Hyperopia in schoolchildren: Investigating the impact on vision and determining appropriate methods for screening.

INTRODUCTION: Hyperopia is associated with reduced vision and educational outcomes in schoolchildren. This study explored the impact of clinically significant hyperopia (≥+2.00 D) on visual function in schoolchildren and compared the ability of different screening tests (alone and in combination) to detect this level of hyperopia. METHODS: Vision testing including monocular logMAR visual acuity (VA) measured to threshold (distance [DVA], near [NVA] and DVA through a plus lens [+2.50 D]), stereoacuity and cycloplegic autorefraction (tropicamide 1%) were undertaken on 263 schoolchildren (mean age: 11.76 years ± 3.38) in Queensland, Australia. Vision measures were compared between children with clinically significant hyperopia in at least one meridian (≥+2.00 D) and emmetropia/low hyperopia (>0.00 and <+2.00 D). Receiver operating curve (ROC) analysis was performed to identify optimal pass/fail criteria for each test and the diagnostic accuracy of individual and combinations of tests. RESULTS: Thirty-two children had clinically significant hyperopia and 225 had emmetropia/low hyperopia. DVA and NVA were worse (p < 0.01), while the difference in DVA through a plus lens was less in children with clinically significant hyperopia (p < 0.01). ROC analysis for individual tests resulted in areas under the curve (AUCs) ranging from 0.65 to 0.85. Combining screening tests revealed that failing one or more of the following tests was most effective for detecting hyperopia: DVA, NVA and difference in DVA through a plus lens, resulting in a sensitivity and specificity of 72% and 81%, respectively. CONCLUSION: Significant differences in visual function existed between schoolchildren with clinically significant hyperopia and emmetropia/low hyperopia. Combining measures of DVA and NVA and the difference in DVA through a plus lens demonstrated good discriminative ability for detecting clinically significant hyperopia in this population.

Assessment of optical quality of ready-made reading spectacles for presbyopic correction.

PURPOSE: Many presbyopic patients in both developed and developing countries use ready-made reading spectacles for their near vision correction even though the quality of these spectacles cannot always be assured. This study assessed the optical quality of ready-made reading spectacles for presbyopic correction in comparison with relevant international standards. METHODS: A total of 105 ready-made reading spectacles with powers ranging from +1.50 to +3.50 dioptres (D) in +0.50 D steps were randomly procured from open markets in Ghana and assessed for their optical quality, including induced prisms and safety markings. These assessments were done in line with the International Organization for Standardization (ISO 16034:2002 [BS EN 14139:2010]) as well as the standards used in low-resource countries. RESULTS: All lenses (100%) had significant induced horizontal prism that exceeded the tolerance levels stipulated by the ISO standards, while 30% had vertical prism greater than the specified tolerances. The highest prevalence of induced vertical prism was seen in the +2.50 and +3.50 D lenses (48% and 43%, respectively). When compared with less conservative standards, as suggested for use in low-resource countries, the prevalence of induced horizontal and vertical prism reduced to 88% and 14%, respectively. While only 15% of spectacles had a labelled centration distance, none had any safety markings per the ISO standards. CONCLUSION: The high prevalence of ready-made reading spectacles in Ghana that fail to meet optical quality standards indicates the need for more robust, rigorous and standardised protocols for assessing their optical quality before they are sold on the market. This will alleviate unwanted side effects including asthenopia associated with their use. There is also the need to intensify public health awareness on the use of ready-made reading spectacles, especially by patients with significant refractive errors and ocular pathologies.

A case-comparison study of pregnant women with mitochondrial disease - what to expect?

OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.

Metabolic features of chronic fatigue syndrome.

More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21-67 y). Females were 52 (±2.5) y old (range, 20-67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females. We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84-100%] in males using eight metabolites and 96% (95% CI, 86-100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

Early growth and development impairments in patients with ganglioside GM3 synthase deficiency.

Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GSD) causes a complete absence of GM3 and all downstream biosynthetic derivatives. The individuals affected by this disorder manifest severe irritability, intractable seizures and profound intellectual disability. However, we have found that most newborns seem symptom-free for a period of time after birth. In order to further understand the onset of the disease, we investigated the early growth and development of patients with this condition through this study. We compared 37 affected individuals with their normal siblings and revealed that all children with GSD had relatively normal intrauterine growth and development, as their weight, length and head circumference were similar to their normal siblings at birth. However, the disease progresses quickly after birth and causes significant constitutional impairments of growth and development by 6 months of age. Neither breastfeeding nor gastrostomy tube placement made significant difference on growth and development as all groups of patients showed the similar pattern. We conclude that GSD causes significant postnatal growth and developmental impairments and the amount of gangliosides in breast milk and general nutritional intervention do not seem to alter these outcomes.

Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families.

Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases) revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone). In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1) on chromosome 1. We observed 18 large-scale (>1 kb on average) deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10(-6) structural variants per base pair per generation). Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0-9.7×10(-9) mutations per base pair per generation), we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum evolves to evade control efforts within both the individual hosts and large populations.

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design.

Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein's ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential pan-protozoan drug target.

Experimentally induced blood-stage Plasmodium vivax infection in healthy volunteers.

BACKGROUND: Major impediments to development of vaccines and drugs for Plasmodium vivax malaria are the inability to culture this species and the extreme difficulty in undertaking clinical research by experimental infection. METHODS: A parasite bank was collected from a 49-year-old woman with P. vivax infection, characterized, and used in an experimental infection study. RESULTS: The donor made a full recovery from malaria after collection of a parasite bank, which tested negative for agents screened for in blood donations. DNA sequence analysis of the isolate indicated that it was clonal. Two subjects inoculated with the isolate became polymerase chain reaction positive on days 8 and 9, with onset of symptoms and positive blood smears on day 14, when they were treated with artemether-lumefantrine, with rapid clinical and parasitologic response. Transcripts of the parasite gene pvs25 that is expressed in gametocytes, the life cycle stage infectious to mosquitoes, were first detected on days 11 and 12. CONCLUSIONS: This experimental system results in in vivo parasite growth, probably infectious to mosquitoes. It offers the opportunity to undertake studies previously impossible in P. vivax that will facilitate a better understanding of the pathology of vivax malaria and development of antimalarial drugs and vaccines. Trial Registration. ANZCTR: 12612001096842.

Genetic analysis of primaquine tolerance in a patient with relapsing vivax malaria.

Patients with Plasmodium vivax malaria are treated with primaquine to prevent relapse infections. We report primaquine failure in a patient with 3 relapses without any possibility of re-infection. Using whole genome sequencing of the relapsing parasite isolates, we identified single nucleotide variants as candidate molecular markers of resistance.

Whole-genome sequencing and microarray analysis of ex vivo Plasmodium vivax reveal selective pressure on putative drug resistance genes.

Plasmodium vivax causes 25-40% of malaria cases worldwide, yet research on this human malaria parasite has been neglected. Nevertheless, the recent publication of the P. vivax reference genome now allows genomics and systems biology approaches to be applied to this pathogen. We show here that whole-genome analysis of the parasite can be achieved directly from ex vivo-isolated parasites, without the need for in vitro propagation. A single isolate of P. vivax obtained from a febrile patient with clinical malaria from Peru was subjected to whole-genome sequencing (30× coverage). This analysis revealed over 18,261 single-nucleotide polymorphisms (SNPs), 6,257 of which were further validated using a tiling microarray. Within core chromosomal genes we find that one SNP per every 985 bases of coding sequence distinguishes this recent Peruvian isolate, designated IQ07, from the reference Salvador I strain obtained in 1972. This full-genome sequence of an uncultured P. vivax isolate shows that the same regions with low numbers of aligned sequencing reads are also highly variable by genomic microarray analysis. Finally, we show that the genes containing the largest ratio of nonsynonymous-to-synonymous SNPs include two AP2 transcription factors and the P. vivax multidrug resistance-associated protein (PvMRP1), an ABC transporter shown to be associated with quinoline and antifolate tolerance in Plasmodium falciparum. This analysis provides a data set for comparative analysis with important potential for identifying markers for global parasite diversity and drug resistance mapping studies.

Whole genome sequencing analysis of Plasmodium vivax using whole genome capture.

BACKGROUND: Malaria caused by Plasmodium vivax is an experimentally neglected severe disease with a substantial burden on human health. Because of technical limitations, little is known about the biology of this important human pathogen. Whole genome analysis methods on patient-derived material are thus likely to have a substantial impact on our understanding of P. vivax pathogenesis and epidemiology. For example, it will allow study of the evolution and population biology of the parasite, allow parasite transmission patterns to be characterized, and may facilitate the identification of new drug resistance genes. Because parasitemias are typically low and the parasite cannot be readily cultured, on-site leukocyte depletion of blood samples is typically needed to remove human DNA that may be 1000X more abundant than parasite DNA. These features have precluded the analysis of archived blood samples and require the presence of laboratories in close proximity to the collection of field samples for optimal pre-cryopreservation sample preparation. RESULTS: Here we show that in-solution hybridization capture can be used to extract P. vivax DNA from human contaminating DNA in the laboratory without the need for on-site leukocyte filtration. Using a whole genome capture method, we were able to enrich P. vivax DNA from bulk genomic DNA from less than 0.5% to a median of 55% (range 20%-80%). This level of enrichment allows for efficient analysis of the samples by whole genome sequencing and does not introduce any gross biases into the data. With this method, we obtained greater than 5X coverage across 93% of the P. vivax genome for four P. vivax strains from Iquitos, Peru, which is similar to our results using leukocyte filtration (greater than 5X coverage across 96% ). CONCLUSION: The whole genome capture technique will enable more efficient whole genome analysis of P. vivax from a larger geographic region and from valuable archived sample collections.

