Differential effects of growth restriction and immaturity on predicted psychomotor development at 4 years of age in preterm infants.

BACKGROUND: Fetal growth restriction and immaturity are associated with poor neurocognitive development and child psychopathology affecting educational success at school and beyond. However, the differential effects of either obstetrical risk factor on predicted psychomotor development have not yet been deciphered. OBJECTIVE: This study aimed to separately study the impact of growth restriction and that of immaturity on predicted psychomotor development at the preschool age of 4.3 (standard deviation, 0.8) years using birthweight percentiles in a prospective cohort of preterm infants born at ≤37+6/7 weeks of gestation. Differences between small for gestational age newborns with intrauterine growth restriction and those without were described. We examined predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, and predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score in 854 preterm infants from a large prospective screening cohort (cranial ultrasound screening, n=5,301). STUDY DESIGN: This was a prospective cranial ultrasound screening study with a single-center cohort observational design (data collection done from 1984-1988, analysis done in 2022). The study included 5,301 live-born infants, of whom 854 (16.1%) were preterm infants (≤37+6/7 weeks' gestation), and was conducted on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development, as assessed by the predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score were calculated. We related psychomotor development indices and measures to gestational age in 3 groups of birthweight percentiles (ie, 10%, 50%, and 90% for small, appropriate, and large for gestational age newborns, respectively) using linear regression analysis, analysis of variance, multivariate analysis of variance, and t test procedures. RESULTS: The key result of our study is the observation that in preterm infants born at ≤37+6/7 weeks of gestation, growth restriction as compared with immaturity is the prime risk factor for impairment of overall predicted psychomotor development, intelligence quotient, Porteus Maze test results, and neurologic examination optimality score at the preschool age of 4.3 (standard deviation, 0.8) years (P<.001). This is particularly true for intrauterine growth restriction. These detrimental effects of growth restriction become more prominent with decreasing gestational age (P<.001). As expected, growth restriction in preterm infants born at ≤37+6/7 weeks of gestation was associated with a number of obstetrical risk factors, including hypertension in pregnancy (P<.001), multiple pregnancy (P<.001), pathologic cardiotocography (P=.001), and low pH (P=.007), increased pCO2 (P=.009), and poor pO2 (P<.001) in umbilical arterial blood. Of note, there were no differences in cerebral hemorrhage or white matter damage among small, appropriate, and large for gestational age birthweight percentile groups, suggesting an independent mechanism of brain injury caused by preterm growth restriction resulting in poor psychomotor development. CONCLUSION: Compared with immaturity, growth restriction in preterm infants has more intense detrimental effects on psychomotor development, necessitating improved risk stratification. This finding has implications for clinical management, parental consultation, and early intervention strategies to improve school performance, educational success, and mental health in children. The mechanisms of brain injury specific to growth restriction in preterm infants require further elucidation.

Standard vs. targeted oxygen therapy prehospitally for chronic obstructive pulmonary disease (STOP-COPD): study protocol for a randomised controlled trial.

BACKGROUND: A high concentration of inspired supplemental oxygen may possibly cause hypercapnia and acidosis and increase mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Even so, patients with AECOPD are being treated with high oxygen flow rates when receiving inhalation drugs in the prehospital setting. A cluster-randomised controlled trial found that reduced oxygen delivery by titrated treatment reduced mortality-a result supported by observational studies-but the results have never been reproduced. In the STOP-COPD trial, we investigate the effect of titrated oxygen delivery compared with usual care consisting of high flow oxygen delivery in patients with AECOPD in the prehospital setting. METHODS: In this randomised controlled trial, patients will be blinded to allocation. Patients with suspected AECOPD (n = 1888) attended by the emergency medical service (EMS) and aged > 40 years will be allocated randomly to either standard treatment or titrated oxygen, targeting a blood oxygen saturation of 88-92% during inhalation therapy. The trial will be conducted in the Central Denmark Region and include all ambulance units. The power to detect a 3% 30-day mortality risk difference is 80%. The trial is approved as an emergency trial. Hence, EMS providers will include patients without prior consent. DISCUSSION: The results will provide evidence on whether titrated oxygen delivery outperforms standard high flow oxygen when used to nebulise inhaled bronchodilators in AECOPD treatment. The trial is designed to ensure unselected inclusion of patients with AECOPD needing nebulised bronchodilators-a group of patients that receives high oxygen fractions when treated in the prehospital setting where the only compressed gas is generally pure oxygen. Conducting this trial, we aim to improve treatment for people with AECOPD while reducing their 30-day mortality. TRIAL REGISTRATION: European Union Clinical Trials (EUCT) number: 2022-502003-30-00 (authorised 06/12/2022), ClinicalTrials.gov number: NCT05703919 (released 02/02/2023), Universal trial number: U1111-1278-2162.

