melanoma and other tumors. The procedure consists of the administration of anticancer drugs followed by locally applied electrical impulses to achieve an effect known as electroporation, which facilitates entry into the cytosol of drugs that cannot cross the cell membrane. The aim of this review is to evaluate the evidence that supports the use of electrochemotherapy as a therapeutic strategy in melanoma. We conducted a qualitative systematic review of the literature using advanced searches of bibliographic databases and full text reviews. Seven studies (3 systematic reviews and 4 cases series) were selected. The quality of the evidence was not good, but the coincidence of results for certain variables supports their consistency. Results of the meta-analyses favored electrochemotherapy over chemotherapy. Electrochemotherapy appears to be an effective procedure for the local treatment of malignant tumor nodules (evidence of intermediate or low quality). This inexpensive method is simple to apply, well tolerated, and achieves objective responses under certain circumstances. There is no evidence that electrochemotherapy alters the natural course of the disease and it should therefore be considered a palliative treatment. With an evidence level of 1- (minus), electrochemotherapy can be recommended for the palliative treatment of unresectable, locoregionally advanced melanoma (grade B recommendation)

Electrochemotherapy for the Treatment of Unresectable Locoregionally Advanced Cutaneous Melanoma: A Systematic Review. / Electroquimioterapia para el tratamiento del melanoma cutáneo locorregionalmente avanzado irresecable. Revisión sistemática.

Electrochemotherapy is a therapeutic option for the treatment of cutaneous and subcutaneous metastases from melanoma and other tumors. The procedure consists of the administration of anticancer drugs followed by locally applied electrical impulses to achieve an effect known as electroporation, which facilitates entry into the cytosol of drugs that cannot cross the cell membrane. The aim of this review is to evaluate the evidence that supports the use of electrochemotherapy as a therapeutic strategy in melanoma. We conducted a qualitative systematic review of the literature using advanced searches of bibliographic databases and full text reviews. Seven studies (3 systematic reviews and 4 cases series) were selected. The quality of the evidence was not good, but the coincidence of results for certain variables supports their consistency. Results of the meta-analyses favored electrochemotherapy over chemotherapy. Electrochemotherapy appears to be an effective procedure for the local treatment of malignant tumor nodules (evidence of intermediate or low quality). This inexpensive method is simple to apply, well tolerated, and achieves objective responses under certain circumstances. There is no evidence that electrochemotherapy alters the natural course of the disease and it should therefore be considered a palliative treatment. With an evidence level of 1- (minus), electrochemotherapy can be recommended for the palliative treatment of unresectable, locoregionally advanced melanoma (grade B recommendation).

Uso adecuado de la prótesis invertida de hombro mediante aplicación del método RAND/UCLA / Appropriateness of the indication for reverse shoulder replacement using the RAND/UCLA method

Objetivo: En las series de casos publicadas sobre artropatía del manguito rotador, tratadas con prótesis invertida de hombro, se analizan factores asociados que pueden influir en su evolución como dolor, edad, calidad ósea o limitación articular. En ningún trabajo se plantea una posible actitud de decisión médica partiendo de estas variables. El objetivo del presente estudio fue desarrollar criterios de uso adecuado de la prótesis invertida de hombro en pacientes con artropatía del manguito rotador a través de escenarios creados con dichas variables. Material y método: Se aplicó el método RAND/ UCLA para combinar la evidencia científica disponible con el juicio de 12 expertos en la materia. Los expertos expresaron su opinión de forma cuantitativa sobre cada situación clínica. Se calificaron como adecuadas, cuando los beneficios superaban con margen a los riesgos o consecuencias negativas, o inadecuadas, si los riesgos superaban a los beneficios. Resultados: El panel de expertos, tras dos rondas de puntuación, encontró que de 192 situaciones clínicas planteadas, 22 (11,4%) fueron consideradas adecuadas, 47 (24,5%) dudosas y 123 (64,1%) inadecuadas. El grado de desacuerdo bajó respecto al obtenido en la primera ronda, calificando con desacuerdo 5 indicaciones (2,6%), indeterminadas 82 (42,7%) y con acuerdo 105 (54,7%). Conclusiones: Los panelistas consideraron adecuadas aquellas indicaciones definidas por dolor severo y limitación funcional importante, combinada con lesión del manguito rotador no reparable y edad mayor a 65 años. Otras variables como la calidad ósea, la existencia de un defecto glenoideo o la reparabilidad de la lesión del manguito, podrían afectar la decisión

