Tissue-specific and endogenous protein labeling with split fluorescent proteins.

The ability to label proteins by fusion with genetically encoded fluorescent proteins is a powerful tool for understanding dynamic biological processes. However, current approaches for expressing fluorescent protein fusions possess drawbacks, especially at the whole organism level. Expression by transgenesis risks potential overexpression artifacts while fluorescent protein insertion at endogenous loci is technically difficult and, more importantly, does not allow for tissue-specific study of broadly expressed proteins. To overcome these limitations, we have adopted the split fluorescent protein system mNeonGreen21-10/11 (split-mNG2) to achieve tissue-specific and endogenous protein labeling in zebrafish. In our approach, mNG21-10 is expressed under a tissue-specific promoter using standard transgenesis while mNG211 is inserted into protein-coding genes of interest using CRISPR/Cas-directed gene editing. Each mNG2 fragment on its own is not fluorescent, but when co-expressed the fragments self-assemble into a fluorescent complex. Here, we report successful use of split-mNG2 to achieve differential labeling of the cytoskeleton genes tubb4b and krt8 in various tissues. We also demonstrate that by anchoring the mNG21-10 component to specific cellular compartments, the split-mNG2 system can be used to manipulate protein localization. Our approach should be broadly useful for a wide range of applications.

Tissue-specific and endogenous protein labeling with split fluorescent proteins.

The ability to label proteins by fusion with genetically encoded fluorescent proteins is a powerful tool for understanding dynamic biological processes. However, current approaches for expressing fluorescent protein fusions possess drawbacks, especially at the whole organism level. Expression by transgenesis risks potential overexpression artifacts while fluorescent protein insertion at endogenous loci is technically difficult and, more importantly, does not allow for tissue-specific study of broadly expressed proteins. To overcome these limitations, we have adopted the split fluorescent protein system mNeonGreen21-10/11 (split-mNG2) to achieve tissue-specific and endogenous protein labeling in zebrafish. In our approach, mNG21-10 is expressed under a tissue-specific promoter using standard transgenesis while mNG211 is inserted into protein-coding genes of interest using CRISPR/Cas-directed gene editing. Each mNG2 fragment on its own is not fluorescent, but when co-expressed the fragments self-assemble into a fluorescent complex. Here, we report successful use of split-mNG2 to achieve differential labeling of the cytoskeleton genes tubb4b and krt8 in various tissues. We also demonstrate that by anchoring the mNG21-10 component to specific cellular compartments, the split-mNG2 system can be used to manipulate protein function. Our approach should be broadly useful for a wide range of applications.

Pólipo fibroepitelial vulvar: una serie de casos

Los pólipos fibroepiteliales son tumores cutáneos benignos frecuentes en la población general. Sin embargo, la afectación del tracto genital es inhabitual. Su etiología no es clara, pero se han descrito asociaciones con trastornos metabólicos y fluctuaciones hormonales, lo cual explica su mayor prevalencia en mujeres. Debido a la variedad de diagnósticos diferenciales, es necesaria la evaluación histopatológica. Su manejo es habitualmente conservador; sin embargo, pueden requerir intervención quirúrgica en algunos casos. Exponemos cuatro casos de tumores fibroepiteliales vulvares de diferentes tamaños, uno de ellos clasificado como gigante, así como la aproximación de manejo. Con esta presentación, esperamos mejorar el conocimiento, la precisión del diagnóstico y contribuir al tratamiento eficaz de las pacientes con esta patología vulvar tan poco frecuente.

Fibroepithelial polyps are common benign skin tumors in the general population. However, genital tract involvement is unusual. Their etiology is unclear, but associations with metabolic disorders and hormonal fluctuations have been described, which explains their higher prevalence in women. Due to the variety of differential diagnoses, histopathological evaluation is necessary. Their management is usually conservative. However, they may require surgical intervention in some cases. We present four cases of vulvar fibroepithelial tumors of different sizes, one of them classified as giant, as well as the management approach. With this presentation, we hope to improve knowledge, diagnostic accuracy and contribute to the effective treatment of patients with this rare vulvar pathology.

Pitx2c deficiency confers cellular electrophysiological hallmarks of atrial fibrillation to isolated atrial myocytes.

