Summary The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia ...and loss of the maternal–fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development.
Various species of the intestinal microbiota have been associated with the development of colorectal cancer
, but it has not been demonstrated that bacteria have a direct role in the occurrence of ...oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin
. This compound is believed to alkylate DNA on adenine residues
and induces double-strand breaks in cultured cells
. Here we expose human intestinal organoids to genotoxic pks
E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
Background
Stillbirth is a global health problem. The World Health Organization (WHO) application of the International Classification of Diseases for perinatal mortality (ICD‐PM) aims to improve data ...on stillbirth to enable prevention.
Objectives
To identify globally reported causes of stillbirth, classification systems, and alignment with the ICD‐PM.
Search strategy
We searched CINAHL, EMBASE, Medline, Global Health, and Pubmed from 2009 to 2016.
Selection criteria
Reports of stillbirth causes in unselective cohorts.
Data collection and analysis
Pooled estimates of causes were derived for country representative reports. Systems and causes were assessed for alignment with the ICD‐PM. Data are presented by income setting (low, middle, and high income countries; LIC, MIC, HIC).
Main results
Eighty‐five reports from 50 countries (489 089 stillbirths) were included. The most frequent categories were Unexplained, Antepartum haemorrhage, and Other (all settings); Infection and Hypoxic peripartum (LIC), and Placental (MIC, HIC). Overall report quality was low. Only one classification system fully aligned with ICD‐PM. All stillbirth causes mapped to ICD‐PM. In a subset from HIC, mapping obscured major causes.
Conclusions
There is a paucity of quality information on causes of stillbirth globally. Improving investigation of stillbirths and standardisation of audit and classification is urgently needed and should be achievable in all well‐resourced settings. Implementation of the WHO Perinatal Mortality Audit and Review guide is needed, particularly across high burden settings.
Funding
HR, SH, SHL, and AW were supported by an NHMRC‐CRE grant (APP1116640). VF was funded by an NHMRC‐CDF (APP1123611).
Tweetable
Urgent need to improve data on causes of stillbirths across all settings to meet global targets.
Plain Language Summary
Background and methods
Nearly three million babies are stillborn every year. These deaths have deep and long‐lasting effects on parents, healthcare providers, and the society. One of the major challenges to preventing stillbirths is the lack of information about why they happen. In this study, we collected reports on the causes of stillbirth from high‐, middle‐, and low‐income countries to: (1) Understand the causes of stillbirth, and (2) Understand how to improve reporting of stillbirths.
Findings
We found 85 reports from 50 different countries. The information available from the reports was inconsistent and often of poor quality, so it was hard to get a clear picture about what are the causes of stillbirth across the world. Many different definitions of stillbirth were used. There was also wide variation in what investigations of the mother and baby were undertaken to identify the cause of stillbirth. Stillbirths in all income settings (low‐, middle‐, and high‐income countries) were most frequently reported as Unexplained, Other, and Haemorrhage (bleeding). Unexplained and Other are not helpful in understanding why a baby was stillborn. In low‐income countries, stillbirths were often attributed to Infection and Complications during labour and birth. In middle‐ and high‐income countries, stillbirths were often reported as Placental complications.
Limitations
We may have missed some reports as searches were carried out in English only. The available reports were of poor quality.
Implications
Many countries, particularly those where the majority of stillbirths occur, do not report any information about these deaths. Where there are reports, the quality is often poor. It is important to improve the investigation and reporting of stillbirth using a standardised system so that policy makers and healthcare workers can develop effective stillbirth prevention programs. All stillbirths should be investigated and reported in line with the World Health Organization standards.
Tweetable
Urgent need to improve data on causes of stillbirths across all settings to meet global targets.
Divine machines Smith, Justin E. H
2011., 20110411, 2011, 2011-04-11
eBook
Though it did not yet exist as a discrete field of scientific inquiry, biology was at the heart of many of the most important debates in seventeenth-century philosophy. Nowhere is this more apparent ...than in the work of G. W. Leibniz. In Divine Machines, Justin Smith offers the first in-depth examination of Leibniz's deep and complex engagement with the empirical life sciences of his day, in areas as diverse as medicine, physiology, taxonomy, generation theory, and paleontology. He shows how these wide-ranging pursuits were not only central to Leibniz's philosophical interests, but often provided the insights that led to some of his best-known philosophical doctrines.
