However, it is unclear whether these benefits are greater in older adults who have an age-related decrease in NO and higher risk of disease. This systematic review examines 12 randomised, crossover, control trials, investigating food-based NO3− supplementation in older adults and its potential benefits on physiological and cognitive performances, and CV, cerebrovascular and metabolic health. Four studies found improvements in physiological performance (time to exhaustion) following dietary NO3− supplementation in older adults. Benefits on cognitive performance were unclear. Six studies reported improvements in CV health (blood pressure and blood flow), while six found no improvement. One study showed improvements in cerebrovascular health and two found no improvement in metabolic health. The current literature indicates positive effects of dietary NO3− supplementation in older adults on physiological performance, with some evidence indicating benefits on cardiovascular and cerebrovascular health. Effects on cognitive performance were mixed and studies on metabolic health indicated no benefit. However, there has been limited research conducted on the effects of dietary NO3− supplementation in older adults, thus, further study, utilising a randomised, double-blind, control trial design, is warranted.Supplementation with nitrate (NO Over the past decade, there has been a decrease in levels of functional activity  and an increase in frailty, in the aging population, alongside increased rates of disease and age-related dysfunction ,2. An in3−). Nitrate is found in high concentrations in green leafy vegetables, such as spinach and rocket, and root vegetables such as beetroot  and [NO2−], and urinary [NO3−] and [NO2−] measures. Seven studies reported both plasma [NO3−] and [NO2−] [2−] [3−] [3−] [3−] and [NO2−] [The 12 studies incorporated various measures to investigate the potential changes in NO concentrations in the body following supplementation with dietary NOd [NO2−] ,17,18,193−] [3−] , and oned [NO2−] . Similard [NO2−] ,14,17,19d [NO2−] ,12,18; od [NO2−] ; one used [NO2−] ; one use3− supplementation resulted in a significant increase in all NO indices (compared to placebo) in all 12 studies. Specifically, increases in plasma [NO3−] ranged from 150% [2−] ranged from 168% [3−] were 283% [2−] was 214% [3−.Despite the different NO indices used between studies, dietary NOrom 150%  to 938% rom 168%  to 503% ere 283% , while t3− supplementation on physiological performance in older adults [3− (7.58 mmol/400 mg NO3−), 2.5 h prior to exercise, significantly improved time to exhaustion during submaximal cycling (p = 0.031) [3− rich beetroot juice (6.1 mmol·day−1/350 mg NO3−) also improved time to exhaustion during submaximal cycling exercise (p = 0.02) [3− rich beetroot juice (9 mmol/500 mg NO3−) improved walking duration prior to onset of pain by 18%, and maximal walking time by 17% in older adults with chronic obstructive pulmonary disease (COPD) [p < 0.05) was shown, following 3 days of supplementation with beetroot juice (9.6 mmol·day−1/550 mg NO3−) [3− rich beetroot juice (12 mmol·day−1/700 mg NO3−) had no effect on O2 consumption, a 10-m walking test, a hand-grip strength test, an up-and-go test, or a repeated chair raising test, in healthy older adults [Five of the 12 studies investigated the effects of dietary NOr adults ,12,13,203− supplementation on cognitive performance in older adults [3− as a cognitive performance aid in older adults consuming a high NO3− diet, including beetroot juice , for 2 days, was shown by an increase in cerebral blood flow to the white matter of the frontal lobe (p < 0.005) [3− rich beetroot juice  in older adults (67.2 ± 4.9 years) with type 2 diabetes, resulted in a significant improvement in simple reaction time, compared to a placebo [3− rich beetroot juice supplementation over 3 days  on cognitive performance, in healthy, older adults (aged 60–70), showed no significant differences in memory, attention and information processing capabilities between the beetroot juice and placebo treatments [Of the 12 studies, only three investigated the effects of dietary NOr adults ,8,14, wir adults ,8. The p3− supplementation on BP in older adults. Five of these studies showed that dietary NO3− supplementation resulted in a significant decrease in systolic blood pressure (SBP) [3− supplementation, compared to a placebo [3− [3− vs. nitrate-depleted PL) in older adults with type 2 diabetes, whereas Kemmner et al. [3− rich beetroot juice  (p = 0.012) [3− supplementation [3− rich beetroot gel (12.2 mmol/700 mg NO3−) in older adults with risk factors of cardiovascular disease has also been reported to significantly improve brachial flow-mediated dilation (FMD) (77%), blood flow velocity (BFV) (31%), and reactive hyperaemia (RH) (18%), thus improving endothelial function [3− rich beetroot juice in older adults with type 2 diabetes had no significant effect on FMD or Doppler perfusion, and thus, did not improve endothelial function [Ten studies investigated the potential benefits of dietary NOre (SBP) ,8,12,13, placebo ,7,8,13. cebo [3− ,18,19,20cebo [3− ,14. Furtcebo [3−  found noentation ,17. Acutfunction . Howeverp = 0.017) following acute supplementation with NO3− rich beetroot juice in older adults with CKD.The study by Kemmner et al.  also rep3− supplementation in older adults [p < 0.005) of older adults following 2 days of a high NO3− diet (including beetroot juice), compared to a diet low in NO3− [Only one study has investigated the potential cerebrovascular health benefits of dietary NOr adults . This st in NO3− .3− supplementation in older adults [3− rich beetroot juice in older adults with type 2 diabetes had no significant effect on insulin sensitivity, measured via the hyperinsulinemic isoglycemic clamp technique [3− rich beetroot juice was also shown to have no significant effect on acute plasma glucose, hepatic blood flow, C-peptide concentration, or incretin concentration (glucagon-like peptide-1 (GLP-1)), in older adults with type 2 diabetes [Of the 12 studies, two investigated various metabolic health parameters following dietary NOr adults ,19. Chroechnique . Further3− supplementation on performance and health-related outcomes in older adults. The current literature indicates positive effects of dietary NO3− supplementation in older adults on physiological performance, with some evidence indicating benefits on cardiovascular and cerebrovascular health. Effects on cognitive performance were mixed and studies on metabolic health indicated no benefit.This systematic review investigated the effects of NO3− supplementation has the potential to improve physiological performance, by prolonging time to exhaustion and increasing the 3− supplementation in exercise performance of healthy, young individuals, who reported a pooled effect size of 0.79 for time to exhaustion trials, with favourable benefits from beetroot juice supplementation.Dietary NOexercise ,12,13, anse time , while onse time . This isnse time  on the e3− rich beetroot juice, during submaximal cycling and walking exercise in older adults with COPD and PAD, respectively [3− depleted beetroot juice as the control. Moreover, Berry et al. [3− and longer absorption periods , while Eggebeen et al. [3−, 1.5–2 h prior to exercise. These reductions in dosage and absorption times could have prevented adequate concentration and/or time for the supplementation to elicit an effect, especially when, in the same study by Eggebeen et al. [3− supplementation. Nevertheless, another study showed no effect of 7 days supplementation (12 mmol·day−1 NO3−) on time to exhaustion during an incremental cycle test [Two studies reported an increase in total exercise capacity following acute supplementation of NOectively ,13. In cectively . The disectively  and oranectively  used a dy et al.  and Kenjn et al.  had partn et al. , while ncle test ; thus, t2 consumption, grip strength, up-and-go test, repeated chair raises, or 10-m walking time. However, upon closer examination of the results there was a trend (p = 0.10) for improved time to exhaustion and an improvement in all tests, following beetroot versus placebo treatment [n = 19). Additionally, the absence of significant differences in this study may have been due to the use of healthy older adults, where the aforementioned studies who showed improvements utilised COPD [3− supplementation [Siervo et al.  also foureatment . This mased COPD , PAD [13sed COPD  patientsentation .3− supplementation may be due to enhanced blood flow to the working muscle, improvements in mitochondrial efficiency, and/or improved muscle contractile function [3− results in a significant reduction in both systolic and diastolic blood pressure in older adults, which is indicative of increased vasodilation and therefore enhanced blood flow [3− rich beetroot juice [The aforementioned improvements in time to fatigue following NOfunction . There iood flow ,8. Kenjaood flow  showed tot juice . Increasot juice .3− rich beetroot juice has been shown to improve mitochondrial efficiency via up-regulation of the protein, adenosine nucleotide translocase (ANT), which is involved in the control of flow of mitochondrial protons, resulting in a reduction in proton leakage and increased efficiency of oxidative phosphorylation [3− supplementation increased the mitochondrial phosphate to oxygen (P/O) ratio (the amount of ATP produced from a given amount of oxygen reduced), thus reducing the amount of O2 required to maintain a given workload and prolonging time to exhaustion [Furthermore, NOrylation . In addihaustion .31P-magnetic resonance spectroscopy to show a decrease in utilisation of skeletal muscle phosphocreatine (PCr), along with a decrease in production of adenosine diphosphate (ADP) and inorganic phosphate (Pi), indicating a reduction in the rate of ATP consumption following consumption of NO3− rich beetroot juice. This effect indicated that supplementation with dietary NO3− (via NO mediated effects) may alter the ATP consumption rates of actomyosin-ATPase and Ca2+-ATPase during muscle contraction [Bailey et al.  used 31Ptraction . Therefotraction .3− supplementation can result in improved blood flow and mitochondrial efficiency, and a reduced rate of ATP utilisation, leading to a prolonged time to exhaustion during submaximal exercise [3− supplementation in older adults.Collectively, the results indicate that dietary NOexercise . It is iexercise ,24,25; h3− rich beetroot juice could have greater benefits on cognitive function in older adults, via its NO mediated increase in CBF [3− supplementation on physiological performance, the effects on cognitive performance in older adults have only just begun to be investigated, thus the effects are less clear [Older adults show reductions in cerebral blood flow (CBF), which may be due to an age-related decrease in the production of NO . This ree in CBF . Howeverss clear .3− supplementation on cognitive performance in older adults [3− rich beetroot juice, 250 mL·day−1, ~7.5 mmol NO3−), in type 2 diabetic, older adults (67.2 ± 4.9 years) [3− supplementation on cognitive performance following 3 days of supplementation with beetroot juice  in healthy, older adults . Specifically, they reported no significant differences in memory, attention and information processing capabilities between beetroot juice and placebo treatments.Only two of the 12 studies directly measured the effects of dietary NOr adults ,8. One s3−; however, these benefits may be specific to certain brain functions, and may be affected by the duration of supplementation as well as participant health status. Nevertheless, with only two studies to draw conclusions from, which provide conflicting results, more research is required to investigate these potential effects.The differences in cognitive performance results seen between these two studies could be attributed to methodological variations, including the duration of supplementation and the cognitive tests used. Gilchrist et al.  used a l3− supplementation in older adults has grown over the past 5 years, with a significant amount of research examining the effects on BP [Investigations into the possible cardiovascular health benefits of NOts on BP ; more rets on BP , changests on BP , and endts on BP  have bec3− increases NO production, which, in turn, has been shown to activate the enzyme, guanylate cyclase, which catalyses the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) [3− supplementation on BP and MAP in older adults. Whilst five of the reviewed studies reported