Characteristics of JN.1-derived SARS-CoV-2 subvariants SLip, FLiRT, and KP.2 in neutralization escape, infectivity and membrane fusion.

SARS-CoV-2 variants derived from the immune evasive JN.1 are on the rise worldwide. Here, we investigated JN.1-derived subvariants SLip, FLiRT, and KP.2 for their ability to be neutralized by antibodies in bivalent-vaccinated human sera, XBB.1.5 monovalent-vaccinated hamster sera, sera from people infected during the BA.2.86/JN.1 wave, and class III monoclonal antibody (Mab) S309. We found that compared to parental JN.1, SLip and KP.2, and especially FLiRT, exhibit increased resistance to COVID-19 bivalent-vaccinated human sera and BA.2.86/JN.1-wave convalescent sera. Interestingly, antibodies in XBB.1.5 monovalent vaccinated hamster sera robustly neutralized FLiRT and KP.2 but had reduced efficiency for SLip. These JN.1 subvariants were resistant to neutralization by Mab S309. In addition, we investigated aspects of spike protein biology including infectivity, cell-cell fusion and processing, and found that these subvariants, especially SLip, had a decreased infectivity and membrane fusion relative to JN.1, correlating with decreased spike processing. Homology modeling revealed that L455S and F456L mutations in SLip reduced local hydrophobicity in the spike and hence its binding to ACE2. In contrast, the additional R346T mutation in FLiRT and KP.2 strengthened conformational support of the receptor-binding motif, thus counteracting the effects of L455S and F456L. These three mutations, alongside D339H, which is present in all JN.1 sublineages, alter the epitopes targeted by therapeutic Mabs, including class I and class III S309, explaining their reduced sensitivity to neutralization by sera and S309. Together, our findings provide insight into neutralization resistance of newly emerged JN.1 subvariants and suggest that future vaccine formulations should consider JN.1 spike as immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection.

Reference Ranges for Arterial Oxygen Saturation, Heart Rate, and Cerebral Oxygen Saturation during Immediate Postnatal Transition in Neonates Born Extremely or Very Preterm.

OBJECTIVE: To define percentile charts for arterial oxygen saturation (SpO2), heart rate (HR), and cerebral oxygen saturation (crSO2) during the first 15 minutes after birth in neonates born very or extremely preterm and with favorable outcome. STUDY DESIGN: We conducted a secondary-outcome analysis of neonates born preterm included in the Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth III (COSGOD III) trial with visible cerebral oximetry measurements and with favorable outcome, defined as survival without cerebral injuries until term age. We excluded infants with inflammatory morbidities within the first week after birth. SpO2 was obtained by pulse oximetry, and electrocardiogram or pulse oximetry were used for measurement of HR. crSO2 was assessed with near-infrared spectroscopy. Measurements were performed during the first 15 minutes after birth. Percentile charts (10th to 90th centile) were defined for each minute. RESULTS: A total of 207 neonates born preterm with a gestational age of 29.7 (23.9-31.9) weeks and a birth weight of 1200 (378-2320) g were eligible for analyses. The 10th percentile of SpO2 at minute 2, 5, 10, and 15 was 32%, 52%, 83%, and 85%, respectively. The 10th percentile of HR at minute 2, 5, 10, and 15 was 70, 109, 126, and 134 beats/min, respectively. The 10th percentile of crSO2 at minute 2, 5, 20, and 15 was 15%, 27%, 59%, and 63%, respectively. CONCLUSIONS: This study provides new centile charts for SpO2, HR, and crSO2 for neonates born extremely or very preterm with favorable outcome. Implementing these centiles in guiding interventions during the stabilization process after birth might help to more accurately target oxygenation during postnatal transition period.

The Bronchopulmonary Dysplasia score: A predictive model for bronchopulmonary dysplasia or death in high-risk preterm infants.