Selenium species, particularly the oxyanions selenite (SeO3 (2-)) and selenate (SeO4 (2-)), are significant pollutants in the environment that leach from rocks and are released by anthropogenic ...activities. Selenium is also an essential micronutrient for organisms across the tree of life, including microorganisms and human beings, particularly because of its presence in the 21st genetically encoded amino acid, selenocysteine. Environmental microorganisms are known to be capable of a range of transformations of selenium species, including reduction, methylation, oxidation, and demethylation. Assimilatory reduction of selenium species is necessary for the synthesis of selenoproteins. Dissimilatory reduction of selenate is known to support the anaerobic respiration of a number of microorganisms, and the dissimilatory reduction of soluble selenate and selenite to nanoparticulate elemental selenium greatly reduces the toxicity and bioavailability of selenium and has a major role in bioremediation and potentially in the production of selenium nanospheres for technological applications. Also, microbial methylation after reduction of Se oxyanions is another potentially effective detoxification process if limitations with low reaction rates and capture of the volatile methylated selenium species can be overcome. This review discusses microbial transformations of different forms of Se in an environmental context, with special emphasis on bioremediation of Se pollution.
We present NASA Van Allen Probes observations of wave‐particle interactions between magnetospheric ultra‐low frequency (ULF) waves and energetic electrons (20–500 keV) on 31 October 2012. The ULF ...waves are identified as the fundamental poloidal mode oscillation and are excited following an interplanetary shock impact on the magnetosphere. Large amplitude modulations in energetic electron flux are observed at the same period (≈ 3 min) as the ULF waves and are consistent with a drift‐resonant interaction. The azimuthal mode number of the interacting wave is estimated from the electron measurements to be ~40, based on an assumed symmetric drift resonance. The drift‐resonant interaction is observed to be localized and occur over 5–6 wave cycles, demonstrating peak electron flux modulations at energies ~60 keV. Our observation clearly shows electron drift resonance with the fundamental poloidal mode, the energy dependence of the amplitude and phase of the electron flux modulations providing strong evidence for such an interaction. Significantly, the observation highlights the importance of localized wave‐particle interactions for understanding energetic particle dynamics in the inner magnetosphere, through the intermediary of ULF waves.
Key Points
First conclusive evidence of electron drift‐resonance with poloidal ULF waves.
First to show the energy dependence to the amplitude/phase expected from theory.
Observation shows the drift‐resonant interaction occurs over a localized region.
Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals ...integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP (also known as GRLF1), controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors, TFII-I (also known as GTF2I) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (also known as KDR). Moreover, this new angiogenesis signalling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is, to our knowledge, the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.
IMPORTANCE: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). OBJECTIVE: To ...determine whether enteral supplementation with fatty acids from birth to 40 weeks’ postmenstrual age reduces ROP in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks’ gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. INTERVENTIONS: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks’ postmenstrual age. MAIN OUTCOMES AND MEASURES: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. RESULTS: A total of 101 infants (58 boys 57.4%; mean SD gestational age, 25.5 1.5 weeks) were included in the AA:DHA group, and 105 infants (59 boys 56.2%; mean SD gestational age, 25.5 1.4 weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 15.8% in the AA:DHA group vs 35 of 105 33.3% in the control group; adjusted relative risk, 0.50 95% CI, 0.28-0.91; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% 95% CI, 0.46-1.18 mol%; P < .001; overall mean difference in control group, 0.13 mol% 95% CI, 0.01-0.24 mol%; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 47.5% vs 48 of 105 45.7%) and of any grade of intraventricular hemorrhage (43 of 101 42.6% vs 42 of 105 40.0%). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. CONCLUSIONS AND RELEVANCE: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03201588
Aims/hypothesis
Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the ...vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR.
Methods
We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27–80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration.
Results
We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (
p
= 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (
p
= 0.0024).
Conclusions/interpretation
These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR.
Graphical abstract
PDF