a reduction in SBP [Due to age-related losses in NO production from decreased activity of NOS, older adults are at a higher risk for endothelial dysfunction and cardiovascular disease, of which, high BP and MAP are major risk factors . Suppleme (cGMP) . Cyclic e (cGMP) . Despiten in SBP ,8,12,13,n in SBP ,7,8,13, n in SBP ,18,19,20n in SBP .3− may be more beneficial for reducing BP in older adults with morbidities closely related to an already reduced endothelial function, beyond that of age-related changes. Furthermore, the study by de Oliveira et al. [3−-rich beetroot juice, while still adhering to their antihypertensive medication protocol, suggesting improvements may still be possible with supplementation in conjunction with drug protocols [The reasons for these conflicting results for BP may be due to differences in the health statuses of the participants. Of the five studies that reported a reduction in BP, only one used healthy older adults , while ta et al.  used a sa et al. ,7. This a et al.  investigrotocols .3− supplementation used prune juice [3− depleted beetroot control, so there was potential for a ‘placebo’ effect. Also, as these three studies [3− source, but did not utilise a NO3− depleted beetroot control, it is possible that other bioactive compounds found in beetroot juice  may have contributed to the reduction in BP [3− rich beverage and NO3− depleted beetroot juice (placebo) crossover design have still shown reductions in BP of older adults [3−–NO2−–NO pathway, via the use of mouthwash or spitting of saliva following beetroot juice consumption, has been shown to negate the reductive effects on BP, indicating high concentrations of NO3− as the major contributor to a decreased BP [Alternatively, the conflicting results seen between these studies may have been due to differences in study design. Three of the studies which reported beneficial outcomes on BP in older adults following dietary NOne juice , water [ne juice  and oranne juice  as the pne juice ,18,19,20 studies ,7,13 ution in BP . Howevereased BP . The reaeased BP , or the 3− in older adults has also been proposed to benefit cardiovascular health of older adults through its effects on blood flow and endothelial function [3− rich beetroot gel  [3−, 3 h prior) [3− have been shown to inhibit blood platelet aggregation and reverse or prevent further degradation in endothelial function [3− supplementation plays an important role in maintaining NO homeostasis when endogenous production may be diminished, thus maintaining adequate blood flow and distribution [3− supplementation in older adults with type 2 diabetes, contradicting the aforementioned findings. As mentioned above, a major limitation in the study by Gilchrist et al. [3− would promote further benefits to result in improved endothelial function. Based on this, the lack of improvements in blood flow and endothelial function seen by Gilchrist et al. [In addition to reductions in BP and MAP, supplementation with dietary NOfunction . Two stuh prior)  or juiceh prior)  improvedfunction , which ifunction . Thereforibution . Despiteribution  found not et al.  was the t et al. . Therefot et al.  are as e3− rich beetroot juice (~6 mmol/300 mg NO3−). Chronic kidney disease is another major risk factor for CVD, where hypertension can both result from, or be a large contributor to, the development of the disease [3− is likely to result in reduced risk of a cardiovascular event, thus improving cardiovascular health [Kemmner et al.  reported disease . Further disease . Therefor health . It is a3− supplementation, the review of the published data indicates that there is potential for beneficial effects which can result in improved cardiovascular health. Furthermore, some evidence from the reviewed studies also indicates potential benefits to cardiovascular health of older adults, via improved blood flow, endothelial function and/or RRI post-supplementation with dietary NO3−. Therefore, the conflicting results warrant further research, to fully evaluate the extent to which dietary NO3− supplementation impacts cardiovascular health in older adults. Additionally, specific attention should be drawn to participant health status and the use of a double-blind study design and NO3− depleted control.Despite the mixed results reported for changes in the BP and MAP of older adults following dietary NO3− consumption and cerebrovascular health. Presley et al. [3− with additional beetroot juice supplementation. This suggests that dietary NO3− supplementation may attenuate the age-related drop in NO activity and loss of cerebral blood flow (a major contributor to neurogenerative diseases) [3− supplementation on the development of neurodegenerative diseases. Therefore, further research is required to investigate the effects of dietary NO3− supplementation on specific diseases of the brain and determine its possible benefits to cerebrovascular health in older adults.Only one study  met the y et al.  showed iiseases) , thus po3− supplementation in older adults, both focusing predominately on insulin sensitivity and changes in plasma glucose levels [3− in older adults may improve insulin sensitivity, improving metabolic health. However, the results from the studies included in this review do not support this suggestion. Neither acute supplementation of NO3− rich beetroot juice  in healthy older adults [−1, ~7.5 mmol/400 mg NO3−) in type 2 diabetic older adults [3− supplementation in older adults does not affect metabolic health via improvements in insulin sensitivity. However, it is important to note that there were some limitations to these studies. Gilchrist et al. [3− supplementation. Additionally, Shepherd et al. [3− supplementation in older adults, further investigation is required to provide a stronger evidence base, to allow more in-depth analyses and conclusions to be made.The current systematic review found two studies which examined the relationship between metabolic health and dietary NOe levels ,19. Nitre levels . A reduce levels . Therefoe levels . Therefor adults  resultedt et al.  had partt et al. , thereby3− supplementation in older adults.Certain limitations for this systematic review should be noted. Firstly, there was incomplete retrieval of identified research, as only English articles were included in this systematic review. Secondly, studies were generally characterised by small sample sizes and there were few studies investigating some outcome variables, which may have affected the reliability of the conclusions drawn in this systematic review. A third limitation to our analysis was the lack of a meta-analysis. Due to the small number of studies for each outcome variable, completing a meta-analysis would have resulted in weak representation of the data, thus, it is suggested that a meta-analysis be conducted in the future, once more studies have been published. This would be beneficial because it would provide greater statistical evidence on the effects of dietary NO3− supplementation. Some evidence suggests positive outcomes of dietary NO3− supplementation on cardiovascular health  and cerebrovascular health (increased CBF), while results are mixed as to whether dietary NO3− supplementation has benefits on cognitive performance. Metabolic health in older adults does not seem to be improved via changes in insulin sensitivity or plasma glucose levels following dietary NO3− supplementation; however, more research is required before firm conclusions can be made. Furthermore, it is evident that these effects may be influenced by the dosage of NO3−, duration of supplementation, blinding/placebo-control, and health status of participants. Therefore, further research is required in this area, with a focus on randomised, double-blind, NO3− depleted control-based studies, with particular attention to participant health status.In summary, the findings of this systematic review provide convincing evidence for improved physiological performance (increased time to fatigue), in older adults following dietary NO


Image sizes have increased exponentially in recent years. The resultinghigh-resolution images are often viewed via remote image browsing. Zooming andpanning are desirable features in this context, which result in disparatespatial regions of an image being displayed at a variety of resolutions. When an image is displayed at a reduced resolution, thequantization step sizes needed for visually lossless quality generally increase.This paper investigates the quantization step sizes needed for visually losslessdisplay as a function of resolution, and proposes a method that effectivelyincorporates the resulting (multiple) quantization step sizes into a singleJPEG2000 codestream. This codestream is JPEG2000 Part 1 compliant and allows forvisually lossless decoding at all resolutions natively supported by the wavelettransform as well as arbitrary intermediate resolutions, using only a fractionof the full-resolution codestream. When images are browsed remotely using theJPEG2000 Interactive Protocol (JPIP), the required bandwidth is significantlyreduced, as demonstrated by extensive experimental results. With recent advances in computer networks and reduced prices of storagedevices, image sizes have increased exponentially and user expectations for imagequality have increased commensurately. Very large images, far exceeding the maximumdimensions of available display devices, are now commonplace. Accordingly, whenpixel data are viewed at full resolution, only a small spatial region may bedisplayed at one time. To view data corresponding to a larger spatial region, theimage data must be displayed at a reduced resolution, i.e., the image data must bedownsampled. In modern image browsing systems, users can trade off spatial extentvs. resolution via zooming. Additionally, at a given resolution, different spatialregions can be selected via panning. In this regard, JPEG2000 has several advantagesin the way it represents images. Owing to its wavelet transform, JPEG2000 supportsinherent multi-resolution decoding from a single file. Due to its independent bitplane coding of “codeblocks” of wavelet coefficients, differentspatial regions can be decoded independently, and at different quality levels. FurtherIn recent years, significant attention has been given to visually losslesscompression techniques, which yield much higher compression ratios compared withnumerically lossless compression, while holding distortion levels below those whichcan be detected by the human eye. Much of this work has employed the contrastsensitivity function (CSF) in the determination of quantization step sizes. The CSFrepresents the varying sensitivity of the human eye as a function of spatialfrequency and orientation, and is obtained experimentally by measuring thevisibility threshold (VT) of a stimulus, which can be a sinusoidal grating,6 or a pet al. denotes the reconstructed value ofy[n] using the quantization indexq̃(z)[n],which has been encoded only up to coding pass z. Coding isterminated whenD(z)falls below the threshold This JPEG2000 Part 1 complaint visually lossless encoder cansignificantly reduce computational complexity since bit-plane coding is notcarried out for coding passes which do not contribute to the final codestream,and provides visually lossless quality at competitive bitrates compared tonumerically lossless or other visually lossless coding methods in theliterature. To further reduce the bitrate, masking effects which take intoaccount locally changing backgrounds can be applied to the threshold values, atthe expense of increased computational complexity .In the following sections, the main contribution of the present work isdescribed. In particular, visually lossless encoding as described in and23]23] is exK levels of dyadic tree-structuredwavelet transform, inherently supports the synthesis of K+ 1 different resolution images. As shown in 0 corresponds to the lowest resolution image. The next lowest resolution levelℛ1 = {, ,} together with can be used to render the next tolowest resolution image .Continuing in this fashion, resolution levelℛr together with the image) can be used to synthesize the image , for 1 ≤r ≤ K, with the full resolutionimage denoted by .JPEG2000, with LL, K − r) canbe thought of as masquerading as a full resolution image. The subbands ofresolution level ℛr can then be seen to playthe role of the highest frequency subbands, normally played byℛK. For example, in 1= {, ,} contains the highest frequency subbands ofthe “image” . Similarly, the subbands ofresolution level ℛr−1play the role