AIMS: Atrial fibrillation (AF) has been associated with altered expression of the transcription factor Pitx2c and a high incidence of calcium release-induced afterdepolarizations. However, the relationship between Pitx2c expression and defective calcium homeostasis remains unclear and we here aimed to determine how Pitx2c expression affects calcium release from the sarcoplasmic reticulum (SR) and its impact on electrical activity in isolated atrial myocytes. METHODS: To address this issue, we applied confocal calcium imaging and patch-clamp techniques to atrial myocytes isolated from a mouse model with conditional atrial-specific deletion of Pitx2c. RESULTS: Our findings demonstrate that heterozygous deletion of Pitx2c doubles the calcium spark frequency, increases the frequency of sparks/site 1.5-fold, the calcium spark decay constant from 36 to 42 ms and the wave frequency from none to 3.2 min-1. Additionally, the cell capacitance increased by 30% and both the SR calcium load and the transient inward current (ITI) frequency were doubled. Furthermore, the fraction of cells with spontaneous action potentials increased from none to 44%. These effects of Pitx2c deficiency were comparable in right and left atrial myocytes, and homozygous deletion of Pitx2c did not induce any further effects on sparks, SR calcium load, ITI frequency or spontaneous action potentials. CONCLUSION: Our findings demonstrate that heterozygous Pitx2c deletion induces defects in calcium homeostasis and electrical activity that mimic derangements observed in right atrial myocytes from patients with AF and suggest that Pitx2c deficiency confers cellular electrophysiological hallmarks of AF to isolated atrial myocytes.

Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes.

Analysis of the spatio-temporal distribution of calcium sparks showed a preferential increase in sparks near the sarcolemma in atrial myocytes from patients with atrial fibrillation (AF), linked to higher ryanodine receptor (RyR2) phosphorylation at s2808 and lower calsequestrin-2 levels. Mathematical modeling, incorporating modulation of RyR2 gating, showed that only the observed combinations of RyR2 phosphorylation and calsequestrin-2 levels can account for the spatio-temporal distribution of sparks in patients with and without AF. Furthermore, we demonstrate that preferential calcium release near the sarcolemma is key to a higher incidence and amplitude of afterdepolarizations in atrial myocytes from patients with AF.

A pilot 1-year follow-up randomised controlled trial comparing metacognitive training to psychoeducation in schizophrenia: effects on insight.

Poor insight in schizophrenia spectrum disorders (SSD) is linked with negative outcomes. This single-centre, assessor-blind, parallel-group 1-year follow-up randomised controlled trial (RCT) tested whether metacognitive training (MCT) (compared to psychoeducation) may improve insight and outcomes in outpatients with SSD assessed: at baseline (T0); after treatment (T1) and at 1-year follow-up (T2). Insight (primary outcome) was measured with (i) the Schedule for Assessment of Insight-Expanded version- (SAI-E), including illness recognition (IR), symptom relabelling (SR), treatment compliance (TC) and total insight scores (TIS); and (ii) the Beck Cognitive Insight Scale (BCIS). Between-group comparisons were nonsignificant, while within the MCT group (but not within controls) there was a significant medium effect size for improved TIS at T2 (d = 0.67, P = 0.02). Secondary outcomes included cognitive measures: Jumping to Conclusions (JTC), Theory of Mind (ToM), plus symptom severity and functioning. Compared to psychoeducation, MCT improved the PANSS excitement (d = 1.21, P = 0.01) and depressed (d = 0.76, P = 0.05) factors at T2; and a JTC task both at T1 (P = 0.016) and at T2 (P = 0.031). Participants in this RCT receiving MCT showed improved insight at 1-year follow-up, which was associated with better mood and reduced JTC cognitive bias. In this pilot study, no significant benefits on insight of MCT over psychoeducation were detected, which may have been due to insufficient power.

Investigating the Role of Insight, Decision-Making and Mentalizing in Functional Outcome in Schizophrenia: A Cross-Sectional Study.