EV products obtained from iPSC-derived MSCs show batch-to-batch variations in their ability to modulate allogeneic immune responses in vitro.

Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in diverse clinical settings, largely due to their ability to produce extracellular vesicles (EVs). These EVs play a pivotal role in modulating immune responses, transforming pro-inflammatory cues into regulatory signals that foster a pro-regenerative milieu. Our previous studies identified the variability in the immunomodulatory effects of EVs sourced from primary human bone marrow MSCs as a consistent challenge. Given the limited proliferation of primary MSCs, protocols were advanced to derive MSCs from GMP-compliant induced pluripotent stem cells (iPSCs), producing iPSC-derived MSCs (iMSCs) that satisfied rigorous MSC criteria and exhibited enhanced expansion potential. Intriguingly, even though obtained iMSCs contained the potential to release immunomodulatory active EVs, the iMSC-EV products displayed batch-to-batch functional inconsistencies, mirroring those from bone marrow counterparts. We also discerned variances in EV-specific protein profiles among independent iMSC-EV preparations. Our results underscore that while iMSCs present an expansive growth advantage, they do not overcome the persistent challenge of functional variability of resulting MSC-EV products. Once more, our findings accentuate the crucial need for batch-to-batch functional testing, ensuring discrimination of effective and ineffective MSC-EV products for considered downstream applications.

Growth variables and obstetrical risk factors in newborns are associated with psychomotor development at preschool age.

BACKGROUND: Low birthweight resulting from preterm birth or fetal growth restriction is associated with poor neurocognitive development and child psychopathology affecting school performance and educational success. Prediction of developmental performance may therefore serve as a basis for early intervention strategies to improve educational success and mental health of our children in a timely manner. OBJECTIVE: This study aimed to explore the predictive capacity of morphometric variables taken at birth and that of obstetrical risk factors to predict developmental performance at 4.3 (standard deviation, 0.8) years preschool age. We examined predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score in a large prospective screening (cranial ultrasound screening, n=5,301) and validation cohort (n=508,926). STUDY DESIGN: In a single-center cohort observational study design (data collection done from 1984-1988, analysis done in 2022), a prospective cranial ultrasound screening study (1984-1988) was carried out on 5,301 live-born infants, including 571 (10.8%) preterm infants (≤36 weeks gestation), on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development as assessed by predicted Total psychomotor development score, predicted Developmental disability index, calculated Morphometric vitality index, and predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, was calculated. We related growth variables and obstetrical risk factors to Psychomotor development indices, and calculated Morphometric vitality index using odds ratios, receiver operating characteristics, analysis of variance, and multivariate analysis of variance. RESULTS: The key result of our study is the observation that simple morphometric measures from newborns at birth like weight/head circumference ratio predict overall psychomotor development at 4.3 years (standard deviation, 0.8) of preschool age. Psychomotor development was assessed by predicted Total psychomotor development score, predicted Intelligence quotient, Maze test, and Neurologic examination optimality score, and related to weight/head circumference ratio in linear regression (P<.001) and ROC curve analyses (P<.001). Further, white matter damage strongly predicted adverse outcome in predicted Developmental disability index (P<.001). There was also a close correlation between calculated Morphometric vitality index and predicted Developmental disability index (P<.001). Finally, brain body weight ratio, weight/head circumference ratio, preterm birth, reduced Apgar at 10 minutes, weight/length ratio, and white matter damage yielded highest odds ratios for adverse outcome in predicted Total psychomotor development score and in predicted Developmental disability index (P<.001) and high effect sizes in reduced predicted Intelligence quotient, Maze test, and Neurologic examination optimality scores. CONCLUSION: Simple morphometric data, birth variables, and obstetrical risk factors bear predictive capacity for neurocognitive performance in children at 4.3 years (standard deviation, 0.8) of age and hence provide a basis for parental consultation and early intervention to improve school performance, educational success, and mental health in developed and developing countries.