normally played by those from resolution levelℛK−1, and so on.In general, when displaying image , resolution levelℛj behaves as resolution levelℛj+(K−r),0 < j ≤ r. The lowest resolutionlevel ℛ0 = behaves as . Therefore, to havevisually lossless quality of the displayed image , the visibility thresholdsused for ℛj should be those normally usedforℛj+(K−r).It then follows that when reduced resolution image  is displayed, thevisibility threshold for subband b ={θ, k} is givenbyIn what follows, it is assumed that images are always displayed so thateach “image pixel” corresponds to one “monitorpixel.” Under this assumption, when displayed as an image,) and b to achieve visually lossless quality when the full resolutionimage  is displayed. As usual, subbands withk ≤ (K −r) are discarded when forming . This can be considered assetting their thresholds to infinity.K = 5, . As mentioned in the previousparagraph, and indicated by  plays the role of  when the image  is displayed. The work of K = 5, andvare listed in LL, K) when displaying image.Specifically,The resulting values forLL, 5)of the luminance component in [LL, k), 0 ≤k ≤ 5. This is due to the large number ofcodeblocks in these subbands exhibiting extreme variability in coefficientvariances. Fixed thresholds still suffice for the chrominance components. tmeasured at an assumed typical variance ofσ2 = 150.Recall that a fixed threshold was employed for ofK = 2. When the full resolution image (r = 2) is displayed,subband  requires thresholdtfor visually lossless quality. However, when the one-level reduced resolutionimage  (r = 1) is displayed,the four subbands with k = 2 which previously neededthresholdstnow require thresholdst.Similarly, when the lowest resolution image (r = 0) is displayed, thresholdtis applied.From 0, image quality is progressively improved by theincremental contributions of subsequent layers. In typical JPEG2000 encoderimplementations, each layer is constructed to have minimum mean squared error(MSE) for a given bitrate, with the aid of post-compression rate-distortionoptimization (PCRD-opt) [JPEG2000 layers are typically used to enable progressive transmission,which can increase the perceived responsiveness of remote image browsing. Thatis, when progressive transmission is used, the user often perceives that usefuldata are rendered faster for the same amount of data received. In JPEG2000, eachcodeblock of each subband of each component contributes 0 or more consecutivecoding passes to a layer. Beginning with the lowest  layer𝒬CRD-opt) . More la0 provides “just” visually losslessreconstruction of . The addition oflayer 𝒬1 enables just visually lossless reconstruction of, and so on. Moreprecisely, layer 𝒬l is constructed so thatwhen layers 𝒬0 through 𝒬lare decoded, the maximum absolute quantization error,D(z) isjust smaller than the visibility threshold l, 0 ≤ l≤ r. In this way, when image  is decoded using onlylayers 𝒬l, 0 ≤ l≤ r, all relevant codeblocks are decoded at the qualitycorresponding to their appropriate visibility thresholds.In the work described here, layers are tied to resolutions so that layer𝒬K= 2). The lowest resolution image  needs onlylayer 𝒬0 for visually lossless reconstruction. At the nextresolution, an additional layer 𝒬1 is decoded. That is, image is reconstructed using both 𝒬0and 𝒬1. At full resolution, the information from the finallayer 𝒬2 is incorporated. It is worth reiterating that theJPEG2000 codestream syntax requires that every codeblock contribute 0 or morecoding passes to each layer. The fact that in the proposed scheme, eachcodeblock in ℛ1 and ℛ2 contribute 0 codingpasses to 𝒬0 (and that ℛ2 contributes 0coding passes to 𝒬1) is indicated in the figure. This resultsin a number of empty JPEG2000 packets. The associated overhead is negligible,since each empty packet occupies only one byte in the codestream.LL, 2), a straightforward treatment would discard through  for considerablesavings. However, it would retain unneeded portions (𝒬1 and𝒬2) of . Similarly, whendisplaying , a straightforward treatment would discard through . However, it wouldstill include unneeded data in the form of 𝒬2 for through . By discardingthese unneeded data, the proposed scheme can achieve significant savings.The advantages of the proposed scheme are clear from LL, K −r + 1) and , there are two possibilities: 1) upscaling from thelower resolution image ; or 2) downscaling from the higher resolutionimage . It isreadily apparent that upscaling a decompressed version of  will be no betterthan an upscaled (interpolated) version of an uncompressed version of. Visual inspection confirms that this approach does not achieve high qualityrendering. Thus, in what follows, we consider only downsampling of the higherresolution image . A decompressed version of  may be efficiently obtained bydecoding 𝒬l, 0 ≤ l≤ r, as described in the previous section. However, eventhis method decodes more data than required for the rendering of imagery downsampledfrom . In whatfollows, the determination of the visibility thresholds for downscaled images isdiscussed.In the previous section, visibility thresholds and visually losslessencoding were discussed for the native resolutions inherently available in aJPEG2000 codestream . In this section,“intermediate” resolutions are considered. Such resolutions may beobtained via resampling of adjacent native resolution images. To obtain an imagewith a resolution between , 0.72 = 0.5(1.2)2, and 0.864= 0.5(1.2)3. These factors are applied as downscaling factorsfrom the one-level higher resolution image  for 0 ≤ r ≤K. On the other hand, they can be thought of  asresulting in successive 20% increases in resolution from. We begin by considering the subsampling of the full resolution image.Measurement of visibility thresholds for downscaled images is conducted inthe fashion as described previously, but stimulus images are resampled by a rationalfactor of t̄b,nfor K = 5. The subscript n has been addedto the notation to indicate the subsampling factor. Values, of n∈ {1, 2, 3} correspond to subsampling factors of0.5(1.2)n, while n = 4corresponds to a subsampling factor of 1.0 (no subsampling). As explained in SectionII-A, quantization distortion varies with the variance of wavelet coefficients.However, the values in tb,4(σ2)corresponds to the non-subsampled case, and is given in  resolutionresults from updating  toyieldb that provides visually lossless quality when image isdownscaled by downsampling factor n, resulting in minimum file sizefor that downsampling. t̄b,nfor b̄ = , 0≤ k < 5.Threshold K + 1) layers – one for each resolution to berendered . Layer𝒬l is then constructed such that codeblocki from subband b contains only all coding passesup to the first coding pass z that ensures the maximum quantizationerror D(z) fallsjust below the threshold r(l)= ⌊l/4⌋ andn(l) = l −4r(l) + 1 and ifrom subband b. Decoding from 𝒬0 to𝒬l then ensures visually losslessreconstruction of image ) when downscaled by downsampling factorn(l).The thresholds defined above are applied in JPEG2000 by defining4 can be obtained by calculating r= K − ⌊ − log2p ⌋, n = ⌈(log2p + ⌊−log2p⌋ + 1)/log2 1.2⌉, andl = n + 4r− 1. The decoded version of image , using layers 𝒬0 through𝒬l, then provides enough quality so thatappropriate resampling yields a visually lossless image with resolution scalep.A visually lossless image with completely arbitrary resolution scalepathology or satellite together with anindex, e.g., pathology 1 or satellite 3.Recent technological developments in digital pathology allow rapid processing ofpathology slides using array microscopes [The proposed multi-resolution visually lossless coding scheme wasimplemented in Kakadu v6.4 . Experimroscopes . The resLL, 5−r), r = 0, 1, ..., 4 werecreated using the 9/7 DWT without quantization or coding. Reference images forintermediate resolutions were obtained by downscaling the next (higher) nativeresolution reference image. In what follows, the statement that a decompressedreduced resolution image is visually lossless means that it is visuallyindistinguishable from its corresponding reference image.In this work, “reference images” corresponding toreduced native resolution images , r = 0, 1, ..., 5(K = 5). The second method, referred to as the24-layer method, uses a total of 24 layers to provide visually lossless qualityat each of the six native resolutions, plus three intermediate resolutions beloweach native resolution. The third method, used as a benchmark, employs themethod from [× 128 at each resolution level.To evaluate the compression performance of the proposed method, eachimage was encoded using three different methods. The first method is referred tohere as the 6-layer method. As the name suggests, codestreams from this methodemploy six layers to apply the appropriate visually lossless thresholds for eachof six native resolution images , r = 0, 1, 2, 3, and 4,respectively. In turn, for the downsampled images , n = 1,r = 0, 1, 2, 3, 4, and 5, the 24-layer methodprovides 25.0%, 30.3%, 35.5%, 39.1%,39.1%, and 36.7% savings in bitrate, respectively compared tothe 6-layer method. These significant gains are achieved by discarding unneededcodestream data in the relevant subbands in a precise fashion, while maintainingvisually lossless quality in all cases. Specifically, the 6-layer case candiscard data in increments of one layer out of 6, while the 24-layer method candiscard data in increments of one layer out of 24. In contrast, the single-layermethod must read all data in the relevant subbands.satellite 2 image reconstructed at resolutionp = 0.09 for the three coding methods. Each ofthese images is downscaled from a version of (p = 0.125). Specifically, for the single-layermethod, the image is downscaled from all  data whichamounts to 5.30 bpp, relative to the reduced resolution dimensions. For theproposed methods, the image is downscaled from 3 of 6 layers and 10 of 24 layersof  data which amounts to 2.98 bpp and 2.09 bpp,respectively. Although the the proposed methods offer significantly lowerbitrates, all three resulting images have the same visual quality. That is, theyare all indistinguishable from the reference image.LL, 0) as well as for the three intermediate resolutionsimmediately below . The average penalty in this case is0.72%. Similarly, the 24-layer case is slightly worse than the 6-layercase at each of the six native resolutions. The average penalty for, r= 0, 1, 2, ..., 5 is 0.19%, 0.48%, 0.88%,1.30%, 1.89%, and 2.23%, respectively. These minor dropsin performance are due to the codestream syntax overhead associated withincluding more layers.Although this multi-layer method provides significant gains for mostresolutions, there exist a few (negligible) losses for some resolutions.Specifically, the 6-layer case is slightly worse than the single-layer case for under the proposed 6-layer visuallylossless coding method vs. the one-layer method with added layers for thepathology 3 and satellite 6 images. Asseen from the table, the results are nearly identical. Results for other imagesas well as for 24-layers are similar. Thus, the overhead associated with theproposed method is no more than that needed to facilitate qualityscalability/progressivity.As mentioned previously, the layer functionality of JPEG2000 enablesquality scalability. As detailed in the previous paragraph, for certain isolatedresolutions, the single-layer method provides slightly higher compressionefficiency as compared to the 6-layer and 24-layer methods. However, it providesLL, 5) (p = 0.03125) and (p = 0.25), as well as twointermediate resolutions corresponding to ,n = 2 (p = 0.09) and, n = 2 (p= 0.72). Full resolution images (p = 1.0) werevalidated in [× 512 at a random image location so that threecopies fit side by side on a Dell U2410 LCD monitor with display size 1920× 1200. The validation experiment consisted of foursessions – one for each resolution tested. In each session, all 15images were viewed five times at the same resolution  in random order. Subjects were allowed to rest between sessions. Twentysubjects, who are familiar with image compression and have normal orcorrected-to-normal vision, participated in the experiment. Each subject gave atotal of 300 responses over the four sessions. The validation was performedunder the same viewing conditions as in [To verify that the images encoded with the proposed scheme are visuallylossless at each resolution, a three-alternative forced-choice (3AFC) method wasused, as in . Tworefdated in . Thesefns as in  . The kdu_show client was adapted to specifically request