BACKGROUND: Recovery has become a priority in schizophrenia spectrum disorders (SSDs). This study aimed to investigate predictors of objective-general functioning and disability-and subjective-quality of life (QoL)-measures of functional outcomes in SSD. METHODS: Sample: n = 77 SSD outpatients (age 18-64, IQ > 70) participating in a randomised controlled trial. Baseline data were used to build three multivariable linear regression models on: (i) general functioning-General Assessment of Functioning (GAF); (ii) disability-the World Health Organization Disability Assessment Schedule (WHODAS-2.0); and (iii) QoL-Satisfaction Life Domains Scale (SLDS). RESULTS: Young age and being employed (R2 change = 0.211; p = 0.001), late adolescence premorbid adjustment (R2 change = 0.049; p = 0.0050), negative symptoms and disorganization (R2 change = 0.087; p = 0.025) and Theory of Mind (R2 change = 0.066, p = 0.053) predicted general functioning. Previous suicidal behaviour (R2 change = 0.068; p = 0.023) and negative and depressive symptoms (R2 change = 0.167; p = 0.001) were linked with disability. Previous suicidal behaviour (R2 change = 0.070, p = 0.026), depressive symptoms (R2 change = 0.157; p < 0.001) and illness recognition (R2 change = 0.046, p = 0.044) predicted QoL. CONCLUSIONS: Negative, disorganization and depressive symptoms, older age, unemployment, poor premorbid adjustment, previous suicide attempts and illness awareness appear to underlie a poor global functional outcome in SSD. Achieving recovery in SSD appears to require both symptomatic remission (e.g., through antipsychotics) and measures to improve mastery and relieve low mood.

Investigating the Contribution of Decision-Making, Cognitive Insight, and Theory of Mind in Insight in Schizophrenia: A Cross-Sectional Study.

INTRODUCTION: Insight in schizophrenia spectrum disorders (SSD) is associated with outcomes. Although the neurocognitive basis of insight is widely accepted, the specific contribution of decision-making (Jumping to Conclusions [JTC]), Cognitive Insight (CI), and Theory of Mind (ToM) to insight remains unclear. METHODS: The sample included N = 77 SSD outpatients aged 18-64 years from a randomized controlled trial of metacognitive training. Assessments included JTC-Beads Task, CI-Beck Cognitive Insight Scale, ToM-Hinting Task, and the Emotions Recognition Test Faces. STATISTICS: hierarchical multivariable linear regression models tested their contribution to total insight (TI) and three insight dimensions - illness recognition (IR), symptom relabelling (SR), and treatment compliance (TC) - measured with the Schedule for the Assessment of Insight - Expanded version, whilst adjusting for potential confounders. RESULTS: Bivariate analyses showed that CI was associated with TI (R2 change = 0.214; p < 0.001), IR (R2 change = 0.154; p = 0.003), and SR (R2 change = 0.168; p = 0.003), while JTC predicted IR (R2 change = 0.790; p = 0.020). Multivariable regression models showed that CI predicted TI (R2 change = 0.116; p = 0.036) and SR (R2 change = 0.166, p = 0.011), whereas JTC was linked with IR (R2 change = 0.710; p = 0.026). ToM was not linked with any insight score. No cognitive variable was associated with treatment compliance. DISCUSSION: Results supported the (meta)cognitive model of insight in SSD. JTC and CI emerged as the main (meta)cognitive processes underlying insight. Metacognitive interventions may therefore improve insight in SSD, although these therapies alone may fail to address treatment compliance.

Parto asincrónico en un embarazo gemelar. Primer reporte de caso en el Perú / Asynchronous delivery in a twin pregnancy. First case report in Peru

RESUMEN El parto asincrónico (PA) o parto diferido (PD) es una presentación poco prevalente de la gestación múltiple. Este ocurre cuando un feto nace por vía vaginal y el -o losfetos restantes se mantienen intraútero y nacen con una diferencia de días o semanas. Se realiza el primer reporte en el Perú de una gestante cuyo primer parto fue a las 20,1 semanas y el segundo a las 24,4 semanas, y se detalla el manejo y los resultados perinatales del caso. La evidencia sugiere que un PD mejora la supervivencia y reduce la morbimortalidad del segundo feto. Es imprescindible continuar la investigación en este tema para describir su prevalencia real, identificar candidatas ideales, estandarizar el manejo obstétrico y así optimizar resultados maternos y fetales.

ABSTRACT Asynchronous delivery (AD) or delayed interval delivery (DID) is a rare presentation of multiple gestation. This occurs when one fetus is delivered vaginally and the remaining fetus or fetuses are kept in utero and are born with a difference of days or weeks. This is the first report in Peru of a pregnant woman whose first delivery was at 20.1 weeks and the second at 24.4 weeks, and the management and perinatal results of the case are detailed. The evidence suggests that a DID improves survival and reduces morbidity and mortality of the second fetus. Further research on this topic is essential to describe its real prevalence, identify ideal candidates, standardize obstetric management and thus optimize maternal and fetal outcomes.

Influence of sex on intracellular calcium homoeostasis in patients with atrial fibrillation.