Purpose: The case series studies performed on rotator cuff arthropathy treated with reverse shoulder replacement (RSR) examine factors influencing the outcome, such as pain, age, bone quality or limited joint mobility. However, none of these studies examine how these variables influence the treatment choice. The aim of this study is to develop appropriateness criteria for the use of RSR in patients with rotator cuff tear arthropathy (RCTA) according to a variety of cases including the variables mentioned above. Material and methods: We applied the RAND/ UCLA appropriateness method to combine the available scientific evidence with the judgment of 12 experts in RCTA. Indication for RSR was considered appropriate when the benefits outweighed the associated risks or complications, and inappropriate when the risks outweighed the benefits. Results: After two rating rounds, the panel of experts found that out of the 192 cases analyzed, 22 (11.4%) were considered appropriate, 47 (24.5%) were uncertain and 123 (64.1%) were considered inappropriate. The level of disagreement was lower in the second rating round: there was agreement on 5 indications (2.6%), indeterminate on 82 (42.7%) and disagreement on 105 cases (54.7%). Conclusion: The experts agreed that appropriateness criteria for indication of reverse shoulder replacement were acute pain and severe functional limitation combined with irreparable rotator cuff dysfunction and older than 65 years. Other variables such as bone quality, the presence of a glenoid defect or the reparability of the cuff failure might affect the treatment choice

Stentoplasty effectiveness and safety for the treatment of osteoporotic vertebral fractures: a systematic review.

UNLABELLED: To assess the effectiveness and safety of stentoplasty in people with osteoporotic vertebral body fractures. A systematic search of databases including MEDLINE, EMBASE and Cochrane library, between others, was conducted to June 9, 2014. Clinical trials and observational studies that included alive adults with osteoporotic vertebral body fractures and the comparators were the intervention himself, vertebroplasty or balloon kyphoplasty were selected. Quality of evidence was graded according to the GRADE approach. Two review authors independently selected studies, assessed risk of bias and extracted data. Forty-two citations were identified during the search. After removing duplicates, five studies were included: two clinical trials and three observational studies. Stentoplasty, showed higher rate of adverse events related to material (P=0.043) and cuff pressure (P=0.014) in comparison to kyphoplasty. There was no difference between two procedures in terms of reduction of kyphosis, time of exposure to radiation or postoperative loss of cement. Stentoplasty in comparison to vertebroplasty, showed an improvement of restoration of vertebral height (P=0.042), kyphosis correction and volume of bone cement. No differences were found between two procedures in terms of loss of vertebral body volume. Based on observational studies, stentoplasty improved vertebral height, pain and functional disability at 6 and 12months follow-up, and corrected the angle vertebral fractures in patients with osteoporotic vertebral body. Stentoplasty was presented as a safe procedure in short-medium term, with a low complication rate, a reduced loss of cement and new vertebral body fractures lower rates. Stentoplasty improves vertebral height, reduces the pain and functional disability and correct the vertebral angle in patients with osteoporotic vertebral body fracture with minimum adverse events. Stentoplasty is comparable to kyphoplasty in terms of correction of kyphosis, time of exposure to radiation and cement postoperative loss, and comparable to vertebroplasty in terms of restoration of vertebral height correction and bone cement volume. LEVEL OF EVIDENCE: Level II systematic review.

Evaluación de la calidad de vida de la braquiterapia vs prostatectomia robotizada en pacientes con carcinoma prostático localizado. Revisión sistemática / Quality of life after brachytherapy or robot-assisted radical prostatectomy for localized prostate cancer

OBJETIVO: Efectuar una revisión sistemática de la literatura evaluando la calidad de vida y complicaciones de la prostatectomía robotizada (PR) frente a la braquiterapia permanente a bajas dosis (BPBD) en pacientes con cáncer de próstata (PCa) localizado. MÉTODOS: Se realizó una búsqueda sistematizada en Pubmed, EMBASE y Cochrane, Centre for Reviews and Dissemination, Emergency Care Research Institute, Web of Knowledge, Technology Evaluation Center, Clinical Evidence, Uptodate, Hayes y Drug Effectiveness Review Project. Se incluyeron las revisiones sistemáticas y estudios prospectivos que comparaban PR frente a BPBD en varones con PCa localizado y confirmado. La variable de resultado principal fue la calidad de vida y la variable secundaria, la tasa de complicaciones. RESULTADOS: Se incluyeron 3 revisiones sistemáticas y 4 estudios prospectivos. PR mostró mejores resultados vs BPBD para el dominio físico del cuestionario SF-12 (p <0,01) y una recuperación más rápida a las puntuaciones previas a la cirugía. BPBD mejoró las puntuaciones para la función urinaria y sexual medidas con el cuestionario UCLA-PCI vs PR durante los tres primeros años de seguimiento (p < 0,001). La tasa de pacientes con incontinencia urinaria en el primer año de seguimiento resultó a favor de BPBD (88,0% vs 84,5%, p < 0,001). No se encontraron diferencias en las puntuaciones para la función intestinal en los tres primeros años posintervención (p = 0,02). Las principales complicaciones de la BPBD fueron la toxicidad gastrointestinal (GI) y genitourinarias (GU), aunque la tasa de eventos ponderada de los estudios incluidos no fue analizada. CONCLUSIÓN: La BPBD ha mostrado una mejora en las puntuaciones para la calidad de vida relacionada con la función urinaria y sexual en pacientes con PCa localizado frente a la PR en los tres primeros años posintervención

OBJECTIVES: To perform a systematic bibliographic review of the literature assessing the quality of life and complications of robotic prostatectomy (RP) versus low-dose rate brachytherapy (LDR-BT) in patients with localized prostate cancer (PCa). METHODS: A systematic search was conducted in PubMed, EMBASE and Cochrane, Centre for Reviews and Dissemination, Emergency Care Research Institute, Web of Knowledge, Technology Evaluation Center, Clinical vidence, Uptodate, Hayes and Drug Effectiveness Review Project. Systematic reviews and prospective studies comparing RP to LDR-BT in men with localized PCa were included. The primary outcome was quality of life and the secondary endpoint complications rate. RESULTS: Three systematic reviews and four prospective studies were included. RP showed better results than LDR-BT for SF-12-physical domain (p <0.01) and faster recovery to pre-operative scores. LDR-BT improved scores for UCLAPCI questionnaire-urinary and sexual domains compared to RP during the first three years of follow-up (p <0.001). First postoperative year urinary incontinence rate was favorable for LDR-BT (88.0% vs 84.5%, p <0.001). No differences for intestinal function scores for the first three post-intervention years (p = 0.02) were found. Major complications of LDR-BT were gastrointestinal and genitourinary toxicity, although pooled weighted events rate of the studies was not analyzed. CONCLUSIONS: LDR-BT improves quality of life in terms of urinary and sexual function in patients with localized PCa vs RP during the first three years post-intervention

Complicaciones y preservación nerviosa de la prostatectomía en relación con el intervalo de tiempo desde la biopsia diagnóstica / Complications and Nerve Preservation in Prostatectomy According to the Time Interval from Diagnostic Biopsy

Objetivos: Sintetizar la evidencia disponible sobre las complicaciones y la capacidad de preservación nerviosa bilateral de la prostatectomía radical en pacientes con cáncer próstatico en función del tiempo transcurrido de la biopsia diagnóstica (superior o inferior a las seis semanas). Material y métodos: Se identificaron los estudios relevantes utilizando estrategias de búsqueda estructuradas y específicas para cada una de las bases de datos consultadas sin ninguna limitación. Se evaluó la calidad metodológica de cada uno de los estudios incluidos y se extrajeron los datos de forma independiente. Resultados: Para la prostatectomía radical abierta, dos de los estudios concluyeron que el intervalo de tiempo transcurrido entre la realización de la biopsia prostática y la cirugía inferior a las 4 o 6 semanas no influye en la tasa de complicaciones posquirúrgicas y la capacidad de preservación nerviosa durante la cirugía. En cuanto a la prostatectomía radical laparoscópica asistida por robot el estudio incluido concluye que la realización de este tipo de intervenciones dentro de un periodo de tiempo inferior a las cuatro o seis semanas posteriores a la biopsia diagnóstica, se asocia a un mayor riesgo de sufrir complicaciones postquirúrgicas. No obstante, estos estudios contaban con importantes limitaciones metodológicas. Conclusiones: El intervalo de tiempo entre la realización de la biopsia diagnóstica y la cirugía abierta no influye en la tasa de complicaciones o preservación nerviosa. En cambio, un periodo de tiempo inferior a las cuatro semanas entre la biopsia diagnóstica y la cirugía laparoscópica se asocia con mayor riesgo de complicaciones quirúrgicas (AU)