Cerebral palsy - brain repair with stem cells.

Cerebral palsy, the most common disability in childhood, is a devastating non-progressive ailment of the infants' brain with lifelong sequelae, e.g., spastic paresis, chronic pain, inability to walk, intellectual disability, behavioral disorders, for which there is no cure at present. CP may develop after pediatric brain damage caused, e.g., by hypoxic-ischemia, periventricular leukomalacia, intracranial hemorrhage, hypoxic-ischemic encephalopathy, trauma, stroke, and infection. About 17 million people worldwide live with cerebral palsy as a result of pediatric brain damage. This reflects both the magnitude of the personal, medical, and socioeconomic global burden of this brain disorder and the overt unmet therapeutic needs of the pediatric population. This review will focus on recent preclinical, clinical, and regulatory developments in cell therapy for infantile cerebral palsy by transplantation of cord blood derived mononuclear cells from bench to bedside. The body of evidence suggests that cord blood cell therapy of cerebral palsy in the autologous setting is feasible, effective, and safe, however, adequately powered phase 3 trials are overdue.

Large-effect loci mediate rapid adaptation of salmon body size after river regulation.

Understanding the potential of natural populations to adapt to altered environments is becoming increasingly relevant in evolutionary research. Currently, our understanding of adaptation to human alteration of the environment is hampered by lack of knowledge on the genetic basis of traits, lack of time series, and little or no information on changes in optimal trait values. Here, we used time series data spanning nearly a century to investigate how the body mass of Atlantic salmon (Salmo salar) adapts to river regulation. We found that the change in body mass followed the change in waterflow, both decreasing to ∼1/3 of their original values. Allele frequency changes at two loci in the regions of vgll3 and six6 predicted more than 80% of the observed body mass reduction. Modeling the adaptive dynamics revealed that the population mean lagged behind its optimum before catching up approximately six salmon generations after the initial waterflow reduction. Our results demonstrate rapid adaptation mediated by large-effect loci and provide insight into the temporal dynamics of evolutionary rescue following human disturbance.

Prehospital fluid therapy in patients with suspected infection: a survey of ambulance personnel's practice.

BACKGROUND: Fluid therapy in patients with suspected infection is controversial, and it is not known whether fluid treatment administered in the prehospital setting is beneficial. In the absence of evidence-based guidelines for prehospital fluid therapy for patients with suspected infection, Emergency Medical Services (EMS) personnel are challenged on when and how to initiate such therapy. This study aimed to assess EMS personnel's decision-making in prehospital fluid therapy, including triggers for initiating fluid and fluid volumes, as well as the need for education and evidence-based guidelines on prehospital fluid therapy in patients with suspected infection. METHODS: An online survey concerning fluid administration in prehospital patients with suspected infection was distributed to all EMS personnel in the Central Denmark Region, including ambulance clinicians and prehospital critical care anaesthesiologists (PCCA). The survey consisted of sections concerning academic knowledge, statements about fluid administration, triggers to evaluate patient needs for intravenous fluid, and clinical scenarios. RESULTS: In total, 468/807 (58%) ambulance clinicians and 106/151 (70%) PCCA responded to the survey. Of the respondents, 73% (n = 341) of the ambulance clinicians and 100% (n = 106) of the PCCA felt confident about administering fluids to prehospital patients with infections. However, both groups primarily based their fluid-related decisions on "clinical intuition". Ambulance clinicians named the most frequently faced challenges in fluid therapy as "Unsure whether the patient needs fluid" and "Unsure about the volume of fluid the patient needs". The five most frequently used triggers for evaluating fluid needs were blood pressure, history taking, skin turgor, capillary refill time, and shock index, the last of which only applied to ambulance clinicians. In the scenarios, the majority administered 500 ml to a normotensive woman with suspected sepsis and 1000 ml to a woman with suspected sepsis-related hypotension. Moreover, 97% (n = 250) of the ambulance clinicians strongly agreed or agreed that they were interested in more education about fluid therapy in patients with suspected infection. CONCLUSION: The majority of ambulance clinicians and PCCA based their fluid administration on "clinical intuition". They faced challenges deciding on fluid volumes and individual fluid needs. Thus, they were eager to learn more and requested research and evidence-based guidelines.

Early-season brown trout (Salmo trutta) migrants grow and survive better at sea.

The timing of seaward migration is a key life-history trait for many anadromous fish species, with growth and survival at sea depending on a match/mismatch scenario between the timing of the sea entry and optimal conditions. Based on a 25-year study with 15,226 individually tagged brown trout (Salmo trutta) in a Norwegian river, we analysed how the within-season timing of sea migration impacted growth and survival. In both first-time and veteran migrants, marine growth was highest for early migrating individuals, large individuals, and those with a low condition factor when entering the sea. Survival was highest for individuals entering the sea early in the season. In first-time migrants, survival increased with body length. Survival also increased with the number of other smolts migrating simultaneously. As the early smolts were the most successful, it may seem strange that many smolts migrate later in the season. We suggest that late-migrating smolts may not be of a size and/or physiological state suitable for early marine conditions, and may make the best of a bad situation.

Ecological regime shift in the Northeast Atlantic Ocean revealed from the unprecedented reduction in marine growth of Atlantic salmon.

Ecological regime shifts are abrupt changes in the structure and function of ecosystems that persist over time, but evidence of contemporary regime shifts are rare. Historical scale data from 52,384 individual wild Atlantic salmon caught in 180 rivers from 1989 to 2017 reveal that growth of Atlantic salmon across the Northeast Atlantic Ocean abruptly decreased following the year 2004. At the same time, the proportion of early maturing Atlantic salmon decreased. These changes occurred after a marked decrease in the extent of Arctic water in the Norwegian Sea, a subsequent warming of spring water temperature before Atlantic salmon entering the sea, and an approximately 50% reduction of zooplankton across large geographic areas of the Northeast Atlantic Ocean. A sudden decrease in growth was also observed among Atlantic mackerel in the Norwegian Sea. Our results point toward an ecosystem-scale regime shift in the Northeast Atlantic Ocean.

Introgression from farmed escapees affects the full life cycle of wild Atlantic salmon.

After a half a century of salmon farming, we have yet to understand how the influx of genes from farmed escapees affects the full life history of Atlantic salmon (Salmo salar L.) in the wild. Using scale samples of over 6900 wild adult salmon from 105 rivers, we document that increased farmed genetic ancestry is associated with increased growth throughout life and a younger age at both seaward migration and sexual maturity. There was large among-population variation in the effects of introgression. Most saliently, the increased growth at sea following introgression declined with the population's average growth potential. Variation at two major-effect loci associated with age at maturity was little affected by farmed genetic ancestry and could not explain the observed phenotypic effects of introgression. Our study provides knowledge crucial for predicting the ecological and evolutionary consequences of increased aquaculture production worldwide.

Repeatable individual variation in migration timing in two anadromous salmonids and ecological consequences.