onlythe number of quality layers commensurate with the codestream construction and the resolution level currently beingdisplayed by the client. All client/server communications were JPIPcompliant.The experimental results described below were obtained using the samecodestreams employed in the experiments described in Section 5.1 above. Asdescribed there, these codestreams were created using 5 levels of 9/7 DWT,precincts of size 128 LL, 5) image (p = 0.03125) wasfirst requested. This resulted in an overview of the entire image beingdisplayed in a window of size 0.03125 times the dimensions of the image undertest  This initialwindow size was maintained throughout the browsing session of the image undertest. Following the initial request, 4 different locations in the image wererequested with progressively higher resolution scales . Three pan operations were included after eachnew location request. As mentioned above, only the appropriate layers weretransmitted for the 6-layer and 24-layer methods. As expected, in each case, thenumber of bytes required by the 6-layer method was significantly less than thatrequired for the single-layer method. In turn, the 24-layer method resulted insignificant savings over the 6-layer method. Averaged over the four images, thenumber of transmitted bytes for the single-layer method was 9180.9 KB, while thenumber of transmitted bytes for the 6-layer and 24-layer methods was 6279.2 KBand 4679.2 KB, representing a decrease of 31.61% and 49.03% overthe single-layer method, respectively. It is clear from these results that thecodestreams encoded by the 6-layer and 24-layer methods require considerablyless bandwidth than a codestream optimized only for full resolution display.1, for the number of bytes transmitted up tothe moment of rendering in the figure, the advantage of progressive transmissionis readily apparent. Using the image from the 24-layer file, the user may beable to make their next request, thus preempting the current request, withoutwaiting for the rest of the data to be transmitted. This can further reducebandwidth, but was not used to obtain the values in As mentioned in Section III, layers are essential to effective browsingof remote images. Specifically, no quality progressivity is possible forsingle-layer codestreams. This paper presents a multi-resolution visually lossless image coding methodusing JPEG2000, which uses visibility threshold values measured for downsampledJPEG2000 quantization distortion. This method is implemented via JPEG2000 layers.Each layer is constructed such that the maximum quantization error in each codeblockis less than the appropriate visibility threshold at the relevant displayresolution. The resulting JPEG2000 Part 1 compliant coding method allows forvisually lossless decoding at resolutions natively supported by the wavelettransform as well as arbitrary intermediate resolutions, using only a fraction ofthe full-resolution codestream. In particular, when decoding the full field of viewof a very large image at various reduced resolutions, the proposed 6-layer methodreduces the amount of data that must be accessed and decompressed by 30 to 50percent compared to that required by single-layer visually lossless compression.This is true despite the fact that the single-layer method does not access nordecode data from unnecessary high frequency subbands. The 24-layer method providesadditional improvements over the 6-layer method ranging from 25 to 40 percent. Thisin turn, brings the gains of the 24-layer method over the single-layer method intothe range of 55 to 65 percent. Stated another way, the gain in the amount of dataaccess and decompressed (effective compression ratio) is improved by a factor ofmore than 2. These gains are born out in a remote image browsing experiment usingdigital pathology images and satellite images. In this experiment, JPIP is used tobrowse limited fields of view at different resolutions while employing zoom and pan.In this scenario, the proposed method exhibits gains similar to those describedabove, with no adverse effects on visual image quality.


Candidatus Synechococcus spongiarum” represents the widespread cyanobacterial symbionts found in marine sponges with relatively high genomic variability and likely important ecological roles. We present here the draft genome sequence of “Candidatus Synechococcus spongiarum” m9, which was assembled from a metagenome of Theonella swinhoei sampled in the South China Sea.“ Candidatus Synechococcus spongiarum” are widespread in sponge symbiotic microbial communities  in the South China Sea. DNA extraction, Illumina sequencing, and metagenome assembling were carried out as described by Liu et al. (https://github.com/lmrodriguezr/enveomics-gui), according to Liu et al.  and a G+C content of 61.9%. enveomics-GUI indicated a genome completeness of 93%, with likely no contamination. Phylogenetically, it is closely related to “Ca. Synechococcus spongiarum” SP3 from the T. swinhoei sampled from the Red Sea (Ca. Synechococcus spongiarum” draft genomes (approx. 84 to 85%). The m9 genome contains 1,659 coding sequences (CDSs)  and 33 tRNAs. It is smaller than any known “Ca. Synechococcus spongiarum” genome , the absence of which was regarded to be a signature of “Ca. Synechococcus spongiarum” (Ca. Synechococcus spongiarum” genomes and suggests the diverse mechanisms in sponge-cyanobacterium recognition.The above-described process resulted in a cyanobacterial metagenome bin, namely, “Ca. Synechococcus spongiarum” m9 draft genome has been deposited at ENA with the contig accession range FITM01000001 to FITM01000179.The “


Cancer has become a global problem. On all continents, a great number of people are diagnosed with this disease. In spite of the progress in medical care, cancer still ends fatal for a great number of the ill, either as a result of a late diagnosis or due to inefficiency of therapies. The majority of the tumors are resistant to drugs. Thus, the search for new, more effective therapy methods continues. Recently, nanotechnology has been attributed with big expectations in respect of the cancer fight. That interdisciplinary field of science creates nanomaterials (NMs) and nanoparticles (NPs) that can be applied, e.g., in nanomedicine. NMs and NPs are perceived as very promising in cancer therapy since they can perform as drug carriers, as well as photo- or sonosensitizers . Consequently, two new treatment modalities, the photodynamic therapy (PDT) and the sonodynamic therapy (SDT) have been created. The attachment of ligands or antibodies to NMs or to NPs improve their selective distribution into the targeted organ or cell; hence, the therapy effectiveness can be improved. An important advantage of the targeted tumor treatment is lowering the cyto- and genotoxicity of active substance towards healthy cells. Therefore, both PDT and SDT constitute a valuable alternative to chemo- or radiotherapy. The vital role in cancer eradication is attributed to two inorganic sensitizers in their nanosized scale: titanium dioxide and zinc oxide. There’s plenty of room at the bottom,” earned him the attribute of a forerunner of nanotechnology. In the lecture, R. Feynman suggested that in his day, the only limit to the development of nanotechnology resulted from the lack of sufficiently precise tools and techniques. For the first time, the term “nanotechnology” was applied by a Japanese scientist N. Taniguchi [Nanosystems: molecular machinery, manufacturing and computation” contributed to the popularization of the knowledge in this area. At present, nanotechnology is a rapidly developing multidisciplinary field that combines the latest achievements of many disciplines of science, including biology, chemistry, physics, informative technology, and mechanics. It designs nanomaterials (NMs) and nanoparticles (NPs) with at least one dimension ranging in the scale from 1 to 100 nm [During the congress of the American Physical Society in Caltech, on 26th December 1959, an American physicist R. Feynman [aniguchi  “Nanosyso 100 nm , conferso 100 nm . Accordio 100 nm , thanks o 100 nm . Anothero 100 nm .The challenge the nanomedicine is now facing is to find the most effective way of the tumor cells eradication . The mai2) and zinc oxide (ZnO) [The past decade brought about the discovery that many materials used in a variety of industries exhibit formerly undisplayed catalytic properties, after they have been powdered to NPs and subsequently exposed to ultraviolet (UV) radiation or ultrasound (US) wave. Among such materials, there are titanium dioxide (TiOde (ZnO) –25.2 NPs) and zinc oxide (ZnO NPs) are single elements with a diameter of 1 < φ ≤ 100 nm [2 and ZnO NPs but also to functionalize their surface. The NP functionalization provides for an easier transport within tissues, creates the NP ability to cross plasma membranes and allows them to be delivered to cancer cells in a targeted manner [2 and ZnO have become a promising tool in medicine [Nanoparticles of titanium dioxide  and nanosized zinc oxide (nano-ZnO), the width of the energy gap is 3.20 and 3.37 eV, respectively [2, ZnO) are excited by the UV radiation (photoexcitation), mainly in the near ultraviolet range  [The electronic structure of TiOoperties . The semectively , 32. Bot 400 nm) –38. Less 400 nm) , 34, 36. 400 nm) , 40.−) transfers from VB to CB, leaving behind a positive hole (h+). Therefore, a specific “electron-hole” pair (e− + h+) is created [−, h+) can migrate to the surface of the catalyst  NPs where they can be trapped by adsorbate molecules, initiating thereby the formation of reactive oxygen species (ROS). Excited negative electrons (e−) reduce molecular oxygen (O2), forming superoxide radical anion (•O2−). Generated positive holes (h+) oxidize water molecules (H2O) and hydroxide ions (OH−), producing hydroxyl radicals (•OH) and hydrogen peroxide molecules (H2O2) [The consequence of the semiconductor photo- or sonoexcitation is that electron (e created –42. Thiss (H2O2) –43  NPs is the decay of exciton. The recombination of the electron-hole pair (e− + h+) is accompanied by the emission of a photon (radiative recombination). In this process, the excitation of ground state oxygen (O2) by photon occurs and singlet oxygen (1O2) is formed [The inverse process to the generation of charge carriers in semiconductor . The third defense line present repair enzymes responsible for nucleic acids damage overhaul, e.g., DNA ligase (EC 6.5.1.1) [Eukaryotic cells, similarly to prokaryotic cells, are equipped with mechanisms protecting them from ROS. The first defense line, preventing ROS from forming and from reactions with cell compounds, are proteins  that sequestrate metal ions . Interruption of free radical chain reactions is the task of the second defense line that consists of a system of three enzymes: superoxide dismutase , catalase , and glutathione peroxidase , supported by low molecular weight antioxidants, such as glutathione (GSH), thioredoxin (Trx), or coenzyme Q6.5.1.1) .2O2) increases, the cell’s viability decreases. In physiological conditions, the concentration of H2O2 is low and ranges within 5–50 nM. The gradual increase of its quantity in a cell up to the level of 0.7 μM triggers mechanisms that result in a cell proliferation and tumor formation. In case the H2O2 concentration reaches the value of 1–3 μM, the apoptosis or autophagy (programmed cell death pathways) induction occurs. The concentration in excess of the level of 3 μM becomes toxic for a cell hence leads to its necrosis (unprogrammed cell death pathway). Therefore, the phenomenon of the oxidative stress in tumor cells has recently been used to design new tumor therapies [ROS can inflict cell injury as an effect of reaction with lipids in cellular membranes , nucleotherapies , 55.2 and ZnO) are going to play the crucial role in medicine as photo- or sonosensitizers applied in ROS-based cancer therapy [Increasingly frequent are the opinions that in near future, the NPs of semiconductor metal oxides  is harmless to people and animals [2 toxicity has been a research subject in many scientific centers. Recent years have witnessed a dynamic development of nanotechnology. Along with it, there has been an increased concern, though that this compound might be toxic in its NPs form. There are studies proving that NPs (1 < φ ≤ 100 nm) of any compound are more harmful to people and animals than microparticles (MPs) (0.1 < φ ≤ 100 μm) of the same compound [Despite the assumption that the microsized titanium dioxide , increased proportionally to the fragmentation of