Objectives: To summarize the available evidence on complications and bilateral nerve preservation in radical prostatectomy in patients according to the time interval from diagnostic biopsy (more or less than six weeks). Material and methods: Relevant studies were identified by using structured and specific search strategies for each of the databases consulted, without limitations. The methodological quality of each of the studies included was evaluated and the data were extracted independently. Results: For open radical prostatectomy, two of the studies concluded that a time interval of less than 4 or 6 weeks between prostate biopsy and surgery had no influence on the postsurgical complications rate or on nerve preservation during surgery. For laparoscopic robotic-assisted radical prostatectomy, the study included concluded that performing this type of intervention in an interval of less than 4 or 6 weeks after diagnostic biopsy was associated with a higher risk of postsurgical complications. However, all these studies had major methodological limitations. Conclusions: The time interval between diagnostic biopsy and open surgery has no influence on the complications rate or nerve preservations. In contrast, an interval of less than 4 weeks between diagnostic biopsy and laparoscopic surgery is associated with a higher risk of surgical complications (AU)

[Complications and nerve preservation in prostatectomy according to the time interval from diagnostic biopsy]. / Complicaciones y preservación nerviosa de la prostatectomía en relación con el intervalo de tiempo desde la biopsia diagnóstica.

OBJECTIVES: To summarize the available evidence on complications and bilateral nerve preservation in radical prostatectomy in patients according to the time interval from diagnostic biopsy (more or less than six weeks). MATERIAL AND METHODS: Relevant studies were identified by using structured and specific search strategies for each of the databases consulted, without limitations. The methodological quality of each of the studies included was evaluated and the data were extracted independently. RESULTS: For open radical prostatectomy, two of the studies concluded that a time interval of less than 4 or 6 weeks between prostate biopsy and surgery had no influence on the postsurgical complications rate or on nerve preservation during surgery. For laparoscopic robotic-assisted radical prostatectomy, the study included concluded that performing this type of intervention in an interval of less than 4 or 6 weeks after diagnostic biopsy was associated with a higher risk of postsurgical complications. However, all these studies had major methodological limitations. CONCLUSIONS: The time interval between diagnostic biopsy and open surgery has no influence on the complications rate or nerve preservations. In contrast, an interval of less than 4 weeks between diagnostic biopsy and laparoscopic surgery is associated with a higher risk of surgical complications.

[18F-fluorodeoxyglucose positron emission tomography in the evaluation of therapy response assessment in lymphomas. Systematic literature review and meta-analysis]. / Tomografía de positrones con 18F-fluorodesoxiglucosa en la valoración de la respuesta de los linfomas al tratamiento. Revisión sistemática de la literatura y metaanálisis.

This systematic review of literature analyze the utility of positron emission tomography (PET or PET-CT) with 18F-fluorodeoxyglucose, as a diagnostic tool in the assessment of response to chemotherapy and immunotherapy in lymphomas, in terms of diagnostic accuracy in prospective publications. A literature search was conducted in major databases and through manual review from the reference lists of articles that were recovered. The methodological quality of the selected items was evaluated using the QUADAS questionnaire. 9 publications were analyzed after the filtering process. The methodological quality of the same was broadly acceptable. In patients with LH, the negative predictive value of FDG-PET after 2-3 cycles of chemotherapy, was ranged between 93.4% (95% CI, 92.6-94.3) and 100% (95% CI, 99.3-100%), and after the treatment, the negative predictive value of PET-FDG, was between 94.3% (95% CI, 92.8-95.7) and 100% (95% CI, 97.1-100). In patients with residual masses and LH, the meta-analysis of results showed a sensitivity of 100% (95% CI, 0.753-1) and a specificity of 84% (95% CI, 0.699-0.934). PET-FDG seems to be a useful tool to evaluate the response to treatment of patients with lymphoma. However, it recommended further prospective studies and that possibly conducted in hybrid PET-CT scans, to determine its usefulness.

Tomografía de positrones con 18F-fluorodesoxiglucosa en la valoración de la respuesta de los linfomas al tratamiento. Revisión sistemática de la literatura y metaanálisis / 18F-fluorodeoxyglucose positron emission tomography in the evaluation of therapy response assessment in lymphomas. Systematic literature review and meta-analysis

La presente revisión sistemática de la literatura pretende evaluar el rendimiento de la tomografía de positrones (PET o PET-TAC) de cuerpo entero con 18F-fluorodesoxiglucosa (FDG), como prueba diagnóstica, en la valoración de la respuesta a la quimioterapia y la inmunoterapia en los linfomas, en términos de validez y utilidad, para ello se utilizaron publicaciones de carácter prospectivo. Se realizó una búsqueda bibliográfica en las principales bases de datos disponibles y mediante revisión manual a partir de las listas de referencia de los artículos encontrados. La calidad metodológica de los artículos seleccionados se evaluó mediante el cuestionario QUADAS. Se analizaron 9 publicaciones tras el proceso de filtrado. La calidad metodológica de aquellos, en general, fue aceptable. En pacientes con linfoma de Hodgkin (LH) el valor predictivo negativo de la PET-FDG, después de 2-3 ciclos de quimioterapia, osciló entre el 93,4% (intervalo de confianza [IC] del 95%, 92,6-94,3) y el 100% (IC del 95%, 99,3-100%), y al finalizar el tratamiento el valor predictivo negativo de la PET-FDG osciló entre el 94,3% (IC del 95%, 92,8-95,7) y el 100% (IC del 95%, 97,1-100). En pacientes con LH y masas residuales el metaanálisis de resultados mostró una sensibilidad total del 100% (IC del 95%, 0,753-1) y una especificidad del 0,841% (IC del 95%, 0,699-0,934). La PET-FDG parece ser una herramienta útil en la valoración de la respuesta al tratamiento de pacientes con linfoma. No obstante, ha de recomendarse la realización de nuevos estudios de carácter prospectivo y que, a ser posible, sean con equipos híbridos PET-TAC para determinar su utilidad(AU)

This systematic review of literature analyze the utility of positron emission tomography (PET or PET-CT) with 18F-fluorodeoxyglucose, as a diagnostic tool in the assessment of response to chemotherapy and immunotherapy in lymphomas, in terms of diagnostic accuracy in prospective publications. A literature search was conducted in major databases and through manual review from the reference lists of articles that were recovered. The methodological quality of the selected items was evaluated using the QUADAS questionnaire. 9 publications were analyzed after the filtering process. The methodological quality of the same was broadly acceptable. In patients with LH, the negative predictive value of FDG-PET after 2-3 cycles of chemotherapy, was ranged between 93.4% (95% CI, 92.6-94.3) and 100% (95% CI, 99.3-100%), and after the treatment, the negative predictive value of PET-FDG, was between 94.3% (95% CI, 92.8-95.7) and 100% (95% CI, 97.1-100). In patients with residual masses and LH, the meta-analysis of results showed a sensitivity of 100% (95% CI, 0.753-1) and a specificity of 84% (95% CI, 0.699-0.934). PET-FDG seems to be a useful tool to evaluate the response to treatment of patients with lymphoma. However, it recommended further prospective studies and that possibly conducted in hybrid PET-CT scans, to determine its usefulness(AU)

[Effects of pepstatin A on neutrophils; cross-deactivation with FMLP]. / Efectos de la pepstatina A sobre los neutrófilos; desactivación cruzada con el FMLP.

The ability of pepstatin A, a protease inhibitor produced by Streptomyces testaceus, to elicit a number of responses by the human PMN has been studied. In lysozyme and beta-glucuronidase release, pepstatin A 10(-5)M is equivalent to the synthetic oligopeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 10(-7)M. In superoxide release, pepstatin A 10(-5)M produces 80% of that originated by FMLP 10(-7). After two minutes of incubation the superoxide release is important, there being no further increase after 10 minutes. Preincubation of the cells with cytochalasin B before stimulation with pepstatin A elicits a noticeable increase in O2- release. In chemotaxis, pepstatin A 10(-6) originates the same cell motility as FMLP 10(-9). Pepstatin A produces a cross deactivation with FMLP which adds further evidence to the hypothesis that both stimuli compete for the same receptor in the PMN.