AIM: Progressive respiratory deterioration in infants at high risk of bronchopulmonary dysplasia (BPD) is associated with patent ductus arteriosus (PDA) exposure. This study aimed to design an early predictive model for BPD or death in preterm infants using early echocardiographic markers and clinical data. METHODS: Infants born with gestational age (GA) ≤ 29 weeks and/or birth weight (BW) < 1500 g at Cork University Maternity Hospital, Ireland were retrospectively evaluated. Those with echocardiography performed between 36 h and 7 days of life were eligible for inclusion. Exclusion criteria were pulmonary hypertension and major congenital anomalies. The primary outcome was a composite of BPD and death before discharge. RESULTS: The study included 99 infants. A predictive model for the primary outcome was developed, which included three variables (BW, Respiratory Severity Score and flow pattern across the PDA), and yielding an area under the curve of 0.98 (95% CI 0.96-1.00, p < 0.001). Higher scores were predictive of the primary outcome. A cut-off of -1.0 had positive and negative predictive values of 89% and 98%, and sensitivity and specificity of 98% and 88%, respectively. CONCLUSION: Our prediction model is an accessible bedside tool that predicts BPD or death in premature infants.

Predicting CO2 production of lactating dairy cows from animal, dietary, and production traits using an international dataset.

Automated measurements of the ratio of concentrations of methane and carbon dioxide, [CH4]:[CO2], in breath from individual animals (the so-called "Sniffer-technique") and estimated CO2 production can be used to estimate CH4 production, provided that CO2 production can be reliably calculated. This would allow CH4 production from individual cows to be estimated in large cohorts of cows, whereby ranking of cows according to their CH4 production might become possible and their values could be used for breeding of low CH4 emitting animals. Estimates of CO2 production are typically based on predictions of heat production, which can be calculated from body weight (BW), energy-corrected milk yield, and days of pregnancy. The objectives of the present study were to develop predictions of CO2 production directly from milk production, dietary, and animal variables, and furthermore develop different models to be used for different scenarios, depending on available data. An international data set with 2,244 records from individual lactating cows including CO2 production and associated traits, as dry matter intake (DMI), diet composition, BW, milk production and composition, days in milk and days pregnant, was compiled to constitute the training data set. Research location and experiment nested within research location were included as random intercepts. The method of CO2 production measurement (respiration chamber (RC) or GreenFeed (GF)) was confounded with research location, and therefore excluded from the model. In total, 3 models were developed based on the current training data set: Model 1 ("Best Model"), where all significant traits were included, Model 2 ("On-Farm Model"), where DMI was excluded, and Model 3 ("Reduced On-Farm Model"), where both DMI and BW were excluded. Evaluation on test data sets either with RC data (n = 103), GF data without additives (n = 478) or GF data only including observations where nitrate, 3-nitrooxypropanol (3-NOP), or a combination of nitrate and 3-NOP were fed to the cows (GF+: n = 295), showed good precision of the 3 models, illustrated by low slope bias both in absolute values (-0.22 to 0.097) and in percentage (0.049 to 4.89) of mean square error (MSE). However, the mean bias (MB) indicated systematic over-prediction and under-prediction of CO2 production when the models were evaluated on the GF and the RC test data set, respectively. To address this bias, the 3 models were evaluated on a modified test data set, where the CO2 production (g/d) was adjusted by subtracting (where measurements were obtained by RC) or adding absolute MB (where measurements were obtained by GF) from evaluation of the specific model on RC, GF, and GF+ test data sets. By this modification, the absolute values of MB and MB as percentage of MSE became negligible. In conclusion, the 3 models were precise in predicting CO2 production from lactating dairy cows.

Integrating traditional and allopathic child health: A healthcare transformation opportunity.

Background: Numerous forums both domestically and internationally have discussed integration of allopathic and traditional healthcare. In South Africa, using traditional child healthcare is popular practice. If properly controlled, integrating this aspect of traditional child-health with allopathic healthcare may be advantageous to communities that use both healthcare systems. Allopathic and traditional healthcare remain separate organisations in South Africa despite efforts and discussions to integrate them. Aim: The study sought to explore the integration of traditional and allopathic child healthcare from the perspectives of children's caregivers and traditional healthcare practitioners. Setting: The study was conducted in a semi-urban area in the city of Tshwane. Methods: An exploratory qualitative research study was conducted using semi-structured interviews to collect data from 11 traditional healthcare practitioners and 15 children's caregivers who were sampled using snowball and convenient sampling respectively. Results: The participants expressed their understanding of the usage of traditional healthcare practitioners in the care of children as well as their support for integration, and further indicated its necessity. Religion and its effects in health-seeking behaviour were cited as a factor in why there has not been greater integration between the two healthcare systems. Conclusion: The undocumented and undisclosed use of traditional healthcare potentially hinders the delivery of therapeutic healthcare. As such, integrating the two systems is essential to ensure patients' safety. Contribution: This article highlights understanding of culture congruence and safe child healthcare that may be brought forward by the integration of the two healthcare systems.

Distinct patterns of SARS-CoV-2 BA.2.87.1 and JN.1 variants in immune evasion, antigenicity, and cell-cell fusion.

The rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly, BA.2.87.1 is more resistant to neutralization by XBB.1.5-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines. IMPORTANCE: This study investigates the recently emerged SARS-CoV-2 variants, BA.2.87.1 and JN.1, in comparison to earlier variants and the parental D614G. Varied infectivity and cell-cell fusion activity among these variants suggest potential disparities in their ability to infect target cells and possibly pathogenesis. BA.2.87.1 exhibits lower nAb escape from bivalent mRNA vaccinee and BA.2.86/JN.1-infected sera than JN.1 but is relatively resistance to XBB.1.5-vaccinated hamster sera, revealing distinct properties in immune reason and underscoring the significance of continuing surveillance of variants and reformulation of vaccines. Antigenic differences between BA.2.87.1 and other earlier variants yield critical information not only for antibody evasion but also for viral evolution. In conclusion, this study furnishes timely insights into the spike biology and immune escape of the emerging variants BA.2.87.1 and JN.1, thus guiding effective vaccine development and informing public health interventions.

Distinct Patterns of SARS-CoV-2 BA.2.87.1 and JN.1 Variants in Immune Evasion, Antigenicity and Cell-Cell Fusion.

The rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly. BA.2.87.1 is more resistant to neutralization by XBB.15-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines.

Immune evasion, infectivity, and fusogenicity of SARS-CoV-2 BA.2.86 and FLip variants.

Evolution of SARS-CoV-2 requires the reassessment of current vaccine measures. Here, we characterized BA.2.86 and XBB-derived variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, and EG.5.1 by sera from 3-dose-vaccinated and bivalent-vaccinated healthcare workers, XBB.1.5-wave-infected first responders, and monoclonal antibody (mAb) S309. We assessed the biology of the variant spikes by measuring viral infectivity and membrane fusogenicity. BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. Importantly, distinct from XBB variants, mAb S309 was unable to neutralize BA.2.86, likely due to a D339H mutation based on modeling. BA.2.86 had relatively high fusogenicity and infectivity in CaLu-3 cells but low fusion and infectivity in 293T-ACE2 cells compared to some XBB variants, suggesting a potentially different conformational stability of BA.2.86 spike. Overall, our study underscores the importance of SARS-CoV-2 variant surveillance and the need for updated COVID-19 vaccines.

The 200-Year Timeline on Botulinum Toxin: From Biologic Poison to Wonder Drug.

The history of botulinum toxin dates back to the late 1700s, when food preparation, storage, and later canning practices led to outbreaks of botulism across Europe and the United States. It is from these initial incidents that the remarkable discovery of botulinum toxin was eventually made, sparking over 200 years of further scientific inquiry and medical innovation. To date, 6 botulinum toxin products have been commercialized in North America with numerous indications across the specialties of ophthalmology, neurology, urology, dermatology, plastic surgery, and otolaryngology. This article traces the key moments and important players in the remarkable journey of this biologic poison and wonder drug. J Drugs Dermatol. 2024;23(1) doi:10.36849/JDD.7288.

Locus folding mechanisms determine modes of antigen receptor gene assembly.

The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bidirectional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5'Vß segment (Trbv1) impaired loop extrusion originating locally and extending to DßJß CBEs at the opposite end of Tcrb. Promoter or CBE mutation nearly eliminated Trbv1 contacts and decreased RAG endonuclease-mediated Trbv1 recombination. Importantly, Trbv1 rearrangement can proceed independent of substrate orientation, ruling out scanning by DßJß-bound RAG as the sole mechanism of Vß recombination, distinguishing it from Igh. Our data indicate that CBE-dependent generation of loops cooperates with promoter-mediated activation of chromatin to juxtapose Vß and DßJß segments for recombination through diffusion-based synapsis. Thus, the mechanisms that fold a genomic region can influence molecular processes occurring in that space, which may include recombination, repair, and transcriptional programming.

mRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell immunity against the Omicron variant, but efficacy of booster vaccination in patients with late-stage lung cancer on immune-modulating agents including anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) has not yet been elucidated. METHODS: We assessed T-cell responses using a modified activation-induced marker assay, coupled with high-dimension flow cytometry analyses. Peripheral blood mononuclear cells (PBMCs) were stimulated with various viral peptides and antigen-specific T-cell responses were evaluated using flow cytometry. RESULTS: Booster vaccines induced CD8+ T-cell response against the ancestral SARS-CoV-2 strain and Omicron variant in both non-cancer subjects and patients with lung cancer, but only a marginal induction was detected for CD4+ T cells. Importantly, antigen-specific T cells from patients with lung cancer showed distinct subpopulation dynamics with varying degrees of differentiation compared with non-cancer subjects, with evidence of dysfunction. Notably, female-biased T-cell responses were observed. CONCLUSION: We conclude that patients with lung cancer on immunotherapy show a substantial qualitative deviation from non-cancer subjects in their T-cell response to mRNA vaccines, highlighting the need for heightened protective measures for patients with cancer to minimize the risk of breakthrough infection with the Omicron and other future variants.

Temporal evolution of electrographic seizures in newborn infants with hypoxic-ischaemic encephalopathy requiring therapeutic hypothermia: a secondary analysis of the ANSeR studies.

BACKGROUND: Despite extensive research on neonatal hypoxic-ischaemic encephalopathy, detailed information about electrographic seizures during active cooling and rewarming of therapeutic hypothermia is sparse. We aimed to describe temporal evolution of seizures and determine whether there is a correlation of seizure evolution with 2-year outcome. METHODS: This secondary analysis included newborn infants recruited from eight European tertiary neonatal intensive care units for two multicentre studies (a randomised controlled trial [NCT02431780] and an observational study [NCT02160171]). Infants were born at 36+0 weeks of gestation with moderate or severe hypoxic-ischaemic encephalopathy and underwent therapeutic hypothermia with prolonged conventional video-electroencephalography (EEG) monitoring for 10 h or longer from the start of rewarming. Seizure burden characteristics were calculated based on electrographic seizures annotations: hourly seizure burden (minutes of seizures within an hour) and total seizure burden (minutes of seizures within the entire recording). We categorised infants into those with electrographic seizures during active cooling only, those with electrographic seizures during cooling and rewarming, and those without seizures. Neurodevelopmental outcomes were determined using the Bayley's Scales of Infant and Toddler Development, Third Edition (BSID-III), the Griffiths Mental Development Scales (GMDS), or neurological assessment. An abnormal outcome was defined as death or neurodisability at 2 years. Neurodisability was defined as a composite score of 85 or less on any subscales for BSID-III, a total score of 87 or less for GMDS, or a diagnosis of cerebral palsy (dyskinetic cerebral palsy, spastic quadriplegia, or mixed motor impairment) or epilepsy. FINDINGS: Of 263 infants recruited between Jan 1, 2011, and Feb 7, 2017, we included 129 infants: 65 had electrographic seizures (43 during active cooling only and 22 during and after active cooling) and 64 had no seizures. Compared with infants with seizures during active cooling only, those with seizures during and after active cooling had a longer seizure period (median 12 h [IQR 3-28] vs 68 h [35-86], p<0·0001), more seizures (median 12 [IQR 5-36] vs 94 [24-134], p<0·0001), and higher total seizure burden (median 69 min [IQR 22-104] vs 167 min [54-275], p=0·0033). Hourly seizure burden peaked at about 20-24 h in both groups, and infants with seizures during and after active cooling had a secondary peak at 85 h of age. When combined, worse EEG background (major abnormalities and inactive background) at 12 h and 24 h were associated with the seizure group: compared with infants with a better EEG background (normal, mild, or moderate abnormalities), infants with a worse EEG background were more likely to have seizures after cooling at 12 h (13 [54%] of 24 vs four [14%] of 28; odds ratio 7·09 [95% CI 1·88-26·77], p=0·0039) and 24 h (14 [56%] of 25 vs seven [18%] of 38; 5·64 [1·81-17·60], p=0·0029). There was a significant relationship between EEG grade at 12 h (four categories) and seizure group (p=0·020). High total seizure burden was associated with increased odds of an abnormal outcome at 2 years of age (odds ratio 1·007 [95% CI 1·000-1·014], p=0·046), with a medium negative correlation between total seizure burden and BSID-III cognitive score (rS=-0·477, p=0·014, n=26). INTERPRETATION: Overall, half of infants with hypoxic-ischaemic encephalopathy had electrographic seizures and a third of those infants had seizures beyond active cooling, with worse outcomes. These results raise the importance of prolonged EEG monitoring of newborn infants with hypoxic-ischaemic encephalopathy not only during active cooling but throughout the rewarming phase and even longer when seizures are detected. FUNDING: Wellcome Trust, Science Foundation Ireland, and the Irish Health Research Board.