Noncoding RNA, antigenic variation, and the virulence genes of Plasmodium falciparum.

Long non-coding RNAs (lncRNA) are being increasingly recognized as important regulators of gene expression. A recent paper in Genome Biology reports the identification of a lncRNA family in Plasmodium falciparum, the cause of the most deadly form of malaria, that may help to explain the mechanism of antigenic variation in virulence genes of this important pathogen.

Building Critical Infrastructures: Evaluating the Roles of Governance and Institutions in Infrastructural Developments in Sub-Sahara African Countries.

BACKGROUND: The Sub-Saharan African (SSA) region has notably been in the limelight of infrastructural deficit discussions over the decades. Although the region's infrastructural development is gradually improving, the levels and pace of development remain generally poor compared to the rest of the world. OBJECTIVES: This study thus aims to empirically examine the roles of governance and institutions in infrastructural developments in the Sub-Sahara African (SSA) region toward addressing the pressing needs for critical infrastructures for the region. RESEARCH DESIGNS: The empirical strategies utilized in the study include the Common Correlated Efficient Mean Group (CCEMG) and Dynamic CCEMG methods among others. These empirical approaches were applied to analyze data on governance and institutional quality proxies for the SSA region to achieve the study's objectives while controlling for the effects of industrial value-added, foreign capital inflow (FDI), and overall economic growth for the understudied period (1990-2019). RESULTS: The results reflect the essence of governance and institutional quality as these variables significantly boost infrastructural development in SSA. In addition, industrialization and growth also show a favorable impact on the development of infrastructure thus reflecting that the transition from agrarian to industrial economies occurs in parallel with infrastructure development in the SSA. However, FDI inflows were not found to be significantly instrumental to infrastructural development in the region. CONCLUSIONS: Hence, the SSA must strive to strengthen institutions and harmonize their industrial and economic push with infrastructural developments while encouraging potential foreign investors to diversify investments to infrastructural projects beyond the usual primary sector/resource-based activities.

Toward the Fourth Industrial Revolution among E7 Economies: Assessment of the Combined Impact of Institutional Quality, Bank Funding, and Foreign Direct Investment.

Technological innovation and its paradigm, that is, the Fourth Industrial Revolution-4IR, have shown strong impact on income levels of adopters across the globe. To this end, this analysis examines the impact of bank funding and institutional quality on technological advancement. This study adds additional variables such as high-technology exports and foreign direct investment (FDI) as control variable. Our study period spans from 2000 to 2018 on an annual frequency for E7 economies (Brazil, Indonesia, Mexico, India, Turkey, Russia, and China). This study leverages on cross-sectional ARDL, Augmented Mean Group (AMG), and Common Correlated Effects Mean Group Estimates (CCEMG) estimation techniques to examine long-run relationship between the outlined variables. Empirical findings show that institution quality, bank finance, income, high-technology exports, and foreign direct investments exert a positive effect on advancements in technology. Furthermore, the interaction between bank finance and institution quality on technological advancement is also positive and statistically significant. Based on the findings, it is concluded that large-scale funding is crucial for businesses to leverage revolutionary technology. Likewise, access to large capital sources if made easier encourages technology affordance as well as innovation and operational excellence. Thus, economies with established legal and financial systems stand to offer businesses such security, which encourages business innovation. Consequently, E7 economies ought to improve their financial and legal systems to boost financial security, creativity, and competitiveness of businesses.

Environmental influences on Adelie penguin breeding schedules, endocrinology, and chick survival.

To understand how the social and physical environment influences behaviour, reproduction and survival, studies of underlying hormonal processes are crucial; in particular, interactions between stress and reproductive responses may have critical influences on breeding schedules. Several authors have examined the timing of breeding in relation to environmental stimuli, while others have independently described endocrine profiles. However, few studies have simultaneously measured endocrine profiles, breeding behaviour, and offspring survival across seasons. We measured sex and stress hormone concentrations (oestrogens, testosterone, and corticosterone), timing of breeding, and chick survival, in Adelie penguins (Pygoscelis adeliae) at two colonies in two different years. Clutch initiation at Cape Bird South (CBS; year 1, ~14,000 pairs) occurred later than at Cape Crozier East (CCE; year 2, ~ 25,000 pairs); however, breeding was more synchronous at CBS. This pattern was probably generated by the persistence of extensive sea ice at CBS (year 1). Higher corticosterone metabolite and lower sex hormone concentrations at CBS correlated with later breeding and lower chick survival compared to at CCE - again, a likely consequence of sea ice conditions. Within colonies, sub-colony size (S, 50-100; M, 200-300; L, 500-600; XL, >1000 pairs) did not influence the onset or synchrony of breeding, chick survival, or hormone concentrations. We showed that the endocrine profiles of breeding Adelie penguins can differ markedly between years and/or colonies, and that combining measures of endocrinology, behaviour, and offspring survival can reveal the mechanisms and consequences that different environmental conditions can have on breeding ecology.

