Case Report: Traumatic cardiac arrest due to pericardial tamponade: successful pericardiocentesis with a Shaldon catheter.

In this report, we describe the successful resuscitation of a 4-year-old child who suffered a traumatic cardiac arrest during a routine procedure in the operating room. The diagnosis of a sanguineous pericardial tamponade was made by emergency ultrasonography. Consecutive subxiphoid pericardiocentesis with an adult Shaldon catheter led to return of spontaneous circulation. Subsequent thoracotomy and surgical suturing definitively stopped the bleeding from the right ventricle. The combined expertise of all perioperative disciplines was decisive for the patient's survival.

Plant mitochondrial RNA editing factors can perform targeted C-to-U editing of nuclear transcripts in human cells.

RNA editing processes are strikingly different in animals and plants. Up to thousands of specific cytidines are converted into uridines in plant chloroplasts and mitochondria whereas up to millions of adenosines are converted into inosines in animal nucleo-cytosolic RNAs. It is unknown whether these two different RNA editing machineries are mutually incompatible. RNA-binding pentatricopeptide repeat (PPR) proteins are the key factors of plant organelle cytidine-to-uridine RNA editing. The complete absence of PPR mediated editing of cytosolic RNAs might be due to a yet unknown barrier that prevents its activity in the cytosol. Here, we transferred two plant mitochondrial PPR-type editing factors into human cell lines to explore whether they could operate in the nucleo-cytosolic environment. PPR56 and PPR65 not only faithfully edited their native, co-transcribed targets but also different sets of off-targets in the human background transcriptome. More than 900 of such off-targets with editing efficiencies up to 91%, largely explained by known PPR-RNA binding properties, were identified for PPR56. Engineering two crucial amino acid positions in its PPR array led to predictable shifts in target recognition. We conclude that plant PPR editing factors can operate in the entirely different genetic environment of the human nucleo-cytosol and can be intentionally re-engineered towards new targets.

Reduction of Platelet Outdating and Shortage by Forecasting Demand With Statistical Learning and Deep Neural Networks: Modeling Study.

BACKGROUND: Platelets are a valuable and perishable blood product. Managing platelet inventory is a demanding task because of short shelf lives and high variation in daily platelet use patterns. Predicting platelet demand is a promising step toward avoiding obsolescence and shortages and ensuring optimal care. OBJECTIVE: The aim of this study is to forecast platelet demand for a given hospital using both a statistical model and a deep neural network. In addition, we aim to calculate the possible reduction in waste and shortage of platelets using said predictions in a retrospective simulation of the platelet inventory. METHODS: Predictions of daily platelet demand were made by a least absolute shrinkage and selection operator (LASSO) model and a recurrent neural network (RNN) with long short-term memory (LSTM). Both models used the same set of 81 clinical features. Predictions were passed to a simulation of the blood inventory to calculate the possible reduction in waste and shortage as compared with historical data. RESULTS: From January 1, 2008, to December 31, 2018, the waste and shortage rates for platelets were 10.1% and 6.5%, respectively. In simulations of platelet inventory, waste could be lowered to 4.9% with the LASSO and 5% with the RNN, whereas shortages were 2.1% and 1.7% with the LASSO and RNN, respectively. Daily predictions of platelet demand for the next 2 days had mean absolute percent errors of 25.5% (95% CI 24.6%-26.6%) with the LASSO and 26.3% (95% CI 25.3%-27.4%) with the LSTM (P=.01). Predictions for the next 4 days had mean absolute percent errors of 18.1% (95% CI 17.6%-18.6%) with the LASSO and 19.2% (95% CI 18.6%-19.8%) with the LSTM (P<.001). CONCLUSIONS: Both models allow for predictions of platelet demand with similar and sufficient accuracy to significantly reduce waste and shortage in a retrospective simulation study. The possible improvements in platelet inventory management are roughly equivalent to US $250,000 per year.

TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis.

The activity of the SMN complex in promoting the assembly of pre-mRNA processing UsnRNPs correlates with condensation of the complex in nuclear Cajal bodies. While mechanistic details of its activity have been elucidated, the molecular basis for condensation remains unclear. High SMN complex phosphorylation suggests extensive regulation. Here, we report on systematic siRNA-based screening for modulators of the capacity of SMN to condense in Cajal bodies and identify mTOR and ribosomal protein S6 kinase ß-1 as key regulators. Proteomic analysis reveals TOR-dependent phosphorylations in SMN complex subunits. Using stably expressed or optogenetically controlled phospho mutants, we demonstrate that serine 49 and 63 phosphorylation of human SMN controls the capacity of the complex to condense in Cajal bodies via liquid-liquid phase separation. Our findings link SMN complex condensation and UsnRNP biogenesis to cellular energy levels and suggest modulation of TOR signaling as a rational concept for therapy of the SMN-linked neuromuscular disorder spinal muscular atrophy.

Ibuprofen versus acetazolamide for prevention of acute mountain sickness. / Ibuprofeno comparado con acetazolamida para prevención de mal agudo de montaña.

INTRODUCTION: Acute mountain sickness is a common condition occurring in healthy subjects that undergo rapid ascent without prior acclimatization, as low as 2500 meters above sea level. The classic preventive agent has been acetazolamide, although in the last decade there has been evidence favoring ibuprofen. However, it is unclear which method is more efficient. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis) and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews that included only one primary study, which is a randomized trial. We concluded it is not possible to establish whether ibuprofen is better or worse than acetazolamide because the certainty of evidence has been evaluated as very low.