Consistent individual differences in behavior have been demonstrated for many animals, but there are few studies of consequences of such repeated behavior in the wild. We tested consistency in migration timing to and from the sea among anadromous Arctic char (Salvelinus alpinus) and brown trout (Salmo trutta), using data from a study period of about 25 years, including more than 27,000 uniquely Carlin-tagged individuals that migrated to sea for feeding in the spring and returned to the river in late summer for up to 13 successive years. Consistency was found between individuals across time in timing of the seaward migration. Individuals migrating early during their first migration tended to migrate early the following years, and late migrants tended to migrate late. The same pattern was found also at ascent to freshwater. Hence, this study demonstrated that individual fish in nature can differ in behavior related to migration timing and that these differences can be consistent during their lifetime. Early migrants increased their mass more than late migrants and had a higher specific growth rate. Early migrating Arctic char, but not brown trout, experienced a longer life after the first migration to sea than late migrants. In both species, maturity occurred earlier in individuals that migrated early. For brown trout, but not for Arctic char, fecundity was significantly correlated to the timing of smolt migration. Hence, the repeatable individual variation in migration timing seemed to have ecological and fitness consequences in terms of growth, longevity, timing of maturity, and lifetime fecundity.

Author Correction: Development and inter-laboratory assessment of droplet digital PCR assays for multiplex quantification of 15 genetically modified soybean lines.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Supplementary stocking selects for domesticated genotypes.

Stocking of hatchery produced fish is common practise to mitigate declines in natural populations and may have unwanted genetic consequences. Here we describe a novel phenomenon arising where broodstock used for stocking may be introgressed with farmed individuals. We test how stocking affects introgression in a wild population of Atlantic salmon (Salmo salar) by quantifying how the number of adult offspring recaptured in a stocked river depend on parental introgression. We found that hatchery conditions favour farmed genotypes such that introgressed broodstock produce up to four times the number of adult offspring compared to non-introgressed broodstock, leading to increased introgression in the recipient spawning population. Our results provide the first empirical evidence that stocking can unintentionally favour introgressed individuals and through selection for domesticated genotypes compromise the fitness of stocked wild populations.

Multiplex Droplet Digital PCR Protocols for Quantification of GM Maize Events.

The standard-curve based simplex quantitative polymerase chain reaction (qPCR) has been the gold standard for DNA target quantification for more than a decade. The large and growing number of individual analyses needed to test for genetically modified organisms (GMOs) is reducing the cost-effectiveness of qPCR. Droplet digital PCR (ddPCR) enables absolute quantification without standard curves, avoids the amplification efficiency bias observed with qPCR, allows more accurate estimations at low target copy numbers and, in combination with multiplexing, significantly improves cost efficiency. Here we describe two protocols for multiplex quantification of GM maize events: (1) nondiscriminating, with multiplex quantification of targets as a group (12 GM maize lines) and (2) discriminating, with multiplex quantification of individual targets (events). The first enables the quantification of twelve European Union authorized GM maize events as a group with only two assays, but does not permit determination of the individual events present. The second protocol enables the quantification of four individual targets (three GM events and one endogene) in a single reaction. Both protocols can be modified for quantification of any other DNA target.

White Matter Damage in 4,725 Term-Born Infants Is Determined by Head Circumference at Birth: The Missing Link.

BACKGROUND: White matter damage (WMD) is a prime risk factor for cerebral palsy, in part occurring unexplained. Though primarily a problem of preterm infants, there is growing evidence that in large newborns cephalopelvic disproportion and prolonged labor are involved. OBJECTIVE: To explore both incidence of and morphometric risk factors for WMD in term-born infants. STUDY DESIGN: We related growth variables and risk factors of term-born infants to WMD (61/4,725) using odds ratios of z-score bands. RESULTS: The key result is the novel observation that head circumference is a prime and unique index for WMD in term-born neonates over the whole range of centiles (U-shaped; WMD (%) = 3.1168-0.12797∗HC (centile) + 0.0014741∗HC2; p < 0.0001). This suggests different mechanisms for WMD in the lowest and highest z-score band. In the latter, cephalic pressure gradients and prolonged labor with preserved neonatal vitality prevail, whereas in the previous one, acute and chronic oxygen deprivation with reduced vitality predominate. CONCLUSIONS: The fact that seemingly healthy term-born neonates are not screened by head imaging, in spite of both large head circumference and prolonged labor, is considered to be the missing link between the insult that escapes diagnosis and the development of unexplained developmental delay and cerebral palsy in childhood.