Hydroxocobalamin Administration After Inhalation Injury Is Not Associated With Mesenteric Ischemia.

Hydroxocobalamin has been administered in the United States since 2006 by first responders and burn centers as a safe antidote for cyanide toxicity, a serious complication of smoke inhalation. There are no current contraindications to the use of this rescue measure. A recent retrospective French publication reported a potential correlation between hydroxcobalamin administration and acute mesenteric ischemia (AMI) in critically ill burn and inhalation injury patients. The purpose of this study is to characterize the risk of AMI related to hydroxocobalamin. A retrospective review of hydroxocobalamin administration among adult burn patients was conducted at a regional burn center over a 2-year period. Injury characteristics, demographics, and outcomes including presence of mesenteric ischemia (defined as presence of pneumatosis or perforation on CT scan or necrotic bowel on laparotomy) were recorded. Of 17 confirmed inhalation injuries, patients had a median (interquartile range) age, total body surface area (TBSA), and abbreviated burn severity (ABSI) index as follows: 60 (45, 65 IQR), 8.5 (1.8, 39 IQR), and 6 (5,7 IQR). Inhalation injury was diagnosed with bronchoscopy, carboxyhemoglobin, or clinical suspicion. Eighty-two percent of those with bronchoscopy had an inhalation grade of 2 or greater. None (0%) of the patients showed signs of mesenteric ischemia, tube feeding intolerance, pneumatosis/perforation on CT, or necrotic bowel on laparotomy. Aware of the study limitations, we conclude that hydroxocobalamin does not increase risk for AMI.

L'hydroxocobalamine (OHB12), antidote peu dangereux en cas d'intoxication cyanhydrique (complication grave de l'inhalation de fumées), est administrée depuis 2006 par les premiers secours étatsuniens. Il n'existe actuellement pas de contre- indication à son utilisation. Une étude rétrospective française récente a rapporté la possible association entre OHB12 et ischémie mésentérique (IM) chez des brûlés graves ayant inhalé des fumées. Cette étude se propose d'étudier cette éventuelle corrélation. Il s'agit d'une étude rétrospective conduite pendant 2 ans dans un CTB régional. Les caractéristiques démographiques, celles de la brûlure et l'évolution (en recherchant particulièrement une IM) ont été relevées. Le diagnostic d'IM était posé devant des images scannographiques évocatrices (pneumopéritoine, perforation digestive) ou la constatation per- opératoire d'une nécrose digestive. Dix- sept patients avaient une inhalation de fumées confirmée par endoscopie (dans ce cas, 87% des patients avec inhalation de fumées avaient des lésions de grade 2 ou plus) ou carboxyhémoglobine ou simple suspicion clinique. Leur âge médian était de 65 ans (Q1: 45, Q3 : 35), leur surface brûlés de 8,5% (Q1: 1,8, Q3 : 39), leur ABSI de 6 (Q1 : 5 ; Q3 : 7). Aucun patient n'a développé une IM ni une intolérance digestive. Bien que cette étude ait des limitations, nous concluons que OHB12 n'est pas un facteur de risque d'IM.

How do trade and economic growth impact environmental degradation? New evidence and policy implications from the ARDL approach.

Due to various environmental degradation and natural resource depletion around the world, researchers' and policymakers' attention has turned to what causes environmental degradation. The pursuit of a healthy environment has become a global challenge, a problem that affects more than one nation. Climate change is causing severe weather conditions in every world, disrupting economies and affecting the lives of many people. Hence, the study analyzes how trade and economic growth impact environmental degradation in Belgium, the USA, and Canada using panel data from 1995 to 2016. The study utilized the autoregressive distributed lag approach to provide new evidence and policy implications. The outcome confirmed the presence of cointegration among the selected variables. However, it was observed that economic growth decreases environmental degradation in the long run while trade openness shows a positively insignificant relationship with carbon emission. Nevertheless, a positive short-run relationship was observed between economic growth and carbon emissions whereas a negatively insignificant relationship was observed for trade and carbon emission. The findings prompted policy implications that more trading could be done between the countries. When countries trade more, their economies will flourish, ensuring global prosperity and minimizing environmental degradation.

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence.

Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69-1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.