Multisite Quality Improvement Program Within the Project ECHO Diabetes Remote Network.

BACKGROUND: The telementoring Project ECHO (Extension for Community Healthcare Outcomes) model has been shown to improve disease management in diabetes in many underserved communities. The authors aim to evaluate if ECHO could also be an effective tool for quality improvement (QI) of diabetes care in these communities. METHODS: Thirteen clinics in underserved communities in California and Florida participating in Project ECHO Diabetes were recruited for a 12-month QI program. The program provided weekly tele-education sessions, including a didactic presentation and case-based discussion. In addition, clinics chose their own set of quality measures to improve and met remotely to discuss their efforts, successes, and setbacks every quarter with mentorship from QI experts. RESULTS: Of the 31 QI initiatives attempted by different clinics, all had either made improvements (25 initiatives, 80.6%) or were in the process of making improvements (6 initiatives, 19.4%) in structural, process, and outcome measures. Examples of these measures include whether clinics have protocols to identify high-risk patients (structure), numbers of continuous glucose monitor prescriptions submitted by the clinics (process), and percentage of patients with diabetes whose most recent HbA1c are > 9% (outcome). For one measure, 40.0% of the clinics had achieved a higher percentage of cumulative HbA1c measurement in the third quarter of the year, compared to the fourth quarter in the previous year. The cost of QI implementation varied widely due to different number of personnel involved across sites. CONCLUSION: A QI program delivered via Project ECHO Diabetes can facilitate quality improvements in underserved communities.

The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes.

Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3-/- CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3-/- and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3-/- CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3-/- CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.

Impact of cord clamping on haemodynamic transition in term newborn infants.

OBJECTIVE: To assess the haemodynamic consequences of cord clamping (CC) in healthy term infants. DESIGN: Cohort study. SETTING: Tertiary maternity hospital. PATIENTS: 46 full-term vigorous infants born by caesarean section. INTERVENTIONS: Echocardiography was performed before CC, immediately after CC and at 5 min after birth. MAIN OUTCOME MEASURES: Pulsed wave Doppler-derived cardiac output and the pulmonary artery acceleration time indexed to the right ventricle ejection time were obtained. As markers of loading fluctuations, the myocardial performance indexes and the velocities of the tricuspid and mitral valve annuli were determined with tissue Doppler imaging. Heart rate was derived from Doppler imaging throughout the assessments. RESULTS: Left ventricular output increased throughout the first minutes after birth (mean (SD) 222.4 (32.5) mL/kg/min before CC vs 239.7 (33.6) mL/kg/min at 5 min, p=0.01), while right ventricular output decreased (306.5 (48.2) mL/kg/min before vs 272.8 (55.5) mL/kg/min immediately after CC, p=0.001). The loading conditions of both ventricles were transiently impaired by CC, recovering at 5 min. Heart rate progressively decreased after birth, following a linear trend temporarily increased by CC. The variation in left ventricular output across the CC was directly correlated to the fluctuation of left ventricular preload over the same period (p=0.03). CONCLUSIONS: This study illustrates the cardiovascular consequences of CC in term vigorous infants and offers insight into the haemodynamic transition from fetal to neonatal circulation in spontaneously breathing newborns. Strategies that aim to enhance left ventricular preload before CC may prevent complications of perinatal cardiovascular imbalance.

Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

BACKGROUND: Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. METHODS: Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). RESULTS: Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. CONCLUSIONS: There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. IMPACT: There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

On the Prevalence and Roles of Proteins Undergoing Liquid-Liquid Phase Separation in the Biogenesis of PML-Bodies.

The formation and function of membrane-less organelles (MLOs) is one of the main driving forces in the molecular life of the cell. These processes are based on the separation of biopolymers into phases regulated by multiple specific and nonspecific inter- and intramolecular interactions. Among the realm of MLOs, a special place is taken by the promyelocytic leukemia nuclear bodies (PML-NBs or PML bodies), which are the intranuclear compartments involved in the regulation of cellular metabolism, transcription, the maintenance of genome stability, responses to viral infection, apoptosis, and tumor suppression. According to the accepted models, specific interactions, such as SUMO/SIM, the formation of disulfide bonds, etc., play a decisive role in the biogenesis of PML bodies. In this work, a number of bioinformatics approaches were used to study proteins found in the proteome of PML bodies for their tendency for spontaneous liquid-liquid phase separation (LLPS), which is usually caused by weak nonspecific interactions. A total of 205 proteins found in PML bodies have been identified. It has been suggested that UBC9, P53, HIPK2, and SUMO1 can be considered as the scaffold proteins of PML bodies. It was shown that more than half of the proteins in the analyzed proteome are capable of spontaneous LLPS, with 85% of the analyzed proteins being intrinsically disordered proteins (IDPs) and the remaining 15% being proteins with intrinsically disordered protein regions (IDPRs). About 44% of all proteins analyzed in this study contain SUMO binding sites and can potentially be SUMOylated. These data suggest that weak nonspecific interactions play a significantly larger role in the formation and biogenesis of PML bodies than previously expected.

Neurodevelopmental outcome of low-risk moderate to late preterm infants at 18 months.

Background: Of the 15 million preterm births that occur worldwide each year, approximately 80% occur between 32 and 36 + 6 weeks gestational age (GA) and are defined as moderate to late preterm (MLP) infants. This percentage substantiates a need for a better understanding of the neurodevelopmental outcome of this group. Aim: To describe neurodevelopmental outcome at 18 months in a cohort of healthy low-risk MLP infants admitted to the neonatal unit at birth and to compare the neurodevelopmental outcome to that of a healthy term-born infant group. Study design and method: This single-centre observational study compared the neurodevelopmental outcome of healthy MLP infants to a group of healthy term control (TC) infants recruited during the same period using the Griffith's III assessment at 18 months. Results: Seventy-five MLP infants and 92 TC infants were included. MLP infants scored significantly lower in the subscales: Eye-hand coordination (C), Personal, Social and Emotional Development (D), Gross Motor Development (E) and General Developmental (GD) (p < 0.001 for each) and Foundations of Learning (A), (p = 0.004) in comparison to the TC infant group with Cohen's d effect sizes ranging from 0.460 to 0.665. There was no statistically significant difference in mean scores achieved in subscale B: Language and Communication between groups (p = 0.107). Conclusion: MLP infants are at risk of suboptimal neurodevelopmental outcomes. Greater surveillance of the neurodevelopmental trajectory of this group of at-risk preterm infants is required.

Sharing and Reusing Computable Phenotype Definitions.

Background: A scalable approach for the sharing and reuse of human-readable and computer-executable phenotype definitions can facilitate the reuse of electronic health records for cohort identification and research studies. Description: We developed a tool called Sharephe for the Informatics for Integrating Biology and the Bedside (i2b2) platform. Sharephe consists of a plugin for i2b2 and a cloud-based searchable repository of computable phenotypes, has the functionality to import to and export from the repository, and has the ability to link to supporting metadata. Discussion: The i2b2 platform enables researchers to create, evaluate, and implement phenotypes without knowing complex query languages. In an initial evaluation, two sites on the Evolve to Next-Gen ACT (ENACT) network used Sharephe to successfully create, share, and reuse phenotypes. Conclusion: The combination of a cloud-based computable repository and an i2b2 plugin for accessing the repository enables investigators to store and retrieve phenotypes from anywhere and at any time and to collaborate across sites in a research network.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Background: Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. Methods and results: In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. Conclusions: These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.