INTRODUCCIÓN: El mal agudo de montaña es una condición frecuente en individuos sanos, sin aclimatación que se exponen a alturas desde 2500 metros sobre el nivel del mar. Clásicamente se ha utilizado acetazolamida para prevenirlo, pero en los últimos años ha surgido evidencia a favor de ibuprofeno. Sin embargo, no está claro cuál de estos tratamientos es más efectivo. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos dos revisiones sistemáticas que en conjunto incluyeron un estudio primario, el cual corresponde a un ensayo aleatorizado. Concluimos que no es posible establecer con claridad si ibuprofeno es mejor o peor que acetazolamida debido a que la certeza de evidencia existente ha sido evaluada como muy baja.

Ibuprofeno comparado con acetazolamida para prevención de mal agudo de montaña / Ibuprofen versus acetazolamide for prevention of acute mountain sickness

INTRODUCCIÓN: El mal agudo de montaña es una condición frecuente en individuos sanos, sin aclimatación que se exponen a alturas desde 2500 metros sobre el nivel del mar. Clásicamente se ha utilizado acetazolamida para prevenirlo, pero en los últimos años ha surgido evidencia a favor de ibuprofeno. Sin embargo, no está claro cuál de estos tratamientos es más efectivo. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos dos revisiones sistemáticas que en conjunto incluyeron un estudio primario, el cual corresponde a un ensayo aleatorizado. Concluimos que no es posible establecer con claridad si ibuprofeno es mejor o peor que acetazolamida debido a que la certeza de evidencia existente ha sido evaluada como muy baja.

INTRODUCTION: Acute mountain sickness is a common condition occurring in healthy subjects that undergo rapid ascent without prior acclimatization, as low as 2500 meters above sea level. The classic preventive agent has been acetazolamide, although in the last decade there has been evidence favoring ibuprofen. However, it is unclear which method is more efficient. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis) and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified two systematic reviews that included only one primary study, which is a randomized trial. We concluded it is not possible to establish whether ibuprofen is better or worse than acetazolamide because the certainty of evidence has been evaluated as very low.

Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs.

PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 × 10-7) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.

UsnRNP biogenesis: mechanisms and regulation.

Macromolecular complexes composed of proteins or proteins and nucleic acids rather than individual macromolecules mediate many cellular activities. Maintenance of these activities is essential for cell viability and requires the coordinated production of the individual complex components as well as their faithful incorporation into functional entities. Failure of complex assembly may have fatal consequences and can cause severe diseases. While many macromolecular complexes can form spontaneously in vitro, they often require aid from assembly factors including assembly chaperones in the crowded cellular environment. The assembly of RNA protein complexes implicated in the maturation of pre-mRNAs (termed UsnRNPs) has proven to be a paradigm to understand the action of assembly factors and chaperones. UsnRNPs are assembled by factors united in protein arginine methyltransferase 5 (PRMT5)- and survival motor neuron (SMN)-complexes, which act sequentially in the UsnRNP production line. While the PRMT5-complex pre-arranges specific sets of proteins into stable intermediates, the SMN complex displaces assembly factors from these intermediates and unites them with UsnRNA to form the assembled RNP. Despite advanced mechanistic understanding of UsnRNP assembly, our knowledge of regulatory features of this essential and ubiquitous cellular function remains remarkably incomplete. One may argue that the process operates as a default biosynthesis pathway and does not require sophisticated regulatory cues. Simple theoretical considerations and a number of experimental data, however, indicate that regulation of UsnRNP assembly most likely happens at multiple levels. This review will not only summarize how individual components of this assembly line act mechanistically but also why, how, and when the UsnRNP workflow might be regulated by means of posttranslational modification in response to cellular signaling cues.

Outcome analysis for prediction of early and long-term survival in patients receiving intra-aortic balloon pumping after cardiac surgery.

BACKGROUND: Patients requiring an intra-aortic balloon pump (IABP) after cardiac surgery are critically ill and need a prolonged ICU stay. Considering limited health care resources, the early identification of patients with an extremely poor prognosis is important as a solid base for the decision whether further aggressive continuation or cessation of the therapy is recommendable. METHODS: From 2001 to 2007, 552 patients with low-output syndrome after open-heart surgery and IABP implantation in OR or within 24 h thereafter on ICU were retrospectively analyzed. RESULTS: The overall mortality at 30 and 180-day were 31 and 40 %, respectively. According to multivariate analyses, following factors were used to generate an IABP score: female gender, age ≥70 years, simultaneous coronary and valve surgery, aortic cross-clamp time >120 min., need of norepinephrin more than 0.4 µg kg(-1) min(-1), postoperative dialysis, and maximal serum creatinine kinase >3000 mg mL(-1). The 30-day mortality continuously increased along the score (10.1 % for score = 0, n = 98; 11.8 % for score = 1, n = 144; 27.5 % for score = 2, n = 153; 40.4 % score = 3, n = 89; 65.2 % for score = 4, n = 46; 77.8 % for score = 5, n = 27) and reached 100 % for all patients with a score of 6 (n = 4). CONCLUSIONS: Prediction of 30 days mortality was possible with our scoring system based on multivariate analysis, and patients with scores of 4 or greater had remarkably worse early and late survival.