Age at First Extubation Attempt and Death or Respiratory Morbidities in Extremely Preterm Infants.

OBJECTIVE: To describe the timing of first extubation in extremely preterm infants and explore the relationship between age at first extubation, extubation outcome, and death or respiratory morbidities. STUDY DESIGN: In this subanalysis of a multicenter observational study, infants with birth weights of 1250 g or less and intubated within 24 hours of birth were included. After describing the timing of first extubation, age at extubation was divided into early (within 7 days from birth) vs late (days of life 8-35), and extubation outcome was divided into success vs failure (reintubation within 7 days after extubation), to create 4 extubation groups: early success, early failure, late success, and late failure. Logistic regression analyses were performed to evaluate associations between the 4 groups and death or bronchopulmonary dysplasia, bronchopulmonary dysplasia among survivors, and durations of respiratory support and oxygen therapy. RESULTS: Of the 250 infants included, 129 (52%) were extubated within 7 days, 93 (37%) between 8 and 35 days, and 28 (11%) beyond 35 days of life. There were 93, 36, 59, and 34 infants with early success, early failure, late success, and late failure, respectively. Although early success was associated with the lowest rates of respiratory morbidities, early failure was not associated with significantly different respiratory outcomes compared with late success or late failure in unadjusted and adjusted analyses. CONCLUSIONS: In a contemporary cohort of extremely preterm infants, early extubation occurred in 52% of infants, and only early and successful extubation was associated with decreased respiratory morbidities. Predictors capable of promptly identifying infants with a high likelihood of early extubation success or failure are needed.

From Peptide Nucleic Acids to Supramolecular Structures of Nucleic Acid Derivatives.

Nucleic acids play a pivotal role in life processes. The endeavours to shed light on the essential properties of these intriguing building blocks led us to the synthesis of different analogues and the investigation of their properties. First various peptide nucleic acid monomers and oligomers have been synthesized, using an Fmoc/acyl protecting group strategy, and their properties studied. The serendipitous discovery of a side reaction of coupling agents led us to the elaboration of a peptide sequencing method. The capricious behaviour of guanine derivatives spurred the determination of their substitution pattern using 13 C, 15 N NMR, and mass spectrometric methods. The properties of guanines initiated the logical transition to the study of supramolecular systems composed of purine analogues. Thus, xanthine and uracil derivatives have been obtained and their supramolecular self-assembly properties scrutinized in gas, solid, and liquid states and at solid-liquid interfaces.

Automated prediction of extubation success in extremely preterm infants: the APEX multicenter study.

BACKGROUND: Extremely preterm infants are frequently subjected to mechanical ventilation. Current prediction tools of extubation success lacks accuracy. METHODS: Multicenter study including infants with birth weight ≤1250 g undergoing their first extubation attempt. Clinical data and cardiorespiratory signals were acquired before extubation. Primary outcome was prediction of extubation success. Automated analysis of cardiorespiratory signals, development of clinical and cardiorespiratory features, and a 2-stage Clinical Decision-Balanced Random Forest classifier were used. A leave-one-out cross-validation was done. Performance was analyzed by ROC curves and determined by balanced accuracy. An exploratory analysis was performed for extubations before 7 days of age. RESULTS: A total of 241 infants were included and 44 failed (18%) extubation. The classifier had a balanced accuracy of 73% (sensitivity 70% [95% CI: 63%, 76%], specificity 75% [95% CI: 62%, 88%]). As an additional clinical-decision tool, the classifier would have led to an increase in extubation success from 82% to 93% but misclassified 60 infants who would have been successfully extubated. In infants extubated before 7 days of age, the classifier identified 16/18 failures (specificity 89%) and 73/105 infants with success (sensitivity 70%). CONCLUSIONS: Machine learning algorithms may improve a balanced prediction of extubation outcomes, but further refinement and validation is required. IMPACT: A machine learning-derived predictive model combining clinical data with automated analyses of individual cardiorespiratory signals may improve the prediction of successful extubation and identify infants at higher risk of failure with a good balanced accuracy. Such multidisciplinary approach including medicine, biomedical engineering and computer science is a step forward as current tools investigated to predict extubation outcomes lack sufficient balanced accuracy to justify their use in future trials or clinical practice. Thus, this individualized assessment can optimize patient selection for future trials of extubation readiness by decreasing exposure of low-risk infants to interventions and maximize the benefits of those at high risk.