the TiO2 particles. Sycheva et al. [2 NPs (φ = 30 nm), as measured by the number of DNA double-strand breaks and the number of micronuclei, was significantly higher in brain, liver, or bone marrow cells in mice, compared to the genotoxicity of TiO2 MPs (φ = 160 nm). Danio rerio, when exposed to TiO2 (50 mg dm−3) in their NPs form, exhibits more serious oxidative injuries of liver and gill cells, in comparison to the exposition to the MPs form of those compounds [2 NPs (50 mg m−3) caused lung inflammation, accompanied by the increase of total neutrophil count in bronchoalveolar lavage (BAL) fluid. Bermudez et al. [2 NPs (10 mg m−3). They concluded there was a clear increase of cytotoxicity markers, i.e., an increase in the total macrophage and neutrophil count in BAL fluid in rats and mice, while in hamsters, there were no distinct changes in the cellular response. Ze et al. [2 NPs, administered to mice through the nose for 90 days, moved up and built up in the brain, leading to the oxidative stress, excessive glial cells proliferation, and tissue necrosis, as well as inflicting hippocampal cells apoptosis. Lindberg et al. [2 NPs to mice resulted in an increase of DNA damages in leukocytes and in higher micronuclei count in peripheral blood polychromatic erythrocytes. The intratracheal instillation of TiO2 NPs showed the same effects in BAL cells. The cyto- and genotoxicity of TiO2 NPs were confirmed by many other authors [2 NPs, introduced into the trachea of a rat in the amount of 5 mg per animal, caused respiratory tract cancer within 4 months. Therefore, TiO2 NPs in the dust form, contrary to the TiO2 MPs in the same form, were classified in the 2B group by the International Agency for Research on Cancer (IARC) [Wang and Fan  conductei et al.  reporteda et al.  pointed ompounds . The stuompounds  showed tz et al.  examinede et al.  proved tg et al.  reported authors –73. Feri authors  showed tr (IARC) . The 2B 2 MPs and TiO2 NPs is a much bigger active surface area of TiO2 NPs, a feature resulting in a higher absorption rate of UV radiation and a greater photocatalytic activity [2 NPs genotoxicity and their diameter. TiO2 NPs (φ < 50 nm) caused the formation of 8-hydroxy-2-deoxyguanosine (8-OHdG) adducts and the increase of the micronuclei number in human bronchial epithelial cells, while TiO2 MPs (φ > 200 nm) in the same concentration were practically harmless. Kongseng et al. [2 NPs (φ < 30 nm) were responsible for the rise of the pro-inflammatory cytokine (IL-1β and TNFα) level in human peripheral blood mononuclear cells (PBMCs) in serum-free medium. The in vitro studies of Long et al. [2 particles with 10 ≤ φ ≤ 20 nm stimulated the generation of ROS and, as a consequence, induced damages of neurons, whereas UV radiation was not a precondition for generating ROS. There are, however, numerous contrary opinions. Fujita et al. [2 NPs was very low. Similar conclusions were presented by Verves and Jha [2 NPs (50 mg mL−1) to rainbow trout (Oncorhynchus mykiss) gonadal tissue cells (RTG-2 line). They reported cyto- and genotoxic effects of TiO2 NPs in irradiated cells, only. Saquib et al. [2 NPs (10 μg mL−1) to UV-A irradiated human amniotic epithelial cells (WISH line), noted a decrease in the CAT activity, lowering the GSH level, as well as the arrest of the cellular cycle in the G2/M phase. In similar studies on human epidermoid carcinoma cells (A431 line), Shukla et al. [2 for 120 min and, subsequently, to UV-A irradiation. After 30 min of UV-A irradiation, significant plasma membrane damages and DNA fragmentation were noticed. Other studies show that TiO2 powdered to NPs exhibited ROS-dependent cyto- and genotoxicity towards human HaCaT cells [Cryptosporidium parvum) oocysts [Giardia lamblia [Acanthamoeba castellanii [One of the main differences between TiOactivity . Gurr etactivity  prove thg et al.  report Tg et al. , 79, cona et al. , drawing and Jha  who examb et al. , while ea et al.  observeda et al.  exposed aT cells , protozo oocysts , as well lamblia  and Acantellanii , only if2, is practically harmless to people and animals [Danio rerio [ZnO toxicity is also dependent on the scale of its fragmentation . Microsi animals , contrar animals  studied  animals , 91 and  animals , as wellio rerio .2 NPs, as well as of ZnO NPs have been proved in vitro also with many other cells, both healthy, e.g., human dermal fibroblasts [Cyto- and genotoxicity of TiOroblasts , 95, humroblasts , human aroblasts , human groblasts ; and malroblasts , human croblasts , 101, huroblasts –105, humroblasts , human hroblasts , human broblasts , 109, orroblasts .2, ZnO) in PDT [In recent years, there has been an increase in cancer disease prevalence, an issue inducing an acute need to invent new, effective, and safe therapy methods. In the past decade, nanotechnology and nanomedicine gained quite an importance in anticancer therapy. Those two fields of science joined forces not only to seek substances that would effectively eradicate cancer cells but also to find ways of delivering chemotherapeutics to tumor cells, in a targeted manner , 112. Th) in PDT , 119, a PDT is a treatment in which the administration of photosensitizer to the tumor tissue is followed by the excitation of a photosensitizer by electromagnetic radiation with a specific wavelength, e.g., UV-A or UV-B. Consequently, on the surface of NPs of photoexcited metal oxides, ROS are formed which then damage cancer cells  Fig. 2)2).Fig. 22 or ZnO NPs, can be delivered to the tumor cells as the result of passive or active processes [2 and ZnO NPs are uptaken into the cells by phagocytosis [Photosensitizers, such as TiOrocesses . The pasrocesses . In the rocesses . The wayrocesses . There aocytosis .2 NPs, if exposed to the UV radiation, induce, depending on their subcellular position, one of the cell death pathways: apoptosis [It is assumed that TiOpoptosis , 126, aupoptosis , 128, orpoptosis , 130, wh2 NPs toxicity towards human hepatocarcinoma cells (SMMC-7721 line), reported an increase and a decrease of protein levels that are, correspondingly, pro-  and anti-apoptotic  molecules. Zhao et al. [2 NPs-treated mouse epidermal cells (JB6 line), this protein playing a crucial role in the involvement of mitochondria in oxidative stress-dependent cell death. PDT-induced mitochondria damages result in a selective Bcl-2 degradation, with no effect on the Bax. Therefore, the Bax/Bcl-2 ratio is increased, and the intrinsic pathway of apoptosis is promoted [−1, 24 h) human HepG2 cells was twofold higher and threefold lower, respectively, compared to control cells [Zhang et al. , having o et al.  point oupromoted –135. Thopromoted , human bpromoted  or humanpromoted . Nearly promoted  and by Wpromoted  whereby ol cells . The priol cells , 142  to human A549 cells, concluded there was an increased H2AX histone phosphorylation that followed the oxidative stress-induced DNA double-strand breaks. Similar results obtained Premanathan et al. [−1). Phosphorylated H2AX (γH2AX) histone is considered to be a marker of DNA damages [2 NP-treated human peripheral blood lymphocytes (PBL) was stressed by Kang et al. [According to many authors , 144, thr et al.  report tr et al. , when exn et al. , having  damages . Its phog et al. . Respondg et al.  Fig. 3)2 or ZnO Yoo et al.  studied 2 NP-treated human bronchial epithelial cells (16HBE14o-line). High level of ROS in a cell results in the increase of the AMP/ATP ratio, an effect stimulating the AMP-activated protein kinase  [PDT-induced damages of the endoplasmic reticulum habitually result in the cell death by autophagy  Fig. 3)3). In th7.11.31) , 173. AM7.11.31) , 175. It7.11.31) .2+ level (>1 μM) that activates Ca2+-dependent proteases. Other effects are dissipation of mitochondrial membrane potential (Δψm) and a dramatic decrease of the intracellular ATP level [2+ level in cytosol that resulted from the downregulation of plasma membrane calcium ATPase isoform 1  activity. Disrupted homeostasis of Ca2+ was also observed in human lens epithelial cells (HLE-B3 line) incubated with ZnO NPs and, subsequently, exposed to UV-B radiation [2 NPs.High level of the PDT-generated ROS, inflicting pro-apoptotic  and pro-autophagic (Beclin 1) protein damages, as well as plasma membrane disruption, results in a cell death by necrosis , 178 Fi. Cell meTP level , 180 expadiation . Typicaladiation . Xu et aadiation  describe2+ homeostasis disruption [PDT-treatment of tumor cells, using the metal oxide nanoparticles, results in the cell death, presenting the consequence of irreversible DNA damage , plasma sruption , 180, stsruption . The maisruption –187.2 (Au/TiO2) [2 (Ag/TiO2) [2 (Pt/TiO2) [2 NPs increases the catalytic activity of this oxide, a phenomenon confirmed in the studies of Abdulla-al-Mamun et al. [2 nanocomposite showed an 80% higher effectiveness in eradication of human HeLa cells than TiO2 NPs. In other studies, TiO2 NPs were conjugated with folic acid (FA) molecules [2 nanocomposite by FA receptors in plasma membrane and, therefore, to leverage the efficiency of cancer cells eradication. Feng et al. [2 nanocomposite and its incorporation into human nasopharyngeal carcinoma (KB) cells. Rozhkova et al. [2-based nanocomposites that target and eradicate brain carcinoma cells in vivo with no harm to adjacent healthy cells. IL13α2R antibodies were conjugated with TiO2 NPs through 3,4-dihydroxyphenylacetic acid (DOPAC). The antibodies recognize cancer cells, bind to them and are eventually uptaken by means of phagocytosis. In the process of tumor cells exposition to UV-A radiation, TiO2-based nanoconstructs generate the formation of ROS that subsequently damage the cancer cells and induce their apoptosis. The selection of suitable antibodies can help design nanocomposites able to precisely target and eradicate many types of cancer cells [2 NPs with monoclonal antibodies, along with reversible plasma membrane injury by means of electric field, so called electroporation. As the authors suggest, such combination may increase the accuracy of cancer cell recognition by TiO2-based nanocomposites and, in consequence, enhance the TiO2-based nanoconstructs penetration into cytosol. Using that method, it was possible to eradicate in vitro all human LoVo cells that were subject to experiment, within merely 90 min.Nanocomposites, e.g., gold-doped TiOAu/TiO2) , silver-Ag/TiO2) , platinuPt/TiO2) , or silvPt/TiO2)  are compn et al. . They reolecules . Such cog et al.  confirmea et al.  designeder cells , 83. Xu er cells  advocate2 and ZnO are conjugated with upconverting nanoparticles (UCNPs) [One of the main disadvantages of PDT is the limited penetration depth of the tissues by the UV radiation. Therefore, this method is suitable to eradicate tumor cells located in superficial depths . This sh (UCNPs) . Ytterbi (UCNPs) . UCNPs a (UCNPs) . This fi (UCNPs) , 197.2 NPs excitation by UV radiation in favor of the chemical functionalization of their surfaces by binding to them –OH, –NH2, or –COOH groups. Then, they examined TiO2 NPs, as modified on their surface, in respect of their influence on the viability of a number of cancer cell lines  in vitro. According to the authors, the viability of the examined cancer cell lines was dependent upon both the concentration of TiO2 NPs in the examined cells and the type of functional group altering the surface properties of TiO2 NPs. The highest cyto- and genotoxicity exhibited NPs functionalized by –OH groups. The design of surface properties of NMs and NPs presents a valuable tool in the targeted cancer therapy.Thevenot et al.  withdrewLimited possibilities to apply PDT in the cancer therapy gave rise to seek different cancer treatment modalities. An example of an alternative tumor eradication method is SDT. This therapy is based on a synergistic effect on a cancer cell by sonosensitizer and US . US can 2 NP-based SDT . Moosavi Nejda et al. [2 NPs (100 μg mL−1) on the viability of human oral squamous carcinoma cells (HSC-2 line). The authors proved the increased intensity of US  and the prolonged sonication period  enhanced the damage ratio in the human HSC-2 cells, finally leading to their necrosis at the conditions of 73 W cm−2 and 3 s. Yamaguchi et al. [2 NP-based cancer therapies will soon become a valuable tool in fighting malignant gliomas. The authors compared PDT to SDT in respect of their effectiveness in eradication of human glioblastoma cells (U251 line). With PDT, the toxicity effect of TiO2 NPs (20 μg mL−1) was noticeable after 2-h exposure of single cancer cell layer to UV-A radiation (5.0 mW cm−2). Moreover, the