AIMS: Atrial fibrillation (AF) has been associated with intracellular calcium disturbances in human atrial myocytes, but little is known about the potential influence of sex and we here aimed to address this issue. METHODS AND RESULTS: Alterations in calcium regulatory mechanisms were assessed in human atrial myocytes from patients without AF or with long-standing persistent or permanent AF. Patch-clamp measurements revealed that L-type calcium current (ICa) density was significantly smaller in males with than without AF (-1.15 ± 0.37 vs. -2.06 ± 0.29 pA/pF) but not in females with AF (-1.88 ± 0.40 vs. -2.21 ± 0.0.30 pA/pF). In contrast, transient inward currents (ITi) were more frequent in females with than without AF (1.92 ± 0.36 vs. 1.10 ± 0.19 events/min) but not in males with AF. Moreover, confocal calcium imaging showed that females with AF had more calcium spark sites than those without AF (9.8 ± 1.8 vs. 2.2 ± 1.9 sites/µm2) and sparks were wider (3.0 ± 0.3 vs. 2.2 ± 0.3 µm) and lasted longer (79 ± 6 vs. 55 ± 8 ms), favouring their fusion into calcium waves that triggers ITIs and afterdepolarizations. This was linked to higher ryanodine receptor phosphorylation at s2808 in women with AF, and inhibition of adenosine A2A or beta-adrenergic receptors that modulate s2808 phosphorylation was able to reduce the higher incidence of ITI in women with AF. CONCLUSION: Perturbations of the calcium homoeostasis in AF is sex-dependent, concurring with increased spontaneous SR calcium release-induced electrical activity in women but not in men, and with diminished ICa density in men only.

ß2-adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co-activation of ryanodine receptor clusters.

AIMS: It is unknown how ß-adrenergic stimulation affects calcium dynamics in individual RyR2 clusters and leads to the induction of spontaneous calcium waves. To address this, we analysed spontaneous calcium release events in green fluorescent protein (GFP)-tagged RyR2 clusters. METHODS: Cardiomyocytes from mice with GFP-tagged RyR2 or human right atrial tissue were subjected to immunofluorescent labelling or confocal calcium imaging. RESULTS: Spontaneous calcium release from single RyR2 clusters induced 91.4% ± 2.0% of all calcium sparks while 8.0% ± 1.6% were caused by release from two neighbouring clusters. Sparks with two RyR2 clusters had 40% bigger amplitude, were 26% wider, and lasted 35% longer at half maximum. Consequently, the spark mass was larger in two- than one-cluster sparks with a median and interquartile range for the cumulative distribution of 15.7 ± 20.1 vs 7.6 ± 5.7 a.u. (P < .01). ß2-adrenergic stimulation increased RyR2 phosphorylation at s2809 and s2815, tripled the fraction of two- and three-cluster sparks, and significantly increased the spark mass. Interestingly, the amplitude and mass of the calcium released from a RyR2 cluster were proportional to the SR calcium load, but the firing rate was not. The spark mass was also higher in 33 patients with atrial fibrillation than in 36 without (22.9 ± 23.4 a.u. vs 10.7 ± 10.9; P = .015). CONCLUSIONS: Most sparks are caused by activation of a single RyR2 cluster at baseline while ß-adrenergic stimulation doubles the mass and the number of clusters per spark. This mimics the shift in the cumulative spark mass distribution observed in myocytes from patients with atrial fibrillation.

Use of Ecological Momentary Assessment Through a Passive Smartphone-Based App (eB2) by Patients With Schizophrenia: Acceptability Study.

