Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

MitoScape: A big-data, machine-learning platform for obtaining mitochondrial DNA from next-generation sequencing data.

The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics.

Stimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid ß-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.

Pioglitazone and Deoxyribonucleoside Combination Treatment Increases Mitochondrial Respiratory Capacity in m.3243A>G MELAS Cybrid Cells.

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.

Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly.

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) must be assembled precisely from 45 protein subunits for it to function correctly. One of its mitochondrial DNA (mtDNA) encoded subunits, ND1, is incorporated during the early stages of complex I assembly. However, little is known about how mutations in ND1 affect this assembly process. We found that in human 143B cybrid cells carrying a homoplasmic MT-ND1 mutation, ND1 protein could not be translated. As a result, the early stages of complex I assembly were disrupted, with mature complex I undetectable and complex I-linked respiration severely reduced to 2.0% of control levels. Interestingly, complex IV (ferrocytochrome c:oxygen oxidoreductase) steady-state levels were also reduced to 40.3%, possibly due to its diminished stability in the absence of respiratory supercomplex formation. This was in comparison with 143B cybrid controls (that contained wild-type mtDNA on the same nuclear background), which exhibited normal complex I, complex IV, and supercomplex assembly. We conclude that the loss of ND1 stalls complex I assembly during the early stages of its biogenesis, which not only results in the loss of mature complex I but also disrupts the stability of complex IV and the respiratory supercomplex to cause mitochondrial dysfunction.-Lim, S. C., Hroudová, J., Van Bergen, N. J., Lopez Sanchez, M. I. G., Trounce, I. A., McKenzie, M. Loss of mitochondrial DNA-encoded protein ND1 results in disruption of complex I biogenesis during early stages of assembly.

Clinical profile, management and outcomes of patients with cardiogenic shock undergoing transfer between centers in Spain.

INTRODUCTION AND OBJECTIVES: The aim of this study was to analyze the clinical profile, management, and prognosis of ST segment elevation myocardial infarction-related cardiogenic shock (STEMI-CS) requiring interhospital transfer, as well as the prognostic impact of structural variables of the treating centers in this setting. METHODS: This study included patients with STEMI-CS treated at revascularization-capable centers from 2016 to 2020. The patients were divided into the following groups: group A: patients attended throughout their admission at hospitals with interventional cardiology without cardiac surgery; group B: patients treated at hospitals with interventional cardiology and cardiac surgery; and group C: patients transferred to centers with interventional cardiology and cardiac surgery. We analyzed the association between the volume of STEMI-CS cases treated, the availability of cardiac intensive care units (CICU), and heart transplant with hospital mortality. RESULTS: A total of 4189 episodes were included: 1389 (33.2%) from group A, 2627 from group B (62.7%), and 173 from group C (4.1%). Transferred patients were younger, had a higher cardiovascular risk, and more commonly underwent revascularization, mechanical circulatory support, and heart transplant during hospitalization (P<.001). The crude mortality rate was lower in transferred patients (46.2% vs 60.3% in group A and 54.4% in group B, (P<.001)). Lower mortality was associated with a higher volume of care and CICU availability (OR, 0.75, P=.009; and 0.80, P=.047). CONCLUSIONS: The proportion of transfers in patients with STEMI-CS in our setting is low. Transferred patients were younger and underwent more invasive procedures. Mortality was lower among patients transferred to centers with a higher volume of STEMI-CS cases and CICU.

Impact of shock aetiology and hospital characteristics on the clinical profile, management and prognosis of patients with non ACS-related cardiogenic shock.

BACKGROUND: A significant proportion of cases of cardiogenic shock (CS) are due aetiologies other than acute coronary syndromes (non ACS-CS). We assessed differences regarding clinical profile, management, and prognosis according to the cause of CS among nonselected patients with CS from a large nationwide database. METHODS: We performed an observational study including patients admitted from the hospitals of the Spanish National Health System (SNHS) with a principal or secondary diagnosis code of CS (2016-2019). Data were obtained from the Minimum Basic Data Set (MBDS). Hospitals were classified according to the availability of cardiology related resources, as well as the availability of Intensive Cardiac Care Unit (ICCU). RESULTS: A total of 10,826 episodes of CS were included, of whom 5,495 (50.8%) were non-ACS related. Non ACS-CS patients were younger (71.5 vs. 72.4 years) and had a lower burden of arteriosclerosis-related comorbidities. Non ACS-CS cases underwent less often invasive procedures and presented lower in-hospital mortality (57.1% vs. 61%,p < 0.001). The most common main diagnosis among non ACS-CS was acute decompensation of chronic heart failure (ADCHF) (35.4%). A lower risk-adjusted in-hospital mortality rate was observed in high volume hospitals (52.6% vs. 56.7%; p < 0.001), as well as in centers with ICCU (OR: 0.71; CI 95%: 0.58-0.87; p < 0.001). CONCLUSIONS: More than a half of cases of CS were due to non-ACS causes. Non ACS-CS cases are a very heterogeneous group, with different clinical profile and management. Management at high-volume hospitals and availability of ICCU were associated with lower risk adjusted mortality among non ACS-CS patients.

Impact of annual volume of cases and intensive cardiac care unit availability on mortality of patients with acute myocardial infarction-related cardiogenic shock treated at revascularization capable centres.

AIMS: Cardiogenic shock (CS) is associated with high mortality. The purpose of this study was to assess the impact of hospital structure-related variables on mortality in patients with CS treated at percutaneous and surgical revascularization capable centres (psRCC) from a large nationwide registry. METHODS AND RESULTS: Retrospective observational study including consecutive patients with main or secondary diagnosis of CS and ST elevation myocardial infarction (STEMI). Patients discharged from Spanish National Healthcare System psRCC were included (2016-20). The association between the volume of CS cases attended by each centre, availability of intensive cardiac care unit (ICCU) and heart transplantation (HT) programmes, and in-hospital mortality was assessed by multilevel logistic regression models. The study population consisted of 3074 CS-STEMI episodes, of whom 1759 (57.2%) occurred in 26 centres with ICCU. A total of 17/44 hospitals (38.6%) were high-volume centres, and 19/44 (43%) centres had HT programmes availability. Treatment at HT centres was not associated with a lower mortality (P = 0.121). Both high volume of cases and ICCU showed a trend to an association with lower mortality in the adjusted model [odds ratio (OR): 0.87 and 0.88, respectively]. The interaction between both variables was significantly protective (OR 0.72; P = 0.024). After propensity score matching, mortality was lower in high-volume hospitals with ICCU (OR 0.79; P = 0.007). CONCLUSION: Most CS-STEMI patients were attended at psRCC with high volume of cases and ICCU available. The combination of high volume and ICCU availability showed the lowest mortality. These data should be taken into account when designing regional networks for CS management.

Effect of temperature, wetness duration, and planting density on olive anthracnose caused by Colletotrichum spp.

The influence of temperature, wetness duration, and planting density on infection of olive fruit by Colletotrichum acutatum and C. simmondsii was examined in laboratory and field experiments. Detached olive fruit of 'Arbequina', 'Hojiblanca', and 'Picual' were inoculated with conidia of several isolates of the pathogen and kept at constant temperatures of 5 to 35°C in humid chambers. Similarly, potted plants and stem cuttings with fruit were inoculated and subjected to wetness periods of 0 to 48 h. Infection occurred at 10 to 25°C, and disease severity was greater and the mean latent period was shorter at 17 to 20°C. Overall, C. acutatum was more virulent than C. simmondsii at temperatures <25°C. When temperature was not a limiting factor, disease severity increased with the wetness period from 0 to 48 h. Disease severity was modeled as a function of temperature and wetness duration; two critical fruit incidence thresholds were defined as 5 and 20%, with wetness durations of 1.0 and 12.2 h at the optimum temperature. In the field, anthracnose epidemics progressed faster in a super-high-density planting (1,904 olive trees/ha) than in the high-density plantings (204 to 816 olive trees/ha) and caused severe epidemics in the super-high-density planting even with the moderately resistant Arbequina. Data in this study will be useful for the development of a forecasting system for olive anthracnose epidemics.

Validation of the inverse method for the determination of the access flow with thermodilution. / Validación del método inverso para la determinación del flujo de acceso con termodilución.

INTRODUCTION: Thermodilution is a widely used method for measuring vascular access flow (QA). Among the possibilities of thermodilution, the reverse method (RM) can be beneficial in the execution time, without impact on the dialysis efficacy (Kt). However, it is not a sufficiently studied technique. METHOD: Transversal study of 117 arteriovenous fistulas. Two QA measurements were taken with the method described by the manufacturer (MR) and another with RM. RM is based on the obtention of an inverted recirculation registry at the beginning of the session and a single subsequent recirculation measurement with the lines in normal position. In the concordance analysis, the Bland-Altman method and Cohen's Kappa index were used. RESULTS: Very good concordance between MR and RM was evidenced for QA below 700ml/min, but it worsens as flow increases. The median variability between the MR measurements (intra-method variability) was 3.4% (-17.13). This value did not differ from the median variability generated between MR and RM (inter-method variability), which was 2% (-14,12) (P=.287). The degree of agreement between the 2 to identify arteriovenous fistulas susceptible to intervention was very good (Kappa=0.834). The time spent using the RM was significantly shorter (P=.000) without evidence of variations in the Kt of the measurement sessions (P=.201). CONCLUSIONS: The thermodilution RM is valid to determine the flow of the vascular access, especially in QA lower than 700ml/min, with great time savings, simplification of the procedure and without modifying the dialysis efficiency. The variability between the measurement by MR and RM is similar to that of MR. The concordance between methods in identifying potentially pathological arteriovenous fistulas is very good.

Methylation of Ribosomal RNA: A Mitochondrial Perspective.

Ribosomal RNA (rRNA) from all organisms undergoes post-transcriptional modifications that increase the diversity of its composition and activity. In mitochondria, specialized mitochondrial ribosomes (mitoribosomes) are responsible for the synthesis of 13 oxidative phosphorylation proteins encoded by the mitochondrial genome. Mitoribosomal RNA is also modified, with 10 modifications thus far identified and all corresponding modifying enzymes described. This form of epigenetic regulation of mitochondrial gene expression affects mitoribosome biogenesis and function. Here, we provide an overview on rRNA methylation and highlight critical work that is beginning to elucidate its role in mitochondrial gene expression. Given the similarities between bacterial and mitochondrial ribosomes, we focus on studies involving Escherichia coli and human models. Furthermore, we highlight the use of state-of-the-art technologies, such as cryoEM in the study of rRNA methylation and its biological relevance. Understanding the mechanisms and functional relevance of this process represents an exciting frontier in the RNA biology and mitochondrial fields.

Nuclear response to divergent mitochondrial DNA genotypes modulates the interferon immune response.

Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges.

OXPHOS bioenergetic compensation does not explain disease penetrance in Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study. / Prevalencia de hipertrigliceridemia en adultos y factores cardiometabólicos asociados. Estudio SIMETAP-HTG.

AIM: To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. METHODS: Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was≥150mg/dL (≥1.7mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. RESULTS: The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2mg/dL in global population, 135.7 and 116.0mg/dL in men, and 108.6 and 95.7mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity (OR: 1.9). CONCLUSIONS: The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity.

Amyloid precursor protein-mediated mitochondrial regulation and Alzheimer's disease.

Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non-amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid ß (Aß) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aß. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate mitochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients and the role of full-length APP and its non-amyloidogenic fragments, particularly soluble APPα, on mitochondrial bioenergetic metabolism. We do not review the plethora of animal and in vitro studies using mutant APP/presenilin constructs or experiments using exogenous Aß. In doing so, we aim to invigorate research and discussion around non-amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

[Influence of nutritional status on clinical outcomes in hospitalised children]. / Influencia del estado nutricional en la evolución clínica del niño hospitalizado.

INTRODUCTION: Paediatric malnutrition during hospital admission is a prevalent comorbidity, which it is estimated around 31.4% in our environment, and could influence the clinical outcomes of paediatric patients. OBJECTIVE: The aim of this study was to describe the malnutrition risk in hospitalised children using STAMP (Screening Tool for the Assessment of Malnutrition in Paediatrics), and to study its relationship with clinical outcomes. METHODS: A single-centre, analytical and prospective study was conducted on children aged 1 month to 15 years hospitalised in a tertiary hospital between October and December 2017. An analysis was made of the clinical data and anthropometric measurements (weight, height, Waterlow weight classification). Patients were classified according to STAMP, which is a validated screening tool used to classify the risk of paediatric malnutrition during hospital admission. Multivariate statistical analysis was used to identify predictive variables of illness severity. RESULTS: An analysis was made on a total of 200 patients (55% male), with a median age of 15.8 months (IQR 2.5-42.8), and a median length of stay of 3 days (IQR 1-18 days). Almost half (48.3%) of them had high risk of malnutrition at admission (STAMP ≥4), and 48.2% showed medium risk (STAMP 2-3). A higher STAMP score was associated with longer length of hospital stay (P<.01) and greater severity (P<.01). Multivariable analysis showed that STAMP could be a predictor of illness severity (OR 1.48, 95% CI: 1.18-1.86, P<.01). CONCLUSIONS: Nearly 50% of hospitalised children have a high risk of malnutrition at admission according to the STAMP screening tool. Risk of malnutrition at admission measured according to STAMP nutritional screening was associated with a longer length of stay and greater severity of illness. It is important to evaluate the risk of malnutrition as this could be related to illness severity.

Correction to: Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.

The original version of this article unfortunately contained a mistake in the author name. The family name of Dr. Vanessa A. Johannsen should be written as "Johanssen."

Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.

Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP-/- mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration.

Mitochondrial DNA Variation and Disease Susceptibility in Primary Open-Angle Glaucoma.

Purpose: To determine whether mitochondrial DNA haplogroups or rare variants associate with primary open-angle glaucoma in subjects of European descent. Methods: A case-control comparison of age- and sex-matched cohorts of 90 primary open-angle glaucoma patients and 95 population controls. Full mitochondrial DNA sequences from peripheral blood were generated by next-generation sequencing and compared to the revised Cambridge Reference Sequence to define mitochondrial haplogroups and variants. Results: Most subjects were of the major European haplogroups H, J, K, U, and T. Logistic regression analysis showed haplogroup U to be significantly underrepresented in male primary open-angle glaucoma subjects (odds ratio 0.25; 95% confidence interval [CI] 0.09-0.67; P = 0.007; Bonferroni multiple testing P = 0.022). Variants in the mitochondrial DNA gene MT-ND2 were overrepresented in the control group (P = 0.005; Bonferroni multiple testing correction P = 0.015). Conclusions: Mitochondrial DNA ancestral lineages modulate the risk for primary open-angle glaucoma in populations of European descent. Haplogroup U and rare variants in the mitochondrial DNA-encoded MT-ND2 gene may be protective against primary open-angle glaucoma. Larger studies are warranted to explore haplogroup associations with disease risk in different ethnic groups and define biomarkers of primary open-angle glaucoma endophenotypes to target therapeutic strategies.