High Throughput Sequencing for Detection of Foodborne Pathogens.

High-throughput sequencing (HTS) is becoming the state-of-the-art technology for typing of microbial isolates, especially in clinical samples. Yet, its application is still in its infancy for monitoring and outbreak investigations of foods. Here we review the published literature, covering not only bacterial but also viral and Eukaryote food pathogens, to assess the status and potential of HTS implementation to inform stakeholders, improve food safety and reduce outbreak impacts. The developments in sequencing technology and bioinformatics have outpaced the capacity to analyze and interpret the sequence data. The influence of sample processing, nucleic acid extraction and purification, harmonized protocols for generation and interpretation of data, and properly annotated and curated reference databases including non-pathogenic "natural" strains are other major obstacles to the realization of the full potential of HTS in analytical food surveillance, epidemiological and outbreak investigations, and in complementing preventive approaches for the control and management of foodborne pathogens. Despite significant obstacles, the achieved progress in capacity and broadening of the application range over the last decade is impressive and unprecedented, as illustrated with the chosen examples from the literature. Large consortia, often with broad international participation, are making coordinated efforts to cope with many of the mentioned obstacles. Further rapid progress can therefore be prospected for the next decade.

Development and validation of a multi-locus DNA metabarcoding method to identify endangered species in complex samples.

DNA metabarcoding provides great potential for species identification in complex samples such as food supplements and traditional medicines. Such a method would aid Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) enforcement officers to combat wildlife crime by preventing illegal trade of endangered plant and animal species. The objective of this research was to develop a multi-locus DNA metabarcoding method for forensic wildlife species identification and to evaluate the applicability and reproducibility of this approach across different laboratories. A DNA metabarcoding method was developed that makes use of 12 DNA barcode markers that have demonstrated universal applicability across a wide range of plant and animal taxa and that facilitate the identification of species in samples containing degraded DNA. The DNA metabarcoding method was developed based on Illumina MiSeq amplicon sequencing of well-defined experimental mixtures, for which a bioinformatics pipeline with user-friendly web-interface was developed. The performance of the DNA metabarcoding method was assessed in an international validation trial by 16 laboratories, in which the method was found to be highly reproducible and sensitive enough to identify species present in a mixture at 1% dry weight content. The advanced multi-locus DNA metabarcoding method assessed in this study provides reliable and detailed data on the composition of complex food products, including information on the presence of CITES-listed species. The method can provide improved resolution for species identification, while verifying species with multiple DNA barcodes contributes to an enhanced quality assurance.

Gene flow from domesticated escapes alters the life history of wild Atlantic salmon.

Interbreeding between domesticated and wild animals occurs in several species. This gene flow has long been anticipated to induce genetic changes in life-history traits of wild populations, thereby influencing population dynamics and viability. Here, we show that individuals with high levels of introgression (domesticated ancestry) have altered age and size at maturation in 62 wild Atlantic salmon Salmo salar populations, including seven ancestral populations to breeding lines of the domesticated salmon. This study documents widespread changes to life-history traits in wild animal populations following gene flow from selectively bred, domesticated conspecifics. The continued high abundance of escaped, domesticated Atlantic salmon thus threatens wild Atlantic salmon populations by inducing genetic changes in fitness-related traits. Our results represent key evidence and a timely warning concerning the potential ecological impacts of the globally increasing use of domesticated animals.