effect was fairly restricted by free radical scavengers. Cytotoxicity of TiO2 NPs (20 μg mL−1) in case of SDT was proportional to the sonication period, and it was not dependent on antioxidants concentration, an observation indicating there must be a different mechanism of intracellular structure damages. US, propagating in cell, induce the formation of cavitation bubbles which free energy as they implode. It is assumed that acoustic cavitation can not only lead to sonosensitizer excitation, the result of which is 1O2 formation, but it can also cause—with no ROS involved—a disruption in plasma membrane integrity. Saito et al. [2 NP-based SDT could be noticed than in the TiO2 NP-based PDT.Harada et al.  showed ia et al.  examinedi et al.  believe o et al.  report t2 NPs are also conjugated with precious metals or antibodies. The subject of studies conducted by Ogino et al. [2 NP toxicity to human HepG2 cells. To increase the TiO2 NPs uptake rate by cancer cells, pre-S1/S2, a model antibody recognizing hepatocytes, was conjugated with the TiO2 NPs. The ability of such conjugates to recognize cancer cells was examined using the surface plasmon resonance and immunofluorescence techniques. Apoptosis of some cells of the human HepG2 cells in vitro was firstly observed after 6 h from the termination of the TiO2 NP sonication , and after the following 90 h, the number of dividing cells decreased by 45%. The studies conducted by Ninomiya et al. [2 NP-based SDT as a tool to reduce the proliferation of human MCF-7 cells, too. In this case, avidin was immobilized on the surface of TiO2 NPs in order to enhance its uptake rate by cancer cells. Within 96 h after the termination of the TiO2 NP sonication , the number of viable cancer cells was reduced by 30%.In SDT, similarly to PDT, TiOo et al. , as wello et al. , 204, waa et al.  revealed2 and ZnO NPs are excellent sensitizers and oxidizing agents. The feature of the ROS generated on their surface is a higher oxidation potential as well as a short half-life (<0.04 μs) [2 NPs in vivo is limited by serum proteins covering their surface that exhibit a trapping ability of photogenerated ROS. The knowledge on the potential application of NPs of TiO2 and ZnO in therapy and diagnostics of neoplastic maladies is continuously growing. Nonetheless, further studies are necessary to improve the tumor targetability of TiO2 and ZnO NPs, as well as to increase the therapeutic window of PDT using metal oxide NPs [TiO0.04 μs) . Therefo0.04 μs) . NPs adm0.04 μs) , 207. Ga0.04 μs)  proved txide NPs , 210.2 and ZnO in their NPs form. UV-excited NPs of TiO2 and ZnO are a source of ROS that form on their surfaces. ROS are agents with a high oxidative potential that damage primarily DNA and cell membranes of cancer cells. Plasma membrane damages lead to cell necrosis, nucleus and mitochondria damages induce apoptotic cell death, and endoplasmic reticulum damages cause cell death by autophagy. Limited tissue penetration ability of UV radiation presents a serious obstacle in the application of UV-sensitizing NPs of TiO2 and ZnO in cancer therapy. Efforts to apply NIR radiation, since it is less harmful and can penetrate deeper depths tissues, have so far not been successful. Therefore, a new method had to be set up, allowing to generate ROS in deeper depths tissues. Such a method is SDT, using US with low tissue attenuation coefficient. However, SDT exhibits one major disadvantage: insufficient tumor targetability by NPs of TiO2 and ZnO. The difficulty in preparation of a drug formula that would allow the targeted delivery of NPs to cancer cells is an important factor that restricts the application of photo- and sonosensitizers in cancer therapy. Thanks to the development of nanotechnology, various drug delivery systems in organisms have been designed. One of them is compiling conjugates of TiO2 or ZnO in their NPs form with monoclonal antibodies, a method that allows targeting the photo- and sonosensitizers on a selected receptor. The design of modern, more effective cancer fight methods remains an important challenge to contemporary medicine. The scientists are still facing many years of studies on how to optimize cancer therapy using nanotechnology whereas the results have so far been fairly promising.Traditional methods of cancer therapy inflict a series of side effects, including the impairment of the immune system. Recent years have witnessed many efforts in creating alternative cancer therapy methods that would be less invasive and would exhibit a site-specific activity. PDT might present a viable solution. Among photosensitizers that have been thoroughly examined in view of their potential application in cancer therapies, there are TiO


The risk calculator of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) has been shown to be useful in predicting postoperative complications. In this study, we aimed to evaluate the predictive value of the ACS-NSQIP calculator in geriatric patients undergoing lumbar surgery.A total of 242 geriatric patients who underwent lumbar surgery between January 2014 and December 2016 were included. Preoperative clinical information was retrospectively reviewed and entered into the ACS-NSQIP calculator. The predictive value of the ACS-NSQIP model was assessed using the Hosmer–Lemeshow test, Brier score (B), and receiver operating characteristics  curve analysis. Additional risk factors were calculated as surgeon-adjusted risk including previous cardiac event and cerebrovascular disease.P = .004), functional independence (P = 0), American Society of Anesthesiologists class , dyspnea (P = 0), dialysis (P = .049), previous cardiac event (P = .001), and history of cerebrovascular disease (P = 0) were significantly associated with a greater incidence of postoperative complications. Observed and predicted incidence of postoperative complications was 43.8% and 13.7% (±5.9%) (P < .01), respectively. The Hosmer–Lemeshow test demonstrated adequate predictive accuracy of the ACS-NSQIP model for all complications. However, Brier score showed that the ACS-NSQIP model could not accurately predict risk of all (B = 0.321) or serious (B = 0.241) complications, although it accurately predicted the risk of death (B = 0.0072); this was supported by ROC curve analysis. The ROC curve also showed that the model had high sensitivity and specificity for predicting renal failure and readmission.Preoperative risk factors including age (The ACS-NSQIP surgical risk calculator is not an accurate tool for the prediction of postoperative complications in geriatric Chinese patients undergoing lumbar surgery. In 2013, The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) developed an online surgical risk calculator, based on analysis of a database of preoperative information and postoperative complications pertaining to more than a million surgical patients across 393 hospitals in the United States. The surgical risk calculator found widespread application in the clinical setting in over 1500 types of surgeries,,6 although with some exceptions including lumbar surgery. This tool helps estimate the risk of postoperative complications based on preoperative data such as patient age, body mass index (BMI), and comorbid conditions . This study was conducted to evaluate the predictive utility of the ACS-NSQIP surgical risk calculator in geriatric patients undergoing lumbar surgery.Lumbar spinal stenosis frequently affects the mobility and quality of life for millions of people, especially the geriatric population. Worldwide, there has been an increase in the need for lumbar surgery in tandem with the phenomenon of population aging.2Elderly patients (age > 60 years) with isolated spinal stenosis who underwent conventional laminectomy without fusion in the period between January 2014 and December 2016 at the Beijing Shijitan Hospital, China were screened for inclusion in the study. Conventional laminectomy was performed in these patients through a midline incision, and the spinous process and lamina removed. Extirpation of herniated discs was performed only in cases where disc bulging or herniation contributed to stenosis. Table Patient information was retrospectively obtained from hospital medical records or telephonic interviews of the patients or their guardians. Demographic data included age, gender, smoking habits, weight, height, and functional status. Clinical information was collected according to the requirements of the ACS-NSQIP risk calculator and comprised preoperative assessments for American Society of Anesthesiologists class, diabetes, hypertension, congestive heart failure, dyspnea, ascites, chronic obstructive pulmonary disease, dialysis, renal failure, sepsis, ventilator dependence, and disseminated cancer. Further, surgical parameters, including emergent or elective operation and current procedural terminology code , were recorded.2.12), patients were further classified into 6 groups: low weight (BMI <18.5); normal weight (≥18.5 to ≤25); overweight (>25 to ≤30); obesity level I (>30 to ≤35); obesity level II (>35 to ≤40); and obesity level III (BMI >40). Further, 3 risk-adjusted subgroups, based on surgeon's assessment of risk, were included: “no adjustment necessary”, “risk somewhat higher than estimated”, and “risk significantly higher than estimated”, on the basis of additional risk factors including prior cardiac event and cerebrovascular disease. Patients with none, 1, or more than 2 of the specified risk factors were assigned to the “no adjustment necessary”, “risk somewhat higher than estimated”, and “risk significantly higher than estimated” categories, respectively . Quantitative data are presented as mean ± standard deviation, and categorical data as frequencies and percentages. Chi-square test was used to assess the difference between the overall predicted risk and the observed risk of complications. Wilcoxon signed-rank test was used to compare hospital stay between study groups. The Hosmer–Lemeshow goodness-of-fit test and receiver-operating characteristics  curve analysis were performed to evaluate the predictive validity of the ACS-NSQIP surgical risk calculator. Brier score (B) was used to assess the deviation between the predicted and observed outcomes, and a score <0.01 indicated predictive precision >90%.33.1P = .004), functional independence (P = 0), American Society of Anesthesiologists class (P = 0), dyspnea (P = 0), dialysis (P = .049), previous cardiac event (P = .001), and history of cerebrovascular disease (P = 0). However, other variables captured for risk assessment were not associated with postoperative complications  underwent conventional laminectomy without fusion (mean operative time: 6.5 ± 2.1 hours). Baseline patient characteristics and preoperative parameters, based on the ACS-NSQIP risk calculator, are presented in Table P = 0; Table P = .001; Table Additional risk factors, including preexisting cardiac event and cerebrovascular disease, are presented in Table 3.2P < .01), while that of serious postoperative complications was 31.8% and 13.0% (±5.6%) (P < .01), respectively. Differences between predicted and observed prevalence were found for all postoperative complications, such as cardiac complication  and hospital stay . Moreover, the ACS-NSQIP underestimated the rates of renal failure, urinary tract infection, deep venous thrombosis, pneumonia, and cardiac complication, whereas it overestimated the rates of surgical-site infection, reoperation, readmission, and mortality , 0.666 (95% CI 0.593–0.783), 0.825 (95% CI 0.641–1.00), 0.843 (95% CI 0.733–0.952), and 0.972 (95% CI 0.929–1.00), respectively .Our study had potential limitations. First, the retrospective study design hampered information collection; therefore, some important factors may have been ignored in the present study. The additional surgeon-adjusted risk based on retrospective design may have introduced an element of bias in the study design. Moreover, the sample size was relatively small and, therefore, the predictive value of ASC-NSQIP model for specific complications might not be acceptable. The reoperation rate was relatively higher in our study (10%) compared to others.5The ACS-NSQIP surgical risk calculator is not an accurate tool for predicting postoperative complications in geriatric Chinese patients undergoing lumbar surgery. Further studies with a larger sample size and prospective design are warranted for investigating a better adjustment regimen or for developing a new risk model for the evaluation of complications in patients undergoing lumbar surgery.