Synthesis and oligomerization of cysteinyl nucleosides.

Nucleoside and nucleic acid analogues are known to possess a considerable therapeutic potential. In this work, by coupling cysteine to nucleosides, we successfully synthesized compounds that may not only have interesting biological properties in their monomeric form, but can be used beyond that, for oligomerization, in order to produce new types of synthetic nucleic acids. We elaborated different strategies for the synthesis of cysteinyl nucleosides as monomers of cysteinyl nucleic acids using nucleophilic substitution or thiol-ene coupling as a synthetic tool, and utilised on two complementary nucleosides, uridine and adenosine. Dipeptidyl dinucleosides and pentameric cysteinyl uridine were prepared from the monomeric building blocks, which are the first members of a new class of peptide nucleic acids containing the entire ribofuranosyl nucleoside units bound to the peptide backbone.

Analytical and Structural Studies for the Investigation of Oxidative Stress in Guanine Oligonucleotides.

DNA damage plays a decisive role in epigenetic effects. The detection and analysis of DNA damages, like the most common change of guanine (G) to 8-oxo-7,8-dihydroguanine (OG), is a key factor in cancer research. It is especially true for G quadruplex structure (GQ), which is one of the best-known examples of a non-canonical DNA arrangement. In the present work, we provided an overview on analytical methods in connection with the detection of OG in oligonucleotides with GQ-forming capacity. Focusing on the last five years, novel electrochemical tools, like dedicated electrodes, were overviewed, as well as different optical methods (fluorometric assays, resonance light scattering or UV radiation) along with hyphenated detection and structural analysis methods (CD, NMR, melting temperature analysis and nanopore detection) were also applied for OG detection. Additionally, GQ-related computational simulations were also summarized. All these results emphasize that OG detection and the analysis of the effect of its presence in higher ordered structures like GQ is still a state-of-the-art research line with continuously increasing interest.

The Impact of Time Interval between Extubation and Reintubation on Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: To explore the relation between time to reintubation and death or bronchopulmonary dysplasia (BPD) in extremely preterm infants. STUDY DESIGN: This was a subanalysis from an ongoing multicenter observational study. Infants with birth weight ≤1250 g, requiring mechanical ventilation, and undergoing their first elective extubation were prospectively followed throughout hospitalization. Time to reintubation was defined as the time interval between first elective extubation and reintubation. Univariate and multivariate logistic regression analyses were performed to evaluate associations between time to reintubation, using different observation windows after extubation (24-hour intervals), and death/BPD (primary outcome) or BPD among survivors (secondary outcome). aORs were computed with and without the confounding effects of cumulative mechanical ventilation duration. RESULTS: Of 216 infants included for analysis, 103 (48%) were reintubated at least once after their first elective extubation. Reintubation was associated with lower gestational age/weight and greater morbidities compared with infants never reintubated. After adjusting for confounders, reintubation within observation windows ranging between 24 hours and 3 weeks postextubation was associated with increased odds of death/BPD (but not BPD among survivors), independent of the cumulative mechanical ventilation duration. Reintubation within 48 hours from extubation conferred higher risk-adjusted odds of death/BPD vs other observation windows. CONCLUSIONS: Although reintubation after elective extubation was independently associated with increased likelihood of death/BPD in extremely preterm infants, the greatest risk was attributable to reintubation within the first 48 hours postextubation. Prediction models capable of identifying the highest-risk infants may further improve outcomes.

Patterns of reintubation in extremely preterm infants: a longitudinal cohort study.

BackgroundThe optimal approach for reporting reintubation rates in extremely preterm infants is unknown. This study aims to longitudinally describe patterns of reintubation in this population over a broad range of observation windows following extubation.MethodsTiming and reasons for reintubation following a first planned extubation were collected from infants with birth weight ≤1,250 g. An algorithm was generated to discriminate between reintubations attributable to respiratory and non-respiratory causes. Frequency and cumulative distribution curves were constructed for each category using 24 h intervals. The ability of observation windows to capture respiratory-related reintubations while limiting non-respiratory reasons was assessed using a receiver operating characteristic curve.ResultsOut of 194 infants, 91 (47%) were reintubated during hospitalization; 68% for respiratory and 32% for non-respiratory reasons. Respiratory-related reintubation rates steadily increased from 0 to 14 days post-extubation before reaching a plateau. In contrast, non-respiratory reintubations were negligible in the first post-extubation week, but became predominant after 14 days. An observation window of 7 days captured 77% of respiratory-related reintubations while only including 14% of non-respiratory cases.ConclusionReintubation patterns are highly variable and affected by the reasons for reintubation and observation window used. Ideally, reintubation rates should be reported using a cumulative distribution curve over time.

Correction to: The effects of the calcium-magnesium-bicarbonate content in thermal mineral water on chronic low back pain: a randomized, controlled follow-up study.

The original article mistakenly displays each set of author names in the wrong order, i.e., first names as last names and vice versa. The author correct names are: Tamás Gáti, Ildikó Katalin Tefner, Lajos Kovács, Katalin Hodosi, Tamás Bender. The original article has been corrected.

The effects of the calcium-magnesium-bicarbonate content in thermal mineral water on chronic low back pain: a randomized, controlled follow-up study.

The aim of this study was to investigate the effects of balneotherapy on chronic low back pain. This is a minimized, follow-up study evaluated according to the analysis of intention to treat. The subjects included in the study were 105 patients suffering from chronic low back pain. The control group (n = 53) received the traditional musculoskeletal pain killer treatment, while the target group (n = 52) attended thermal mineral water treatment for 3 weeks for 15 occasions on top of the usual musculoskeletal pain killer treatment. The following parameters were measured before, right after, and 9 weeks after the 3-week therapy: the level of low back pain in rest and the level during activity are tested using the Visual Analog Scale (VAS); specific questionnaire on the back pain (Oswestry); and a questionnaire on quality of life (EuroQual-5D). All of the investigated parameters improved significantly (p < 0.001) in the target group by the end of the treatment compared to the base period, and this improvement was persistent during the follow-up period. There were no significant changes in the measured parameters in the control group. Based on our results, balneotherapy might have favorable impact on the clinical parameters and quality of life of patients suffering from chronic low back pain.

[Solid organ transplantation in childhood]. / Szervtranszplantáció gyermekkorban.

Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948-1956.

[The start of the Hungarian lung transplantation program and the first results]. / A magyar tüdotranszplantációs program indulása és elso eredményei.

The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung-kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 ± 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 ± 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859-1868.

Early-Onset Invasive Candidiasis in Extremely Low Birth Weight Infants: Perinatal Acquisition Predicts Poor Outcome.

BACKGROUND: Neonatal invasive candidiasis (IC) presenting in the first week of life is less common and less well described than later-onset IC. Risk factors, clinical features, and disease outcomes have not been studied in early-onset disease (EOD, ≤7 days) or compared to late-onset disease (LOD, >7 days). METHODS: All extremely low birth weight (ELBW, <1000 g) cases with IC and controls from a multicenter study of neonatal candidiasis enrolled from 2001 to 2003 were included in this study. Factors associated with occurrence and outcome of EOD in ELBW infants were determined. RESULTS: Forty-five ELBW infants and their 84 matched controls were included. Fourteen (31%) ELBW infants had EOD. Birth weight <750 g, gestation <25 weeks, chorioamnionitis, and vaginal delivery were all strongly associated with EOD. Infection with Candida albicans, disseminated disease, pneumonia, and cardiovascular disease were significantly more common in EOD than in LOD. The EOD case fatality rate (71%) was higher than in LOD (32%) or controls (15%) (P = .0001). The rate of neurodevelopmental impairment and mortality combined was similar in EOD (86%) and LOD (72%), but higher than in controls (32%; P = .007). CONCLUSIONS: ELBW infants with EOD have a very poor prognosis compared to those with LOD. The role of perinatal transmission in EOD is supported by its association with chorioamnionitis, vaginal delivery, and pneumonia. Dissemination and cardiovascular involvement are common, and affected infants often die. Empiric treatment should be considered for ELBW infants delivered vaginally who have pneumonia and whose mothers have chorioamnionitis or an intrauterine foreign body.

Synthesis and in vitro investigation of potential antiproliferative monosaccharide-d-secoestrone bioconjugates.

The syntheses of monosaccharide-d-secoestrone conjugates are reported. They were prepared from 3-(prop-2-inyloxy)-d-secoestrone alcohol or oxime and monosaccharide azides via Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The antiproliferative activities of the conjugates were investigated in vitro against a panel of human adherent cancer cell lines (HeLa, A2780 and MCF-7) by means of MTT assays. The protected d-glucose-containing d-secoestrone oxime bioconjugate (24b) proved to be the most effective with an IC50 value in the low micromolar range against A2780 cell line.

The evaluation of 5-amino- and 5-hydroxyuracil derivatives as potential quadruplex-forming agents.

5-Substituted uracils (NH2 or OH groups in position 5) have been examined theoretically and experimentally as potential building blocks in quadruplex structures. Our high level Density Functional Theory (DFT) calculations showed that the tetramer formation and stacking energies for 5-substituted uracils are similar to the energies of purine-based xanthine (X) or guanine (G) structures. As tetrads of 5-substituted uracils cover almost exactly the same area as purine tetrads, mixed tetrads or quadruplex structures based on X or G and 5-substituted uracil motifs are possible. According to the calculations, 5-hydroxyuracil-based structures are the best candidates for experimental implementation which was corroborated by the existence of higher complexes in the mass spectra of 1-benzyl-5-hydroxyuracil. These pyrimidine-based molecules can be used as efficient building blocks in different applications including aptamers, bio-sensors or - taking into account the larger cavity in the central region of 5-hydroxyuracil structures - as an artificial ion channel.

Prediction of Extubation readiness in extremely preterm infants by the automated analysis of cardiorespiratory behavior: study protocol.

BACKGROUND: Extremely preterm infants (≤ 28 weeks gestation) commonly require endotracheal intubation and mechanical ventilation (MV) to maintain adequate oxygenation and gas exchange. Given that MV is independently associated with important adverse outcomes, efforts should be made to limit its duration. However, current methods for determining extubation readiness are inaccurate and a significant number of infants fail extubation and require reintubation, an intervention that may be associated with increased morbidities. A variety of objective measures have been proposed to better define the optimal time for extubation, but none have proven clinically useful. In a pilot study, investigators from this group have shown promising results from sophisticated, automated analyses of cardiorespiratory signals as a predictor of extubation readiness. The aim of this study is to develop an automated predictor of extubation readiness using a combination of clinical tools along with novel and automated measures of cardiorespiratory behavior, to assist clinicians in determining when extremely preterm infants are ready for extubation. METHODS: In this prospective, multicenter observational study, cardiorespiratory signals will be recorded from 250 eligible extremely preterm infants with birth weights ≤1250 g immediately prior to their first planned extubation. Automated signal analysis algorithms will compute a variety of metrics for each infant, and machine learning methods will then be used to find the optimal combination of these metrics together with clinical variables that provide the best overall prediction of extubation readiness. Using these results, investigators will develop an Automated system for Prediction of EXtubation (APEX) readiness that will integrate the software for data acquisition, signal analysis, and outcome prediction into a single application suitable for use by medical personnel in the neonatal intensive care unit. The performance of APEX will later be prospectively validated in 50 additional infants. DISCUSSION: The results of this research will provide the quantitative evidence needed to assist clinicians in determining when to extubate a preterm infant with the highest probability of success, and could produce significant improvements in extubation outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01909947 . Registered on July 17 2013. Trial sponsor: Canadian Institutes of Health Research (CIHR).

A three-component reagent system for rapid and mild removal of O-, N- and S-trityl protecting groups.

A new reagent system consisting of a Lewis acid such as BF3·Et2O or Cu(OTf)2, the mild protic acid hexafluoroisopropanol and the reducing quenching agent triethylsilane was elaborated for O-, N- and S-detritylation of nucleoside, carbohydrate and amino acid derivatives. The method is compatible with acetyl, silyl, acetal and Fmoc groups.

Home-Based Screening for Biliary Atresia Using Infant Stool Color Cards in Canada: Quebec Feasibility Study.

