Acute and chronic effects of intravitreal bevacizumab on lung biomarkers of angiogenesis in the rat exposed to neonatal intermittent hypoxia.

PURPOSE/AIM: Intravitreal bevacizumab (Avastin) is an irreversible vascular endothelial growth factor (VEGF) inhibitor used to treat severe retinopathy of prematurity (ROP) in extremely low gestational age neonates (ELGANs). ELGANs who are at the highest risk for developing severe ROP often experience brief intermittent hypoxia (IH) episodes which may cause oxidative damage. We tested the hypothesis that intravitreal Avastin leaks into the systemic circulation during exposure to IH and has adverse effects on biomarkers of pulmonary microvascular maturation, thus leading to pulmonary hemorrhage and long-term pulmonary sequelae. METHODS: Neonatal rats at postnatal day (PN) 0 (birth) were exposed to either: 1) hyperoxia (50% O2) or 2) neonatal IH (50% O2 with brief episodes of 12% O2) from PN0 to PN14. Room air (RA) littermates served as controls. At PN14, the time of eye opening in rats, a single dose of Avastin (0.125 mg in 5 µL) was injected into the vitreous cavity of the left eyes. A control group received equivalent volume saline. At PN23 and PN45, blood gases, lung-to-body weight ratios, histology, immunofluorescence, and lung biomarkers of angiogenesis were examined. RESULTS: At PN23, Avastin increased lung VEGF, nitric oxide derivatives (NOx), and hypoxia-inducible factor (HIF)1a in the hyperoxia-exposed groups, but decreased soluble VEGFR-1 (sVEGFR-1). At PN45, lungs from animals exposed to neonatal IH and treated with Avastin were severely hemorrhagic with morphologic changes in lung architecture consistent with chronic lung disease. This was associated with higher VEGF and NOx levels, and lower insulin-like growth factor (IGF)-I and sVEGFR-1. CONCLUSIONS: These findings prove our hypothesis that intravitreal Avastin penetrates the blood-ocular barrier in IH and alters lung biomarkers of angiogenesis. Avastin targeting of VEGF could affect normal lung development which may be exaggerated under pathologic conditions such as IH, ultimately leading to vascular permeability, vessel rupture, and pulmonary hemorrhage.

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model.

Given the complexity of oxygen-induced retinopathy (OIR), we tested the hypothesis that combination therapies and modes of administration would synergistically optimize efficacy for prevention of OIR. Newborn rats were exposed to neonatal intermittent hypoxia (IH) from the first day of life (P0) until P14 during which they received: (1) oral glutathione nanoparticles (nGSH) with topical ocular phosphate buffered saline (PBS); (2) nGSH with topical ocular Acuvail (ACV); (3) oral coenzyme Q10 (CoQ10) + ACV; (4) oral omega 3 polyunsaturated fatty acids (n-3 PUFAs) + ACV; (5) CoQ10 + n-3 PUFAs + PBS; or (6) CoQ10 + n-3 PUFAs + ACV. Treated groups raised in room air (RA) served as controls. At P14, pups were placed in RA with no treatment until P21. Retinal vascular pathology, ocular angiogenesis biomarkers, histopathology, and morphometry were determined. All combination treatments in IH resulted in the most beneficial retinal outcomes consistent with suppression of angiogenesis growth factors during reoxygenation/reperfusion and no significant adverse effects on somatic growth. nGSH + PBS also reversed IH-induced retinopathy, but had negative effects on growth. Simultaneously targeting oxidants, inflammation, and poor growth mitigates the damaging effects of neonatal IH on the developing retina. Therapeutic synergy with combination delivery methods enhance individual attributes and simultaneously target multiple pathways involved in complex diseases such as OIR.

Multiple cause of death analysis in multiple sclerosis: A population-based study.