BACKGROUND: Ecological momentary assessment (EMA) tools appear to be useful interventions for collecting real-time data on patients' behavior and functioning. However, concerns have been voiced regarding the acceptability of EMA among patients with schizophrenia and the factors influencing EMA acceptability. OBJECTIVE: The aim of this study was to investigate the acceptability of a passive smartphone-based EMA app, evidence-based behavior (eB2), among patients with schizophrenia spectrum disorders and the putative variables underlying their acceptance. METHODS: The participants in this study were from an ongoing randomized controlled trial (RCT) of metacognitive training, consisting of outpatients with schizophrenia spectrum disorders (F20-29 of 10th revision of the International Statistical Classification of Diseases and Related Health Problems), aged 18-64 years, none of whom received any financial compensation. Those who consented to installation of the eB2 app (users) were compared with those who did not (nonusers) in sociodemographic, clinical, premorbid adjustment, neurocognitive, psychopathological, insight, and metacognitive variables. A multivariable binary logistic regression tested the influence of the above (independent) variables on "being user versus nonuser" (acceptability), which was the main outcome measure. RESULTS: Out of the 77 RCT participants, 24 (31%) consented to installing eB2, which remained installed till the end of the study (median follow-up 14.50 weeks) in 14 participants (70%). Users were younger and had a higher education level, better premorbid adjustment, better executive function (according to the Trail Making Test), and higher cognitive insight levels (measured with the Beck Cognitive Insight Scale) than nonusers (univariate analyses) although only age (OR 0.93, 95% CI 0.86-0.99; P=.048) and early adolescence premorbid adjustment (OR 0.75, 95% CI 0.61-0.93; P=.01) survived the multivariable regression model, thus predicting eB2 acceptability. CONCLUSIONS: Acceptability of a passive smartphone-based EMA app among participants with schizophrenia spectrum disorders in this RCT where no participant received financial compensation was, as expected, relatively low, and linked with being young and good premorbid adjustment. Further research should examine how to increase EMA acceptability in patients with schizophrenia spectrum disorders, in particular, older participants and those with poor premorbid adjustment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04104347; https://clinicaltrials.gov/ct2/show/NCT04104347.

[Orthotopic kidney transplant (OKT): An alternative when heterotopic transplant is not feasible.] / Trasplante renal ortotópico (TRO): una alternativa cuando el heterotópico no es posible.

OBJECTIVE: Kidney transplant is the treatmentof election of end-stage chronic renal disease, usually being heterotopic extraperitoneal in the iliac fossae, with successful results. This technique can be challenging or even not feasible, usually in cases of severe vasculopathy or previous grafts, so urologists should consider alternatives such as orthotopic transplant. MATERIAL AND METHODS: We present three cases oforthotopic kidney transplant (OKT) made in Cruces University Hospital from 2001 to 2019, out of 2580 cases. We review recipients' medical history, indication,surgical technique and post surgical evolution. RESULTS: The average age of the patients was 51.6 years. The indication was severe vasculopathy of iliac vessels. We made left nephrectomy, followed by venous renal end-to-end anastomosis, arterial end-to-side anastomosis to aorta and pyelo-pyelic anastomosis with catheter,with immediate function of the graft. The patients' evolution was favourable, without significant complications and no differences with heterotopic transplant. CONCLUSION: OKT is a good alternative when heterotopicis not feasible, with an acceptable number of complications and similar survival.

OBJETIVO: El trasplante renal es el tratamiento de elección de la enfermedad renal crónica terminal. Habitualmente es heterotópico extraperitoneal en fosa ilíaca, presentando buenos resultados. En ocasiones no es factible (por vasculopatía severa, espacio reducido por injertos previos…), habiendo que considerar otras técnicas, como el trasplante ortotópico. MATERIAL Y MÉTODOS: Revisión retrospectiva de los trasplantes renales ortotópicos (TRO) realizados en el Hospital Universitario Cruces entre 2001 y 2019, de un total de 2580 trasplantes. Se revisa la historia clínica, indicación, técnica quirúrgica, evolución y complicaciones. RESULTADOS: Tres pacientes con media de 51,6 años se sometieron a trasplante ortotópico por vasculopatía severa de vasos ilíacos. Se realizó nefrectomía izquierda y anastomosis venosa termino-terminal a vena renal propia, arterial termino-lateral a aorta y pielo-piélica con catéter, presentando función inmediata. La evolución fue favorable, sin complicaciones significativas y sin diferencias con el trasplante heterotópico. CONCLUSIÓN: El TRO es una buena alternativa cuando el heterotópico no es factible, con un número aceptable de complicaciones y supervivencia similar.

Trasplante renal ortotópico (tro): una alternativa cuando el heterotópico no es posible / Orthotopic kidney transplantation (ORT): an alternative when heterotopic is not possible