Due to the fact that early objective identification of polytraumatized patients in extremis is crucial for carrying out immediate life-saving measures, our objectives were to provide and scrutinize a definition that results in a particularly high mortality rate and to identify predictors of mortality in this group.2  > 50 mmHg, hemoglobin < 9.5 g/dl, pH value < 7.2, lactate level > 4 mmol/l, base excess < −6 mmol/l, shock index > 1, and Horowitz index < 300) were met. By applying this definition, polytraumatized patients (age ≥ 18 years), admitted to our level I trauma center within a time period of three years, were retrospectively allocated to the “in extremis” group and to an age-, gender-, and ISS-matched “non-in extremis” group for comparison. A polytraumatized patient (ISS ≥ 16) was classified “in extremis” if five out of seven parameters , who formed the “in extremis” group, 36 patients (56.3%) died, thus revealing a threefold higher mortality rate than in the matched group (18.9%). Within the “in extremis” group, age and ISS were identified as predictors of mortality. Our definition might serve as a valuable early warning score or at least an impetus for defining polytraumatized patients in extremis in clinical practice. Polytrauma victims in extremis (very close to death) present the ultimate challenge to trauma surgeons and anesthesiologists. The prompt and accurate identification of these patients, who require the highest resuscitation efforts, is of pivotal importance to increase survival chances by choosing the appropriate life-saving measures, followed by a damage control approach to their injuries . Unfortu2 and thus in an increase of the partial pressure of arterial carbon dioxide (paCO2) [2 values higher than 50 mmHg defining hypercapnia [2) and the percentage or concentration of oxygen (FiO2) that an individual inhales [Several parameters referring to hemodynamic and cardiorespiratory instability, which indicate an unfavorable prognosis, have already been presented in the literature. In trauma victims blood loss often causes anemia, which is usually detected by low blood hemoglobin concentration. Moderate anemia may be defined by hemoglobin levels between 8 g/ml and 9.5 g/ml and severe anemia by levels lower than or equal to 8 g/ml . In 4,47 (paCO2) , with paercapnia  that comercapnia . Due to ercapnia . The Hor inhales . An inde inhales , a commo inhales .Due to the fact that isolated vital signs are unreliable in the assessment of hemodynamic and/or cardiorespiratory instability  we preseOur retrospective analysis was approved by the local institutional review board. All patients suffering blunt trauma, who were directly admitted to our level I trauma center within a time period of three years, were included, if they were at least 18 years old and if their Injury Severity Score (ISS) was equal to or higher than 16. From personal experience we combined seven parameters to a concise definition based on threshold values already presented in the literature .t-tests. The Chi-square test was applied to analyze categorical data. Differences in survival were determined by the log-rank test performed on Kaplan-Meier curves. For Receiver Operating Characteristic (ROC) curves the Area under the Curve (AUC) was calculated and presented with a 95% confidence interval (CI). Cut-off values were determined by the maximum sum of sensitivity and specificity [p value < 0.05.Individuals were classified “in extremis,” if five or more criteria were met at hospital admission. According to probability calculations this specification was suggested to classify approximately 20% of the polytraumatized patients, a proportion that was exactly what we were striving for as we aimed to identify polytrauma victims with the least prospects of survival. Demographic data  of all polytrauma victims, who were classified “in extremis,” were statistically analyzed. For comparison, patients, who did not meet our definition, were matched according to age, gender, and ISS in an equal number. They were combined to the “non-in extremis” group. Statistical analysis was performed using IBM SPSS Statistics Version 23, 64-bit. Parameters were displayed by mean ± standard deviation (SD) and were compared by means of Student's cificity . FinallyOut of 347 polytraumatized patients, who met our inclusion criteria, 64 patients (18.4%), 44 men, and 20 women  were classified “in extremis” according to our definition .Their injuries were caused by falls from a great height (22 patients), motor vehicle accidents (18 patients), pedestrian casualties (16 patients), domestic falls (5 patients), and nonmotorized bicycle accidents (3 patients). The most common injured body region was the thorax (75.0%), followed by the lower extremity (67.2%), head (57.8%), upper extremity (50.0%), abdomen (43.8%), spine (35.9%), face (31.3%), and neck (1.6%). The assessment of injury severity according to the Abbreviated Injury Scale (AIS) is presented in Thirty-six patients (24 men and 12 women) died, including 20 patients (31.3%), who deceased within the first 24 hours, and four patients (6.3%), who deceased on day 2. The mortality rate was 45.3% for the first seven days and 51.6% for the first 30 days. The relevant Kaplan-Meier curve is presented in Of our study population, 283 polytrauma victims, 210 men and 73 women, did not conform to our definition, thus meeting four of the five criteria at most. Their mean age was 46.3 ± 19.6 years and their mean ISS was 25.9 ± 9.9; 44 patients (15.5%) died. In order to obtain a meaningful comparison with regard to mortality we matched 64 patients classified “non-in extremis,” who presented statistically equivalent distributions according to age, gender and ISS .As anticipated, a significantly higher mortality rate was calculated in polytraumatized patients, who were classified “in extremis” by our definition.In order to reveal predictors of mortality we subdivided the “in extremis” group into deceased and survivors. Relevant demographic data are presented in p > 0.106) and to gender distribution (p = 0.683). However, mean age and mean ISS value were significantly higher in the deceased group. The corresponding boxplots are presented in Surprisingly, the comparison of any of the five parameters included in our definition did not show significant differences between the deceased and the survivors in the “in extremis” group. The same applies to the AIS values (p = 0.036) and a cut-off of 40.5 years  were calculated, whereas an AUC of 0.820  and a cut-off of 36  were computed for the ISS value.ROC statistics identified age and the ISS value as predictors of mortality in the “in extremis” group, as graphically displayed in Of interest, “in extremis” survivors had to stay 16.1 ± 11.1 days at the intensive care unit, where they were ventilated for 7.5 ± 5.2 days. They had to spend 66.1 ± 54.3 days at our trauma center until they were discharged or transferred.p that a polytrauma victim, who meets the inclusion criterion for that particular parameter, will belong to the “in extremis” group. Due to the fact that a predicted probability in the range of 25.9% to 32.0% was calculated for each parameter , temperature (30°C or less), and soft tissue injuries . A patient is rated “in extremis” if he/she meets the criteria of at least three pathophysiological parameters. We did not rely on the available definitions for several reasons. Abrassart et al. [2, or base excess to their definition, although lactic acidosis is commonly caused by hemorrhagic shock and is associated with a poor prognosis [Our literature search revealed solely four definitions dealing with patients rated “unstable” or “in extremis.” Abrassart et al.  defined t et al.  did not t et al. . Moreovet et al.  and Youst et al.  did not rognosis . Finallyrognosis  focused Fatalities were the key factor of our retrospective analysis. The overall mortality rate referring to all polytrauma victims admitted to our level I trauma center during the observation period of three years was 23.1%. This percentage is in line with 19.1%  and 23.4By revealing age and ISS as predictors of mortality in polytraumatized patients in extremis we achieved our second objective. With regard to patient age, our result corresponds to already published findings. According to Vanzant et al.  advancedLimitations of our study include its single center and retrospective design. Our results are based on the analysis of prerecorded data of one level I trauma center that were originally assessed and collected for reasons other than research. Furthermore, selection bias cannot be ruled out for the matched control group.Our allocation of polytraumatized patients to an “in extremis” group and an age-, gender-, and ISS-matched “non-in extremis” group according to our definition, which is based on seven parameters dealing with hemodynamic and cardiorespiratory instability, has resulted in a threefold higher mortality rate in the “in extremis” group. Polytrauma victims in extremis, more than 40 years of age, presenting with an ISS higher than or equal to 36 have the worst prognosis of survival. Our novel approach to identify polytrauma victims at the highest risk of death immediately after admission might serve as a helpful tool in clinical practice. At least, it might be considered as an impetus for further prospective investigations as part of multicenter studies.


African Americans with systemic lupus erythematosus (SLE) have increased renal disease compared to Caucasians, but differences in other comorbidities have not been well-described. We used an electronic health record (EHR) technique to test for differences in comorbidities in African Americans compared to Caucasians with SLE.p value of 0.05 was used.We used a de-identified EHR with 2.8 million subjects to identify SLE cases using a validated algorithm. We performed phenome-wide association studies (PheWAS) comparing African American to Caucasian SLE cases and African American SLE cases to matched non-SLE controls. Controls were age, sex, and race matched to SLE cases. For multiple testing, a false discovery rate (FDR) p = 5.49 × 10− 15; renal dialysis OR = 10.90, FDR p = 8.75 × 10− 14; and pneumonia OR = 3.57, FDR p = 2.32 × 10− 8. Compared to the African American matched controls without SLE, African Americans with SLE were more likely to have comorbidities in every organ system. The most significant codes were renal and cardiac, and included renal failure  and hypertensive heart and renal disease . Adjusting for race, age, and sex in a model including both African American and Caucasian SLE cases and controls, SLE was independently associated with renal, cardiovascular, and infectious diseases .We identified 270 African Americans and 715 Caucasians with SLE and 1425 matched African American controls. Compared to Caucasians with SLE adjusting for age and sex, African Americans with SLE had more comorbidities in every organ system. The most striking included hypertension odds ratio (OR) = 4.25, FDR African Americans with SLE have an increased comorbidity burden compared to Caucasians with SLE and matched controls. This increase in comorbidities in African Americans with SLE highlights the need to monitor for cardiovascular and infectious complications.The online version of this article (10.1186/s13075-018-1561-8) contains supplementary material, which is available to authorized users. Health disparities are defined as “differences in the incidence, prevalence, mortality and burden of diseases and other adverse health conditions that exist among specific population groups in the US” . Among rRacial disparities in SLE have mainly been studied using cohort and administrative database studies. Cohort studies typically have focused on SLE-related disease measures such as disease activity and may not capture other important comorbidities. Alternatively, administrative studies may not capture detailed data on a patient’s SLE disease course or comorbidities. Therefore, studies have not fully examined the impact of both the SLE disease course and comorbidities on outcomes. Electronic health records (EHRs) serve as an efficient and cost-effective discovery tool –9 to proAfter approval from the Institutional Review Board of Vanderbilt University Medical Center (VUMC), we identified potential SLE subjects in Vanderbilt’s Synthetic Derivative . VUMC isTo identify SLE patients within the Synthetic Derivative, we used our validated EHR algorithm  of ≥ 4 cn = 25) or Hispanic (n = 30), analyses were restricted to Caucasian and African American subjects with SLE, as PheWAS requires models to have at least 20 subjects for a particular code to be used in the model.Non-SLE controls were defined as subjects within the Synthetic Derivative who did not have ICD-9 codes for the 710.* heading “Diffuse diseases of connective tissue,” 714.* heading of “Rheumatoid Arthritis and other inflammatory polyarthropathies,” or ICD-10 codes under M05.* (“Rheumatoid Arthritis with rheumatoid factor”), M06.* (“Other rheumatoid arthritis”), M32.* (“SLE”), M33.* (“Dermatopolymyositis”), M34.* (“Systemic sclerosis”), M35.* (“Other systemic involvement of connective tissue”), and M36.* (“Systemic disorders of connective tissue in diseases classified elsewhere”). Controls were age (± 5 years), race, and sex matched in a 5:1 ratio to SLE cases to maximize power while allowing for close matching. Controls were “medical home” patients  who recehttp://phewascatalog.org. To be a case, we required the subject to have at least two instances of the PheWAS code on different days, at least 1 day apart. A subject is a control if there are no instances of the ICD-9 code for the given disease or related diseases. Subjects having only one instance of the code are excluded to eliminate the possibility of coding errors or preliminary diagnoses that may be ultimately ruled out [p values <0.05 were considered to indicate statistical significance. Analyses were conducted using IBM SPSS software, version 24.0 (SPSS).In PheWAS, the 18,000 ICD-9 codes are collapsed into 1800 PheWAS codes that represent distinct clinical diagnoses. The ICD-9 codes that are mapped to PheWAS codes are version 1.2 and available at uled out . For eaculed out , 11 for uled out  in R verp = 0.83). Compared to Caucasians, African Americans were younger  and had an earlier age at first SLE code  with similar mean years of EHR follow up  . Other significant cardiac codes covered a range of cardiovascular comorbidities including congestive heart failure (CHF) (FDR p = 5.63 × 10− 6), cerebrovascular disease (CVD) (FDR p = 4.23 × 10− 4), thromboembolism (FDR p = 4.47 × 10− 4), peripheral vascular disease (PVD) (FDR p = 0.04), coronary artery disease (CAD) (FDR p = 0.04), and arrhythmias (FDR p = 0.04) (Table p = 8.75 × 10− 14) (Table p = 1.05 × 10− 11), chronic renal failure (FDR p = 7.08 × 10− 10), renal transplant (FDR p = 2.32 × 10− 8), and nephritis related codes. In addition to cardiovascular and renal disease, African Americans with SLE were also more likely to have codes related to infection. The most significant code was pneumonia  with other significant codes related to cellulitis, pyelonephritis, and bacteremia  and nephritis; nephrosis; renal sclerosis . African Americans had more codes related to serositis including pericarditis (FDR p = 5.52 × 10− 4) and hematologic abnormalities such as thrombocytopenia (FDR p = 7.03 × 10− 4). African Americans were also more likely to have codes related to arthritis including joint effusions (FDR p = 8.41 × 10− 4) and neuropsychiatric involvement with encephalopathy (FDR p = 0.04).Compared to Caucasians with SLE, African Americans with SLE were more likely to have codes related to SLE criteria  and were predominantly female .To examine the increased cardiac, renal, and infectious comorbidities seen in the African Americans with SLE, we compared African Americans with SLE to African Americans without SLE as our controls, given known health disparities in African Americans. We identified 1425 control subjects who were age (± 5 years), sex, and race matched in a 5:1 ratio to the 270 African American SLE case subjects. African American SLE case subjects and their matched controls had similar mean current age  with other significant codes including renal dialysis, end-stage renal disease, and renal transplant . Other significant codes covered a range of cardiovascular disease comorbidities including thromboembolism (FDR p = 4.74 × 10− 13), CHF (FDR p = 4.17 × 10− 10), PVD (FDR p = 8.84 × 10− 8), atrial fibrillation (AF) (FDR p = 1.91 × 10− 4), and CAD (FDR p = 0.02). The most significant infection code was pneumonia OR = 5.77 . Other significant codes included sepsis (FDR p = 7.49 × 10− 9), candidiasis (FDR p = 1.34 × 10− 7), and cellulitis (FDR p = 5.41 × 10− 4).Using PheWAS to compare African Americans with SLE to matched controls, there were 213 codes that met the FDR of 5%. Compared to controls, African American SLE case subjects had more codes related to comorbidities in every organ system Fig. . Africanp = 7.33 × 10− 39), hypertensive heart and/or renal disease , and pneumonia .As SLE cases had significantly longer EHR follow up compared to controls, we conducted a sensitivity analysis adjusting for years of EHR follow up to see if the longer follow up could account for the higher risk of comorbidities in the SLE cases. Adjusting for years of follow up, case subjects with SLE were still more likely to have codes related to cardiovascular, renal, and infectious diseases. The most significant renal, cardiovascular, and infectious diseases were relatively unchanged with renal failure  and glomerulonephritis . Other significant codes represented serositis, arthritis, and hematologic and neuropsychiatric involvement  SLE criteria  with thep = 0.86) and were predominantly female . Using PheWAS to compare Caucasians with SLE to matched Caucasian controls, there were 262 codes that met the FDR of 5%. Compared to the controls, the Caucasians with SLE had more codes that represented SLE-related and renal comorbidities , which signifies fibromyalgia in our EHR, based on a prior study [p = 5.01 × 10− 48), which includes a code for discoid lupus, and renal failure . Other renal codes included nephritis; nephrosis; renal sclerosis (FDR p = 4.88 × 10− 28) and chronic kidney disease (FDR p = 3.17 × 10− 21). Notably, there were fewer cardiac and infection codes compared to the PheWAS of African Americans with SLE and African American controls. The most significant cardiac code was peripheral vascular disease . The most significant infection code was pneumonia . As expected, similar to the PheWAS of the African Americans with SLE and African American controls, codes that represent ACR SLE criteria [We compared 715 Caucasian subjects with SLE to 3731 controls who were age (± 5 years), sex, and race matched in a 5:1 ratio. Caucasian subjects with SLE and their matched controls had similar mean current age , CHF , CVD , and cardiac dysrhythmias  , end-stage renal disease , and renal transplant . Lastly, SLE disease status was independently associated with infections including pneumonia  and sepsis/bacteremia .Using a conditional logistic regression model of SLE cases and matched controls (including both Caucasians and African Americans), we examined the association of SLE with PheWAS codes adjusting for age, race, and sex. SLE was significantly associated with hypertension  of 89% and sensitivity of 86% . DespiteUsing PheWAS, we demonstrated an increased burden of comorbidities in African Americans with SLE compared to Caucasians with SLE and matched controls, including a spectrum of renal, cardiovascular, and infectious diseases. These findings suggest that clinicians managing patients with SLE should not only screen for SLE disease manifestations but also have suspicion of multiple cardiovascular and infectious diseases in their workup of common signs and symptoms to ensure appropriate and timely referrals and management. This high comorbidity burden in SLE, particularly in African Americans, argues for the need for access to care to not only rheumatology but also to primary and other subspecialty care. Further, this study demonstrates that an EHR-based approach can build upon traditional cohort and administrative database studies to examine racial disparities in SLE.Additional file 1:Table S1. Significant codes from the PheWAS of African Americans vs. Caucasians with SLE. Figure S1. Selected SLE disease criteria codes in the PheWAS of African Americans and Cauasians with SLE. Table S2. Selected SLE criteria codes from the PheWAS of African Americans and Caucasians with SLE. Table S3. Selected codes related to renal, cardiovascular disease, and infection from the PheWAS of African American SLE cases compared to matched African American controls. Table S4. Selected codes related to SLE criteria from the PheWAS of African American SLE cases and matched African American controls. Table S5. Selected codes from the PheWAS of Caucasian SLE cases compared to matched Caucasian controls. Table S6. Conditional logistic regression models with SLE cases and matched controls. (DOCX 134 kb)