OBJECTIVE: To gain a better understanding of the complex patterns of causes that contribute to death due to multiple sclerosis (MS) by assessing the relationship between MS and other causes of death listed on death certificates. METHODS: Multiple cause of death data for all adult deaths (aged ≥18 years) in British Columbia, Canada, between 1986 and 2013 were accessed. All causes, as listed on the death certificate, whether underlying or contributing, were considered "any mention" causes. The associations between mention of MS on the death certificate and mention of other causes of death were examined by logistic regression, adjusted for age, sex, and calendar year (Bonferroni-corrected α level = 0.002). Findings were also sex-stratified. RESULTS: Among 771,288 deaths, MS was mentioned on 2,153 certificates. If MS was mentioned (versus not mentioned), there was a greater chance that specific conditions contributed to the death: respiratory infection (adjusted odds ratio [aOR], 3.03 [95% confidence interval (CI), 2.73-3.36]), aspiration pneumonia (aOR, 7.15 [95% CI, 6.23-8.22]), urinary tract infection (UTI) (aOR, 10.2 [95% CI, 8.7-12.0]), other infection including sepsis (aOR, 1.34 [95% CI, 1.15-1.56]), and skin disease (aOR, 5.06 [95% CI, 3.96-6.46]). Sex differences existed for urinary tract infection (men: aOR, 14.9 [95% CI, 11.5-19.3]; women: aOR, 8.00 [95% CI, 6.53-9.81]) and chronic respiratory disease (men = aOR, 1.36 [95% CI, 1.14-1.63]; women = aOR, 0.97 [95% CI, 0.84-1.13]). CONCLUSIONS: Deaths attributed to MS were commonly caused by infection (especially respiratory and urinary tract-related); conditions associated with advanced disability and immobility, such as aspiration pneumonia; and chronic respiratory disease in men. All are potentially modifiable; interventions that reduce the frequency or severity of these complications could improve survival in MS.

Causes that Contribute to the Excess Mortality Risk in Multiple Sclerosis: A Population-Based Study.

BACKGROUND: Lifespan is 6-10 years shorter in multiple sclerosis (MS), but the reasons remain unclear. Using linked clinical- and population-based administrative health databases, we compared cause-specific mortality in an MS cohort to the general population. METHODS: MS patients in British Columbia (BC), Canada, were followed from the later of first MS clinic visit or January 1, 1986, to the earlier of death, emigration, or December 31, 2013. Comprehensive mortality information was obtained by linkage to BC's multiple-cause-of-death mortality data. Causes were grouped using International Classification of Disease codes. Standardized mortality ratios (SMRs) were calculated for underlying cause, and relative mortality ratios (RMRs) for any mention cause, by comparison to mortality rates in the age-, sex-, and calendar year-matched general population. Cause-specific relative mortality was explored by sex and disease course (relapsing onset and primary progressive). RESULTS: Among 6,629 MS patients with 104,236 patient-years of follow-up, 1,416 died. The all-cause mortality risk was increased relative to the general population (SMR 2.71; 95% CI 2.55-2.87). MS was the underlying cause in 50.4%, and a mentioned cause in 77.9%, of deaths. Mortality by underlying cause was higher than expected for genitourinary disorders/infections (SMR 3.55; 95% CI 2.25-5.32), respiratory diseases/infections (SMR 2.69; 95% CI 2.17-3.28), suicide (SMR 2.40; 95% CI 1.61-3.45), cardiovascular disease (SMR 1.57; 95% CI 1.36-1.81), and other infections/septicemia (SMR 1.83; 95% CI 1.15-2.78). Risks of death due to overall cancer, accidents, digestive system disorders, and endocrine/nutritional diseases as underlying causes were similar to the general population. However, mortality with any mention of accidents (RMR 2.71; 95% CI 2.22-3.29) or endocrine/nutritional diseases (RMR 1.75; 95% CI 1.46-2.09) was greater. Bladder cancer mortality was increased in women (SMR 3.87; 95% CI 1.42-8.42) but not men. No notable differences were observed by disease course. CONCLUSIONS: MS itself was the most frequent underlying cause of death. Infections (genitourinary, respiratory, and septicemia), suicides, cardiovascular disease, and accidents contributed significantly to the increased risk of death. Some findings differed by sex, but not disease course. Multiple-cause death data offer advantages over "traditional" use of underlying cause only.