OBJETIVO: El trasplante renal es el tratamiento de elección de la enfermedad renal crónicaterminal. Habitualmente es heterotópico extraperitoneal en fosa ilíaca, presentando buenos resultados. En ocasiones no es factible (por vasculopatía severa, espacio reducido por injertos previos…), habiendo que considerar otras técnicas, como el trasplante ortotópico. MATERIAL Y MÉTODOS: Revisión retrospectiva de los trasplantes renales ortotópicos (TRO) realizados en el Hospital Universitario Cruces entre 2001 y 2019, de un total de 2580 trasplantes. Se revisa la historia clínica, indicación, técnica quirúrgica, evolución y complicaciones. RESULTADOS: Tres pacientes con media de 51,6 años se sometieron a trasplante ortotópico por vasculopatía severa de vasos ilíacos. Se realizó nefrectomía izquierda y anastomosis venosa termino-terminal a vena renal propia, arterial termino-lateral a aorta y pielo-piélica con catéter, presentando función inmediata. La evolución fue favorable, sin complicaciones significativas y sin diferencias con el trasplante heterotópico. CONCLUSIÓN: El TRO es una buena alternativa cuando el heterotópico no es factible, con un número aceptable de complicaciones y supervivencia similar.(AU)

OBJECTIVE: Kidney transplant is the treatment of election of end-stage chronic renal disease, usually being heterotopic extraperitoneal in the iliac fossae, with successful results. This technique can be challenging or even not feasible, usually in cases of severe vasculopathy or previous grafts, so urologists should consider alternatives such as orthotopic transplant. MATERIAL AND METHODS: We present three cases of orthotopic kidney transplant (OKT) made in Cruces University Hospital from 2001 to 2019, out of 2580 cases. We review recipients’ medical history, indication, surgical technique and postsurgical evolution. RESULTS: The average age of the patients was 51.6 years. The indication was severe vasculopathy of iliac vessels. We made left nephrectomy, followed by venousrenal end-to-end anastomosis, arterial end-to-side anastomosis to aorta and pyelo-pyelic anastomosis with catheter, with immediate function of the graft. The patients’ evolution was favourable, without significant complications and no differences with heterotopic transplant. CONCLUSION: OKT is a good alternative when heterotopic is not feasible, with an acceptable number ofcomplications and similar survival.(AU)

TAEL 2.0: An Improved Optogenetic Expression System for Zebrafish.

Inducible gene expression systems are valuable tools for studying biological processes. We previously developed an optogenetic gene expression system called TAEL that is optimized for use in zebrafish. When illuminated with blue light, TAEL transcription factors dimerize and activate gene expression downstream of the TAEL-responsive C120 promoter. By using light as the inducing agent, the TAEL/C120 system overcomes limitations of traditional inducible expression systems by enabling fine spatial and temporal regulation of gene expression. In this study, we describe ongoing efforts to improve the TAEL/C120 system. We made modifications to both the TAEL transcriptional activator and the C120 regulatory element, collectively referred to as TAEL 2.0. We demonstrate that TAEL 2.0 consistently induces higher levels of reporter gene expression and at a faster rate, but with comparable background and toxicity as the original TAEL system. With these improvements, we were able to create functional stable transgenic lines to express the TAEL 2.0 transcription factor either ubiquitously or with a tissue-specific promoter. We demonstrate that the ubiquitous line in particular can be used to induce expression at late embryonic and larval stages, addressing a major deficiency of the original TAEL system. This improved optogenetic expression system will be a broadly useful resource for the zebrafish community.

Una causa singular de hipertensión endocrina / A remarkable cause of endocrine hypertension

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Can metacognitive interventions improve insight in schizophrenia spectrum disorders? A systematic review and meta-analysis.

BACKGROUND: Patients with schizophrenia spectrum disorders (SSD) tend to lack insight, which is linked to poor outcomes. The effect size of previous treatments on insight changes in SSD has been small. Metacognitive interventions may improve insight in SSD, although this remains unproved. METHODS: We carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the effects of metacognitive interventions designed for SSD, namely Metacognitive Training (MCT) and Metacognitive Reflection and Insight Therapy (MERIT), on changes in cognitive and clinical insight at post-treatment and at follow-up. RESULTS: Twelve RCTs, including 10 MCT RCTs (n = 717 participants) and two MERIT trials (n = 90), were selected, totalling N = 807 participants. Regarding cognitive insight six RCTs (n = 443) highlighted a medium effect of MCT on self-reflectiveness at post-treatment, d = 0.46, p < 0.01, and at follow-up, d = 0.30, p < 0.01. There was a small effect of MCT on self-certainty at post-treatment, d = -0.23, p = 0.03, but not at follow-up. MCT was superior to controls on an overall Composite Index of cognitive insight at post-treatment, d = 1.11, p < 0.01, and at follow-up, d = 0.86, p = 0.03, although we found evidence of heterogeneity. Of five MCT trials on clinical insight (n = 244 participants), which could not be meta-analysed, four of them favoured MCT compared v. control. The two MERIT trials reported conflicting results. CONCLUSIONS: Metacognitive interventions, particularly Metacognitive Training, appear to improve insight in patients with SSD, especially cognitive insight shortly after treatment. Further long-term RCTs are needed to establish whether these metacognitive interventions-related insight changes are sustained over a longer time period and result in better outcomes.

Retraso diagnóstico y terapéutico en el hiperparatiroidismo primario. Un problema no resuelto / Diagnostic and treatment delay in primary hyperparathyroidism. A pending issue

INTRODUCCIÓN: El HPTP frecuentemente permanece sin diagnosticar en pacientes con hipercalcemia, lo que podría ocasionar un aumento de la morbilidad en estos sujetos. OBJETIVO: Identificar la presencia de hipercalcemia y de criterios de tratamiento quirúrgico (CTQ) no identificados desde al menos un año antes de su remisión a endocrinología en pacientes operados de HPTP. Valorar si este retraso terapéutico se asocia a mayor morbilidad. MÉTODOS: Estudio observacional en 116 pacientes consecutivos. Mediante la revisión de los registros anteriores a 12 meses previos a su derivación a endocrinología se dividieron en 4 grupos: hipercalcemia con CTQ (grupo 1, n = 43), hipercalcemia sin CTQ (grupo 2, n = 23), calcemias normales (grupo 3, n = 18) o ausencia de calcemias en dichos registros (grupo 4, n = 32). RESULTADOS: En 84 pacientes (72,4%) había calcemias previas, 66 (56,9%) con hipercalcemia, de ellos 43 (37%) con CTQ no valorados. La demora media hasta su remisión fue de 57 meses. Casi la mitad de las calcemias del grupo 1 procedían de urgencias. Respecto al grupo 4 los pacientes del grupo 1 tenían menor edad, mayor incidencia de nefrolitiasis e insuficiencia renal al remitírseles. Las calcemias en el momento de su derivación eran similares, superiores a las de los grupos 2 y 3. DISCUSIÓN: Los pacientes con HPTP y CTQ se remiten a endocrinología con un retraso medio de 5 años. La inadvertencia de la hipercalcemia y/o el desconocimiento de los CTQ retrasan esta derivación, determinada por hipercalcemias superiores, y se asocian a una afectación renal más severa. Son precisas medidas correctoras para evitar este retraso en el diagnóstico y curación del HPTP

INTRODUCTION: Primary hyperparathyroidism (PHPT) remains underdiagnosed among patients with hypercalcemia, potentially causing increased morbidity. OBJECTIVE: To identify in surgically operated patients the presence of overlooked hypercalcemia and patients with criteria for surgery (CFS) for PHPT at least one year prior to referral to Endocrinology, and to determine whether this diagnostic delay leads to increased morbidity. METHODS: An observational study was carried out in 116 consecutive patients. We evaluated electronic medical records registered at least 12 months prior to referral and divided them in four groups: hypercalcemia with CFS (group 1), hypercalcemia without CFS (group 2), normocalcemia (group 3), and cases without previous biochemical evaluation (group 4). RESULTS: A total of 84 patients (72.4%) had a previous measurement of serum calcium at a time interval of ≥ 12 months. Sixty-six (56.9%) had hypercalcemia and 43 of them (37%) had ≥ 1 CFS, with an average delay of 57 months in receiving proper evaluation. Almost half of the calcemia measurements in group 1 had been made in the emergency room. Patients from group 1 were younger, and had a greater frequency of nephrolithiasis and renal impairment than patients in group 4. The serum calcium values at referral were similar in both groups and higher than the values found in patients from the other two groups. DISCUSSION: In patients with PHPT and CFS, referral to an endocrinologist is made with an average delay of almost 5 years. The identified causes of this delay, which conditions more kidney disease, are unrecognized hypercalcemia and/or unawareness of the surgical criteria, while calcium elevations promote referral. Interventions are needed to avoid this delay in the diagnosis and resolution of PHPT

¿Hay vida después de teduglutida? / Is there life after teduglutide?

El fallo intestinal (FI) se define como una reducción de la función intestinal por debajo del mínimo necesario para la absorción de nutrientes y que precisa suplementación intravenosa para mantener la salud y/o el crecimiento. La causa más frecuente es el síndrome de intestino corto (SIC). Aproximadamente el 50 % de los pacientes con SIC presenta FI y requiere soporte parenteral. La teduglutida es un análogo del péptido-2 similar al glucagón (GLP-2) humano aprobado para el tratamiento de pacientes con SIC. Los resultados de ensayos clínicos han probado su eficacia: se reducen el volumen y los días de administración de nutrición parenteral y fluidoterapia. Pocas publicaciones evalúan los efectos sobre la función intestinal a largo plazo en pacientes respondedores tras la suspensión de teduglutida. Se describe un paciente con SIC tipo I (yeyunostomía terminal) debido a múltiples intervenciones quirúrgicas por enfermedad de Crohn, que recibió tratamiento con liraglutida un año y teduglutida secuencial durante 21 meses. Con el primero, se objetivó una reducción en la necesidad de aporte y débito por yeyunostomía. El análogo del GLP-2 consiguió una mayor reducción del desequilibrio hídrico que permitió suspender la sueroterapia nocturna, con ganancia ponderal y mantenimiento de parámetros nutricionales, situación mantenida dos años después de su suspensión

Intestinal failure (IF) is defined as a reduction in intestinal function below the minimum necessary for the absorption of nutrients, requiring intravenous supplementation to maintain health and/or growth. The most common cause is short bowel syndrome (SBS). Approximately 50 % of patients with SBS have IF and require parenteral support. Teduglutide is a human glucagon-like peptide-2 analogue (GLP-2) approved for the treatment of patients with SBS. Clinical trial results have proven its efficacy by reducing volume and days of administration of parenteral nutrition and fluid therapy. Few publications evaluate the effects on long-term bowel function in respondent patients after teduglutide suspension. A patient with type I SBS (terminal jejunostomy) due to multiple surgeries for Crohn's disease, who was treated with liraglutide for one year and sequential teduglutide for 21 months, is described. With the former, a reduction in the need for contribution and debit by jejunostomy was observed. The GLP-2 analogue achieved a greater reduction in the hydric disbalance that allowed the suspension of the nocturnal suerotherapy, with weight gain and maintenance of nutritional parameters; situation maintained two years after its suspension

[Is there life after teduglutide?] / ¿Hay vida después de teduglutida?

INTRODUCTION: Intestinal failure (IF) is defined as a reduction in intestinal function below the minimum necessary for the absorption of nutrients, requiring intravenous supplementation to maintain health and/or growth. The most common cause is short bowel syndrome (SBS). Approximately 50% of patients with SBS have IF and require parenteral support. Teduglutide is a human glucagon-like peptide-2 analogue (GLP-2) approved for the treatment of patients with SBS. Clinical trial results have proven its efficacy by reducing volume and days of administration of parenteral nutrition and fluid therapy. Few publications evaluate the effects on long-term bowel function in respondent patients after teduglutide suspension. A patient with type I SBS (terminal jejunostomy) due to multiple surgeries for Crohn's disease, who was treated with liraglutide for one year and sequential teduglutide for 21 months, is described. With the former, a reduction in the need for contribution and debit by jejunostomy was observed. The GLP-2 analogue achieved a greater reduction in the hydric disbalance that allowed the suspension of the nocturnal suerotherapy, with weight gain and maintenance of nutritional parameters; situation maintained two years after its suspension.

INTRODUCCIÓN: El fallo intestinal se define como una reducción de la función intestinal por debajo del mínimo necesario para la absorción de nutrientes y que precisa suplementación intravenosa para mantener la salud y/o el crecimiento. La causa más frecuente es el síndrome de intestino corto. Aproximadamente el 50% de pacientes con SIC presenta FI y requiere soporte parenteral. Teduglutida es un análogo del péptido-2 similar al glucagón (GLP-2) humano aprobado para el tratamiento de pacientes con SIC. Los resultados de ensayos clínicos han probado su eficacia: se reducen el volumen y los días de administración de nutrición parenteral y fluidoterapia. Pocas publicaciones evalúan los efectos sobre la función intestinal a largo plazo en pacientes respondedores tras la suspensión de teduglutida. Se describe un paciente con SIC tipo I (yeyunostomía terminal) debido a múltiples intervenciones quirúrgicas por enfermedad de Crohn, que recibió tratamiento con liraglutida un año y teduglutida secuencial durante 21 meses. Con el primero, se objetivó una reducción en la necesidad de aporte y débito por yeyunostomía. El análogo del GLP-2 consiguió una mayor reducción del desequilibrio hídrico que permitió suspender sueroterapia nocturna, con ganancia ponderal y mantenimiento de parámetros nutricionales, situación mantenida dos años después de su suspensión.