OBJECTIVES: Biliary atresia (BA) is a leading cause of liver failure and liver transplantation in pediatrics. BA manifests by 3 weeks of life with jaundice and pale stools. Delayed diagnosis and surgical intervention with Kasai portoenterostomy after 3 months of age is significantly associated with poor prognosis for native liver survival. A national Taiwan infant stool color card (SCC) screening program has entirely eliminated late Kasai portoenterostomy >90 days of age and improved native liver survival. A recent large-scale prospective cohort study in British Columbia, Canada, indicated that distribution of SCC on the maternity ward was feasible, led to high utilization rate, and was cost-effective. The aim of the present study was to assess the generalizability of this screening strategy in another Canadian jurisdiction with a different sociodemographic profile. METHODS: An SCC was distributed to families of newborns discharged at St Mary's Hospital Center, Montreal, Quebec. Families were instructed to monitor their infant's stool color for 21 days and then complete and mail the SCC to the study center. Phone surveys to families who did not return cards were used to estimate total card utilization rate. RESULTS: Two thousand two hundred forty-six infants were eligible for inclusion; 99.9% were enrolled. Mail SCC return rate was 63.3%. No cases of BA were identified. All of the 118 families who completed the phone survey reported that they had utilized the SCC. Conservative and optimistic estimates for total card utilization rates were 82% and 100%, respectively. CONCLUSIONS: The high enrollment and utilization rates in this screening study strongly support the feasibility of implementing a Canadian SCC screening program to improve outcomes of children with BA.

Effects of sulfur bath on hip osteoarthritis: a randomized, controlled, single-blind, follow-up trial: a pilot study.

The effects of balneotherapy were evaluated in patients with osteoarthritis of the hip. This randomized, controlled, investigator-blinded study enrolled outpatients with hip osteoarthritis according to ACR criteria. In addition to home exercise therapy, one patient group received balneotherapy for 3 weeks on 15 occasions. The mineral water used in this study is one of the mineral waters with the highest sulfide ion content (13.2 mg/L) in Hungary. The control group received exercise therapy alone. The WOMAC Likert 3.1 index and the EQ-5D quality of life self-administered questionnaire were completed three times during the study: prior to first treatment, at the end of the 3-week treatment course, and 12 weeks later. The main endpoint was achievement of Minimal Clinically Important Improvement (MCII) at 12 weeks, defined as ≥7.9 points in a normalized WOMAC function score. The intention to treat analysis included 20 controls and 21 balneotherapy patients. At 12 weeks, 17 (81 %) balneotherapy group patients had Minimal Clinically Important Improvement and 6 (30 %) of controls (p = 0.001). Comparing the results of the two groups at the end of treatment, there was a significant difference in the WOMAC stiffness score only, whereas after 12 weeks, the WOMAC pain, stiffness, function, and total scores also showed a significant difference in favor of the balneotherapy group. The difference between the two groups was significant after 12 weeks in point of EQVAS score, too. The results of our study suggest that the combination of balneotherapy and exercise therapy achieves more sustained improvement of joint function and decreases in pain than exercise therapy alone.

Xanthines Studied via Femtosecond Fluorescence Spectroscopy.

Xanthines represent a wide class of compounds closely related to the DNA bases adenine and guanine. Ubiquitous in the human body, they are capable of replacing natural bases in double helices and give rise to four-stranded structures. Although the use of their fluorescence for analytical purposes was proposed, their fluorescence properties have not been properly characterized so far. The present paper reports the first fluorescence study of xanthine solutions relying on femtosecond spectroscopy. Initially, we focus on 3-methylxanthine, showing that this compound exhibits non-exponential fluorescence decays with no significant dependence on the emission wavelength. The fluorescence quantum yield (3 × 10-4) and average decay time (0.9 ps) are slightly larger than those found for the DNA bases. Subsequently, we compare the dynamical fluorescence properties of seven mono-, di- and tri-methylated derivatives. Both the fluorescence decays and fluorescence anisotropies vary only weakly with the site and the degree of methylation. These findings are in line with theoretical predictions suggesting the involvement of several conical intersections in the relaxation of the lowest singlet excited state.

Synthesis and Biological Evaluation of Triazolyl 13α-Estrone-Nucleoside Bioconjugates.

2'-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne-azide click reaction (CuAAC). For the introduction of the azido group the 5'-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3'-hydroxy groups of the nucleosides were protected by acetyl groups and the 5'-hydroxy groups were modified by the tosyl-azide exchange method. The commonly used conditions for click reaction between the protected-5'-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17ß-hydroxysteroid dehydrogenase 1 (17ß-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 µM). The thymidine conjugate displayed considerable 17ß-HSD1 inhibitory activity (IC50 = 19 µM).