Electronic Health Record-Embedded Decision Support Platform for Morphine Precision Dosing in Neonates.

Morphine is the opioid most commonly used for neonatal pain management. In intravenous form, it is administered as continuous infusions and intermittent injections, mostly based on empirically established protocols. Inadequate pain control in neonates can cause long-term adverse consequences; however, providing appropriate individualized morphine dosing is particularly challenging due to the interplay of rapid natural physiological changes and multiple life-sustaining procedures in patients who cannot describe their symptoms. At most institutions, morphine dosing in neonates is largely carried out as an iterative process using a wide range of starting doses and then titrating to effect based on clinical response and side effects using pain scores and levels of sedation. Our background data show that neonates exhibit large variability in morphine clearance resulting in a wide range of exposures, which are poorly predicted by dose alone. Here, we describe the development and implementation of an electronic health record-integrated, model-informed decision support platform for the precision dosing of morphine in the management of neonatal pain. The platform supports pharmacokinetic model-informed dosing guidance and has functionality to incorporate real-time drug concentration information. The feedback is inserted directly into prescribers' workflows so that they can make data-informed decisions. The expected outcomes are better clinical efficacy and safety with fewer side effects in the neonatal population.

Publisher Correction: The poetry of materials.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intravitreal bevacizumab alters type IV collagenases and exacerbates arrested alveologenesis in the neonatal rat lungs.

Purpose/Aim: Intravitreal bevacizumab (Avastin) is an irreversible vascular endothelial growth factor (VEGF) inhibitor used off-label to treat severe retinopathy of prematurity in extremely low gestational age neonates. VEGF and matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) participate in lung maturation. We tested the hypothesis that intravitreal bevacizumab enters the systemic circulation and has long-lasting effects on lung MMPs. MATERIALS AND METHODS: Neonatal rats were exposed to: (1) hyperoxia (50% O2); (2) intermittent hypoxia (IH) (50% O2 with brief episodes of 12% O2); or (3) room air (RA) from birth (P0) to P14. At P14, the time of eye opening in rats, a single dose of Avastin (0.125 mg) was injected into the vitreous cavity of the left eye. A control group received equivalent volume saline. At P23 and P45, lung MMP-2 and MMP-9, and TIMP-1, and TIMP-2 were assessed in the lungs. RESULTS: At P23, Avastin increased MMP-2, MMP-9, and TIMP-1 levels in the hyperoxia group but decreased TIMP-1 levels in the IH group. The ratios of MMP-2/TIMP-1 and MMP-9/TIMP-1 were significantly elevated at P23 in the IH group treated with Avastin. At P45, the levels of MMP-2 and MMP-9 remained elevated in the hyperoxia and IH groups treated with Avastin, while a rebound increase in TIMP-1 levels was noted in the IH group. CONCLUSIONS: Avastin treatment in IH has lasting alterations in the balance between MMPs and their tissue inhibitors. These changes may lead to impaired alveologenesis and tissue damage consistent with bronchopulmonary dysplasia/chronic lung disease.

Programming function into mechanical forms by directed assembly of silk bulk materials.

We report simple, water-based fabrication methods based on protein self-assembly to generate 3D silk fibroin bulk materials that can be easily hybridized with water-soluble molecules to obtain multiple solid formats with predesigned functions. Controlling self-assembly leads to robust, machinable formats that exhibit thermoplastic behavior consenting material reshaping at the nanoscale, microscale, and macroscale. We illustrate the versatility of the approach by realizing demonstrator devices where large silk monoliths can be generated, polished, and reshaped into functional mechanical components that can be nanopatterned, embed optical function, heated on demand in response to infrared light, or can visualize mechanical failure through colorimetric chemistries embedded in the assembled (bulk) protein matrix. Finally, we show an enzyme-loaded solid mechanical part, illustrating the ability to incorporate biological function within the bulk material with possible utility for sustained release in robust, programmably shapeable mechanical formats.

Risk factors associated with the onset of relapsing-remitting and primary progressive multiple sclerosis: a systematic review.

Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10-15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS.